Open AccessReview

Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

Paweł Bryniarski

Katarzyna Nazimek

and

Janusz Marcinkiewicz

Department of Immunology, Jagiellonian University Medical College, 18 Czysta Street, 31-121 Krakow, Poland

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2022, 23(3), 1772; https://doi.org/10.3390/ijms23031772

Submission received: 12 January 2022 / Revised: 1 February 2022 / Accepted: 2 February 2022 / Published: 4 February 2022

(This article belongs to the Special Issue Human and Animal Monocytes and Macrophages in Homeostasis and Disease 3.0)

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Abstract

This review article is focused on antihypertensive drugs, namely angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), and their immunomodulatory properties reported in hypertensive patients as well as in experimental settings involving studies on animal models and cell lines. The immune regulatory action of ACEI and ARB is mainly connected with the inhibition of proinflammatory cytokine secretion, diminished expression of adhesion molecules, and normalization of CRP concentration in the blood plasma. The topic has significant importance in future medical practice in the therapy of patients with comorbidities with underlying chronic inflammatory responses. Thus, this additional effect of immune regulatory action of ACEI and ARB may also benefit the treatment of patients with metabolic syndrome, allergies, or autoimmune disorders.

Keywords:

angiotensin converting enzyme inhibitors; angiotensin II receptor blockers; immunomodulation; immunology; cellular response; humoral response

1. Introduction

Hypertension is a common, chronic disease, which significantly influences the quality of a patient’s life. In a group of US adults (excluding pregnant women) treatment of hypertension was the most popular reason for visiting a doctor’s office and for the chronic use of prescribed medications [1,2]. According to the guidelines of American College of Cardiology/American Heart Association (ACC/AHA), normal blood pressure is below 120 mmHg (systolic)/80 mmHg (diastolic), elevated blood pressure is 120–129/<80 mmHg, while the first stage of hypertension is 130–139/80–89 mmHg and the second stage of hypertension is at least 140/at least 90 mmHg. We can also distinguish isolated systolic hypertension when blood pressure is ≥130/<80 mmHg, and isolated diastolic hypertension when blood pressure is <130/≥80 mmHg [3]. Patients with a blood pressure ≥130/≥80 mmHg are considered to suffer from mixed systolic/diastolic hypertension.

We can also diagnose hypertension by ambulatory blood pressure monitoring (ABPM). Diagnostic criteria according to ACC/AHA guidelines published in 2017 are then as follows: a 24-h mean blood pressure of 125/75 mmHg or above, daytime (awake) mean of 130/80 mmHg or above, and nighttime (asleep) mean of 110/65 mmHg or above [3].

According to its pathogenesis, we can divide hypertension into two types: primary (so-called essential hypertension, involving over 90% of cases) and secondary hypertension with known cause. Development of primary hypertension is connected with numerous environmental and genetic factors that have multiple compounding effects on renal and cardiovascular structure and function. The main risk factors related to primary hypertension are age, obesity [4,5], family history [6,7], race [8], reduced nephron number, high-sodium diet, excessive alcohol consumption, and physical inactivity [4,9]. The most common causes of secondary hypertension are primary kidney disease, primary aldosteronism, and sleep apnea syndrome. Less common causes of secondary hypertension include oral contraceptives, pheochromocytoma, Cushing’s syndrome, coarctation of the aorta [10,11], chemiotherapeutic agents and other endocrine disorders (such as hypothyroidism or primary hyperparathyroidism).

Lifestyle modification is essential in all patients with elevated blood pressure or hypertension. These changes should include dietary salt restriction, potassium supplementation, weight loss, exercise, limited alcohol intake, and following the rules of the Dietary Approaches to Stop Hypertension (DASH), which include diet that high in vegetables, fruits, poultry, fish, low-fat dairy products, whole grains, and nuts, and low in sugar-sweetened beverages, red meats, and sweets. However, in most cases pharmacologic therapy is also necessary [12,13,14].

Drugs that are appropriate for initial therapy in most patients with hypertension include thiazide-type diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) and calcium channel blockers.

Since hypertension is usually associated with a chronic inflammation, examining the effects of drugs on the immune system is a needed research direction in immunology. Resulting knowledge could be then applied to clinical practice, similarly the results of experiments on antidepressant drugs [15,16]. In the precise selection of the drug, the physico-chemical properties of the substance as well as the effects of the substance on the immune system are important.

In this paper, the influence of the most commonly used first-line drugs in the treatment of hypertension, i.e., angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, on the immune system will be discussed.

2. Angiotensin Converting Enzyme Inhibitors (ACEI)

2.1. Characteristics of the ACEI Drug Group

ACEI inhibit the enzyme that converts angiotensin I to angiotensin II, thereby reducing the concentration of angiotensin II, the vasoconstrictively acting peptide [17]. Due to inhibition of angiotensin conversion, ACEI induce hypotensive, nephroprotective (inhibit proteinuria and progression of renal failure), and antiatherosclerotic effects. ACEI are used especially when, in addition to hypertension, the patient suffers from heart failure or other left ventricular dysfunction (such as hypertrophy or left ventricular malfunction), diabetes or metabolic syndrome, nephropathy, atrial fibrillation or carotid atherosclerosis, or is at a high risk of cardiovascular complications (i.e., stroke or heart attack). Additionally, a previous heart attack or stroke also prompts a recommendation for the use of ACEI. The contraindications to the use of ACEI are pregnancy (these drugs may cause fetal defects) [18], bilateral narrowing of the renal arteries or the unilateral artery stenosis of the only functioning kidney, vascular edema, and hyperkalemia. The most common side effect is cough (caused by an increased concentration of bradykinin) [19,20,21,22], less common are hypotension, hyperkalemia, renal failure, and angioedema [23,24,25,26]. The impact of ACEI on the immune system is shown in Table 1.

2.2. Captopril

Captopril (in a dose of 3, 1, or 0.3 micrograms per mL) causes a dose-dependent inhibition of TNF-α synthesis by immune cells. Interestingly, generation of TNF-α by peripheral blood mononuclear cells (PBMC) is increased in patients with chronic heart failure (CHF), especially when accompanied by cachexia, and this effect can be reversed by captopril up to 74% reduction of TNF-α synthesis [27]. At these concentrations, the drug also inhibits the synthesis of IL-1 by 60%, but does not reduce the synthesis of complement C3 by PBMC [28]. However, in another study captopril failed to modulate IL-1beta/IL-2-dependent signaling cascade [29]. The immunomodulatory properties of captopril may contribute to its beneficial effects in heart failure patients [27]. Accumulation of mRNA for IL-1 and TNF is not affected by this drug, suggesting a posttranscriptional effect at a protein level [28,30]. Accordingly, another studies suggest that captopril and lisinopril reduce the release of IL-1beta [31], IL-6, and IL-8 by various cells [32]. A decrease in relative mass and suppression of inflammatory response in the left ventricle, a reduction in plasma levels of IL-1beta and IL-6 and heart expression of their mRNAs, as well as an increase in plasma levels of IL-10 and its mRNA expression in the heart are observed after captopril treatment [33]. In hepatic fibrosis, the use of this medicament has a protective effect as it reduces the levels of the pro-inflammatory cytokine TNF-α and increases the anti-inflammatory cytokine IL-10 in the liver [34]. Captopril enhances IL-10 and IL-2 production by mouse immune cells [35]. In myocarditis caused by clozapine (e.g., indicated in therapy for schizophrenia), captopril reverses the detrimental effect of clozapine on parameters of oxidative stress, such as protection against oxidative DNA damage, production of pro-inflammatory cytokines, and modulation of antioxidant activity [36]. Captopril can also be used in laryngology. This drug used with ARB representative losartan weakened the progression of tympanosclerosis (middle ear sclerosis) by inhibiting TGF-β1 overexpression [37]. Conversely, in psychiatry, chronic treatment with high doses of captopril may cause an increase in plasma IL-1β and IL-6 levels. In addition, this drug may promote depressive behavior by reducing the number of Treg cells and activating microglia [38]. These observations imply that captopril-induced immune effects cause different clinical outcomes depending on patients’ disease history. Accordingly, in cardiovascular disorders, captopril-induced immunomodulation most commonly exerts beneficial effects. In coronary artery disease this medicament decreases IL-6 level, increases TGF-β and IL-22 [39,40], while in acute myocardial infarction it decreases IL-6, TNF-alfa, and C reactive protein (CRP) [41], which in both cases should lead to alleviation of inflammation-related complications. In acute pancreatitis captopril induces a significant decrease in TNF-α concentration in the pancreas, along with decreased MPO activity, NO concentration, and reduction of iNOS gene expression [42]. These observations suggest that administration of captopril before induction of acute pancreatitis suppresses the inflammatory response, which seems to be beneficial in preventing or healing the L-arginine-induced pancreas injury. In addition, after radiation exposure this drug reduces the expression of angiotensin II, inhibits the NF-κB pathway and reduces the overexpression of TGF-β1, protecting the endothelium from radiation-induced injury [43]. This ACEI representative prevents the increase in IL-6, TNF-α, malondialdehyde (MDA), and NO in the hippocampus of rats suffering from experimentally induced memory defects [44]. In the aortic tissue, it clearly reduces the expression of the CD103, CD80, CD86, and MHC-II proteins, while increasing the expression of Foxp3. While used to stimulate splenic dendritic cells, captopril increases IL-10 and TGF-β production, while reducing IL-6 and IL-12 synthesis. This drug inhibits dendritic cell maturation and promotes Treg cell differentiation [45]. In aorta wall tissues captopril reduces the number of infiltrating CCR9+CCL25+ cells, which alleviates the course of atherosclerosis [46]. The synthesis of anti-inflammatory IL-1 receptor antagonist (IL-1RA) is increased by captopril, which induces a systemic beneficial effect on immune reactivity [30]. Additionally, this medicament exerts a dose-dependent immunosuppressive effect on the activity of NK cells in vitro [47].

2.3. Cilazapril, Delapril

It was shown that ACEI, such as captopril, delapril, and cilazapril, inhibit TNF-α production in vitro and in vivo when used at high doses [48]. Another report demonstrated that certain ACEI suppress IL-1 and TNF synthesis at a posttranscriptional level and thus could influence cytokine-mediated cell growth [28]. However, these effects were induced only by some ACEI, i.e., enalapril and cilazapril, but not by ramipril, lisinopril, perindopril, or spirapril. This suggests that the effect is not due to the inhibition of angiotensin converting enzyme, but instead results from an additional immune-related activity of some of ACEI, which requires further investigation.

2.4. Lisinopril

Accordingly, lisinopril was shown to decrease levels of IL-6, IL-8 [49], and to inhibit ROI’s production [50]. Similarly to captopril, lisinopril inhibits IL-12 and IFN-gamma production [51]. Altogether, the data suggest that the use of ACEI reduces plasma concentrations of TNF-α and CRP [52], which seems to be responsible for ACEI-induced anti-inflammatory effects in patients with cardiovascular diseases.

2.5. Enalapril

While analyzing other immune-related beneficial effects of ACEI, anti-inflammatory activity of enalapril was observed in diabetic nephropathy. Navarro et al. showed that the levels of TNF-α mRNA in renal cortex are doubled in diabetic rats as compared to non-diabetic control animals, and this increase could be prevented by administering enalapril [53]. It is worth adding that daily urinary albumin excretion is correlated with levels of TNF-α in urine and with renal expression of TNF-α, which suggests that enalapril may protect patients with kidney disease against albuminuria [53]. Other studies examining the impact of enalapril on immune system demonstrated that this medicament causes an increase in IL-2 and IL-10 synthesis, which correlates with an increase in the number of CD4+CD103+CD25-spleen-resident T cells [35], and that it significantly increases the number of circulating endothelial progenitor cells after ischemic stress [54]. This drug impacts the humoral immunity as well. It has been shown that enalapril administration significantly increases the production of IgG2c without affecting IgG1 synthesis in mice immunized with ovalbumin [55]. However, enalapril-induced effects seem to depend on mouse sex, and thus likely on the activity of sex hormones, since this drug causes the reduction of production of pro-inflammatory IL-1α, protein-1 monocyte chemoattractant, and macrophage-1a protein in females, and increases the synthesis of anti-inflammatory cytokine IL-10 in males [56]. Additionally, it may affect the intracellular inflammatory signaling cascades. In intestinal epithelial cells and in peritoneal macrophages, enalapril inhibits IκBα phosphorylation and degradation, and reduces NF-κB binding activity, which results in decreased pro-inflammatory cytokine production [57]. In an experimental model of infection with dengue virus, enalapril administration seemed to normalize the levels of IL-1beta and decreased the number of cells expressing viral antigen [58]. In diabetic nephropathy this medicament failed to modulate the B cell-mediated immune response [59], which is contradictory to the previously mentioned impact of enalapril on humoral immunity in healthy mice [55]. On the other hand, treatment with this drug may promote macrophage polarization towards the M1 phenotype [59]. However, in mouse experimental colitis, enalapril significantly reduces TNF-α, IFN-gamma, IL-8, and IL-6 production and thus alleviates the course of intestinal inflammation [60]. This drug attenuates colitis by reducing the infiltration of inflammatory cells in the colon and reducing the expression of pro-inflammatory IL-1β [61]. While this drug failed to affect inflammatory markers in plasma and plaque remodeling in aorta and thus may not prevent thrombosis [62], in inflammatory lung injury enalapril exerted protective effects on the respiratory tract by reducing the concentration of IL-1beta and IL-6 [63].

2.6. Perindopril

Perindopril inhibits monocyte secretory activity more potently than enalapril and has a stronger anti-inflammatory effect in patients with normal blood pressure and coronary artery disease. Perindopril normalizes the disease-enhanced release of TNF-α, IL-6, IL-1beta, monocyte-1 chemoattractant protein, and CRP [64,65,66]. Similarly, a further report demonstrated that this ACEI representative decreases serum CRP concentration in humans [67], while another study showed that treatment with perindopril causes an increase in IL-10 concentration [66,68], without affecting the levels of IL-4, IL-13, and CRP [68]. This medicament also decreases IL-2 and prevents the unwanted T-cell stimulation [67], as well as inhibits TGF-β1 release in patients with chronic kidney disease [69]. Imidapril and perindopril significantly decrease secretion of TNF-α by human primary monocytes and THP-1 cells [70].

2.7. Benazepril

Benazepril significantly reduces TNF-α production [71]. In diabetic nephropathy, it significantly reduces NF-κB and TGF-β levels [72], while in left ventricular hypertrophy, benazepril reduces TGF-β, VCAM-1, and NF-κB expression, and ROI’s production. Consequently, this leads to a significant reduction in left ventricular hypertrophy and fibrosis, as well as to an improvement in hemodynamic function [73].

2.8. Fosinopril

Similarly, fosinopril, when administered alone or in combination with pravastatin (then producing much stronger effect) has a beneficial effect on left ventricular remodeling after acute myocardial infarction by normalizing elevated matrix metalloproteinase (MMP)-2, MMP-9, and TNF-α levels in the left ventricle [74]. In addition, fosinopril-induced effects were superior to captopril treatment as expressed by significantly better improvement of the overall left ventricular systolic function and stronger reduction of CRP and TNF-α concentrations [75].

2.9. Alacepril

Because of having –SH group, alacepril strongly reduces the over-activated production of monocyte chemoattractant protein-1 (MCP-1) and TNF-α and inhibits production of ROIs by human aortic endothelial cells more effectively than lisinopril [50,76].

2.10. Zofenopril

Zofenopril also has a sulfhydryl (–SH) group and its administration reduces the level of IL-1beta and decreases expression of CD40 and CD31 that are responsible for recruitment of mononuclear cells and platelets [77]. This drug increases nitric oxide production and its bioactivity [78], but reduces TNF-α levels [79].

2.11. Ramipril

In hemodialyzed patients, ramipril increases IL-1beta and decreases IL-10 and IL-6 levels [80]. In young convalescents recovered from aortic coarctation and without elevated blood pressure, ramipril reduces IL-6, sCD40L, and sVCAM-1 levels, but does not affect CRP concentration [81,82]. Ramipril, used in diabetes mellitus type I patients that do not suffer from diabetic nephropathy, does not affect TGF-β and VEGF levels [83].

2.12. COVID-19

The impact of ACE inhibitors on the coronavirus infection is ambiguous. On the one hand, ACEIs facilitate the entry of SARS-CoV-2 into cells. On the other hand, they appear to increase the chance of a milder disease course by lowering the concentration of angiotensin II. Increased levels of angiotensin II have been observed in most patients with COVID-19 pulmonary complications. Moreover, the positive hypotensive effect of the ACEI must not be forgotten. Accordingly, at the beginning of the pandemic the European Society of Cardiology advised not to abandon the ACEI administration to patients, by assuming that this action has more pros than cons [84].

Table 1. The effect of angiotensin converting enzyme inhibitors (ACEI) on selected parts of the immune system. Abbreviations: TNF-α—tumor necrosis factor alpha; IL—interleukin; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; NO—nitric oxide; iNOS—inducible nitric oxide synthase; MPO—myeloperixidase, TGF—Transforming Growth Factor; CRP—C reactive protein, CD—cluster of differentiation, IFN—interferon, VCAM—vascular cell adhesion protein.

Drug	Immunological Mechanism (Reference)
Captopril	Reduction in: - TNF-α synthesis [27,33,41,42,44]; - IL-1 [28]; - the release of IL-1beta [31], IL-6 and IL-8 by various cells [32]; - production of pro-inflammatory cytokines and modulation of antioxidant’s activity [36]; - TGF-β1 overexpression [37,43]; - the number of Treg cells [38]; - C reactive protein (CRP) [41]; - MPO activity, NO concentration and reduction of iNOS gene expression [42] - expression of the CD103, CD80, CD86 and MHC-II proteins [45]; - inhibits dendritic cell maturation [45]; - the number of infiltrating CCR9+CCL25+ cells [46]; - activity of NK cells in vitro [47]. No significant effect on: - synthesis of complement C3 [28]; - IL-1beta/IL-2-dependent signaling cascade [29]; - Accumulation of mRNA for IL-1 and TNF [28,30]; Increase in: - plasma levels of IL-10 [33,34]; - IL-10 and IL-2 production by mouse immune cells [35]; - TGF-β and IL-22 [39,40]; - promotes Treg cell differentiation [45]; - the synthesis of anti-inflammatory IL-1 receptor antagonist (IL-1RA) [30].
Cilazapril	Reduction in: - TNF-α production not only in vitro, but also in vivo, when used at high doses [48].
Delapril	Reduction in: - TNF-α production not only in vitro, but also in vivo, when used at high doses [48].
Lisinopril	Reduction in: - the release of IL-1beta [31], IL-6 and IL-8 by various cells [32]; - inhibition in ROI’s production [50]; - IL-12 and IFN-gamma production [51]; - plasma concentrations of TNF-α and CRP [52].
Enalapril	Reduction in: - TNF-α production [53,60]; - pro-inflammatory IL-1α, protein-1 monocyte chemoattractant and macrophage-1a protein in females [56]; - normalize the levels of IL-1beta [58,61,63]; - IFN-gamma, IL-8 and IL-6 production [60,63]; - colitis by reducing the infiltration of inflammatory cells in the colon [61]; No significant effect on: - the B cell-mediated immune response [59]; Increase in: - IL-2 and IL-10 synthesis, which correlates with an increase in the number of CD4+CD103+CD25- spleen-resident T cells [35]; - the number of circulating endothelial progenitor cells after ischemic stress [54]; - the production of IgG2c without affecting IgG1 synthesis in mice immunized with ovalbumin [55]; - the synthesis of anti-inflammatory cytokine IL-10 in males mice [56].
Perindopril	Reduction in: - monocyte secretory activity [63,64,65,66]; - TNF-α, IL-6, IL-1beta, monocyte-1 chemoattractant protein, and CRP [64,65,66]; - secretion of TNF-α by human primary monocytes and THP-1 cells [70]; - serum CRP concentration in humans [67]; - IL-2 and prevents the unwanted T-cell stimulation [67]; - inhibits TGF-β1 release in patients with chronic kidney disease [69]. No significant effect on: - IL-4, IL-13, and CRP [68]. Increase in: - IL-10 concentration [66,68].
Benazepril	Reduction in: - TNF-α production [71]; - NF-κB and TGF-β levels in diabetic nephropathy [72]; - TGF-β, VCAM-1, and NF-κB expression, and ROI’s production [73]; - left ventricular hypertrophy and fibrosis [73].
Fosinopril	Reduction in: - matrix metalloproteinase (MMP)-2, MMP-9 and TNF-α levels in the left ventricle [74]; - CRP concentration [75].
Alacepril	Reduction in: - the over-activated production of monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, and production of ROIs by human aortic endothelial cells [50,76].
Zofenopril	Reduction in: - IL-1beta and expression of CD40 and CD31 [77]; - TNF-α levels [79]. Increase in: - nitric oxide production and its bioactivity [78].
Ramipril	Reduction in: - IL-10 and IL-6 levels [80]; - sCD40L and sVCAM-1 levels [81,82]. No significant effect on: - CRP concentration [81,82]; - TGF-β and VEGF levels [83]. Increase in: - IL-1beta [80].

3. Angiotensin II Receptor Blockers (ARBs)

3.1. Characteristics of the ARB Drug Group

Hypotensive action of ARBs results from their antagonistic activity against the type 1 angiotensin receptor (AT₁). The indications and contraindications for use of ARBs are the same as for ACEI, excluding angioedema from the list of contraindications. In addition, ARBs should be used when the patient cannot take ACEI because of a tiring, dry cough. However, so far less is known on the possible immunomodulatory activity of ARBs than of ACEI. The impact of ARBs on the immune system can be seen in Table 2.

3.2. Valsartan, Losartan

Valsartan has a strong inhibitory effect on lipopolysaccharide (LPS)-stimulated production of TNF-α and IL-1 by PBMC in vitro. This drug also reduces IL-6 production [30]. Similar effects are induced by candesartan and losartan, which are able to reduce IL-1beta [31], IL-6, and IL-8 concentration [31,32,85]. In acute myocardial infarction, valsartan decreases IL-6, TNF-alfa and CRP [41]. Losartan induces release of TGF-β, which is likely related to its anti-atherosclerotic activity [86]. However, other contradictory data report that losartan administration either decreases the plasma concentration of TGF-β 1 [87], or does not impact the TGF-β 1 serum level and urinary excretion [88]. In coronary artery disease, losartan was shown to decrease IL-6 level, and increase both TGF-β and IL-22 levels [39,40]. In dengue infection, losartan, similarly to enalapril, decreases the number of cells expressing viral antigen and normalizes IL-1beta level [58]. In rheumatoid arthritis, losartan reduces IFN-gamma, IL-6, IL-17F, and IL-22 levels, show strong anti-inflammatory effect, while enalapril and valsartan do not have these properties. Thus, losartan was suggested as a therapeutic agent for patients who suffered from hypertension and rheumatoid arthritis [89]. In hemodialysis patients, valsartan decreases IL-6 concentrations [80]. In addition, valsartan reduces the level of TGF-β1 [90,91]. In rats that underwent myocardial infarction, valsartan decreased Th1 cell numbers and cytokine production, but increased Kir2.1 expression [92]. This drug also potently inhibits the production of IL-1β, IL-6, and TNFα and thereby abolishes the inflammatory activation of macrophages and adipocytes [93]. In mild to moderate essential hypertension, valsartan decreases the disease-increased levels of monocyte/macrophage chemotactic proteins and soluble P-selectin better than indapamide with a similar hypotensive effect [94].

When administered to smokers, losartan normalized the smoking-increased levels of IL-6 [95]. Macrophages co-cultured with losartan poorly produced IL-1beta, but this drug failed to reduce IL-1beta mRNA expression [96]. In different animal models, this drug was found to attenuate inflammation by lowering the levels of IL-6, TNF-α, MCP-1, and IL-1beta [97,98]. Losartan also inhibits M1 macrophage polarization and promotes the shift towards M2 phenotype [99]. Losartan was demonstrated to suppress inflammatory responses by inhibiting Th22 cell chemotaxis in IgA nephropathy [100]. In acute lung injury, losartan inhibits the maturation of dendritic cells accumulated in the respiratory tract, and blocks the Th1 and Th17 polarization of lymphocytes, which leads to a milder disease course [101]. This drug also improves colitis by reducing the infiltration of inflammatory cells [61]. In collagen-induced arthritis, losartan reduces the inflammatory response by inhibiting the MAPK and NF-κB pathways in B and T lymphocytes, which leads to significant alleviation of clinical symptoms. Interestingly, when losartan was administered with a low dose of methotrexate, similar therapeutic effect was achieved, and, importantly, ARB prevented the methotrexate-induced liver and kidney damage [102].

3.3. Olmesartan, Telmisartan

In rat model of glomerulonephritis, high doses of olmesartan were demonstrated to reduce both infiltration of CD8+ T cells and activation of M1 macrophages, thus limiting the necrotic lesions. Simultaneously, increase in the number of M2 macrophages and upregulated production of anti-inflammatory cytokines were observed in olmesartan-administered animals [103]. These observations suggest the anti-inflammatory potential of ARBs.

Accordingly, telmisartan therapy seems to induce similar anti-inflammatory effect in various conditions, including hypertension, atherosclerosis, and brain and nervous system disorders. Treatment with telmisartan reduces IL-6, IL-1beta, TNF-α, and MCP-1 levels, inhibits NADPH oxidase activity and ROI production, and decreases the infiltration of CD4+ T cells, likely through acting on peroxisome proliferator-activated receptor gamma (PPARγ) [104,105,106,107,108,109,110]. This drug increases the concentration of anti-inflammatory IL-10 stronger than perindopril, an ACEI representative, without affecting IL-4, IL-13, and CRP levels in hypertensive patients [68]. Furthermore, telmisartan reduced TNF-α, and neutrophil infiltration as well as increased IL-10 in a rat model of ulcerative colitis [111]. After myocardial infarction was induced in rats, this medicament reduced arrhythmias by elevating the level of cardiac connexin 43, likely by inhibiting IL-17 activity [112].

Olmesartan reduces the release of TNF-alfa by macrophages [79,113,114]. Olmesartan, candesartan, and telmisartan administration into mice with collagen-induced arthritis, which is a mouse model of human rheumatoid arthritis, diminished lymphocyte proliferation and IFN-gamma production in vitro assays, and suppressed antigen-specific Th1 and Th2 lymphocytes in vivo. Additionally, olmesartan therapy prevented severe joint destruction in these mice [115]. In rats with hypertension and nephrosclerosis, this medicament significantly reduced renal interstitial fibrosis by lowering the number of infiltrating macrophages [116]. This drug was found more effective in reducing inflammation and protecting myocardial structure and function than an ACEI representative, ramipril [82]. In rats with methotrexate-induced intestinal mucositis, pretreatment with olmesartan suppressed the inflammatory response [117]. However, this beneficial effect was accompanied with an enteropathy of a yet undefined cause. On the other hand, this medicament was found to alleviate intestinal inflammation better than sulfasalazine in a rat model of ulcerative colitis [118]. In a mouse model of Alport syndrome, olmesartan alleviated renal fibrosis by reducing tubular TGFβ expression [119], while in periodontitis it reduced inflammation by lowering IL-1β and TNF-α levels, down-regulating the expression of MMP-2, MMP-9, COX-2, and RANKL, and up-regulating osteoprotegerin [120]. Olmesartan also reversed left ventricular hypertrophy in rats with restorative hypertension by lowering IL-6 levels [121].

3.4. Candesartan, Irbesartan

Similar antioxidant properties were observed in the case of eprosartan. This drug was found to reduce the neutrophil ability to generate peroxide anions as well as macrophage infiltration [122,123]. Furthermore, candesartan inhibits inflammation by modulating signaling cascades dependent on TNF-α, IL-1beta, IL-2, IL-6, TGF-β, and NF-κB. In addition, it reduces the formation of ROIs by phagocytes and lowers the expression of CD25 and IL-2 release by T cells [113,124,125,126,127,128,129]. However, this medicament seems to not affect the secretion of IL-10 [130], similarly to olmesartan [121]. Candesartan also prevents NF-κB activation by modulating the TLR4 expression, and reduces the release of chemokines by LPS-stimulated human renal tubular epithelial cells [131]. In mice with allergic asthma, administration of candesartan and irbesartan lowered the general number of immune cells in bronchoalveolar lavage fluid and reduced the release of Th2-lymphocyte (IL-4, IL-5 and IL-13) and Th1-lymphocyte (IL-2 and IFN-γ) cytokines [125].

Irbesartan exerts a neuroprotective effect by inhibiting the activation of microglia and macrophages [132]. This medicament reduces the production of IFN-beta and the expression of iNOS, and thus inhibiting NO production [133]. Irbesartan also inhibits the expression of MCP-1 mRNA in THP-1 monocyte cell line stimulated with TNF-α and activates PPARγ [134]. In patients with chronic kidney disease, this drug also modulates the urinary excretion of various cytokines in a dose-dependent manner [135]. Combined therapy with clopidogrel and irbesartan was found to inhibit nephritis by abolishing macrophage infiltration and thus to reduce early kidney damage caused by nephrectomy [136]. There are also some contradictory observations regarding the irbesartan ability to influence the concentration of CRP, TGF-β, TNF-alfa, IL-6, and the expression of NF-κB, ICAM-1, VCAM-1, and MCP-1 [137,138,139,140,141].

Table 2. The effect of angiotensin II receptor blockers (ARB) on selected parts of the immune system. Abbreviations: TNF-α—tumor necrosis factor alpha; IL—interleukin; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; NO—nitric oxide; iNOS—inducible nitric oxide synthase; TGF—Transforming Growth Factor, CRP—C reactive protein; CD—cluster of differentiation, IFN—interferon.

Drug	Immunological Mechanism (Reference)
Valsartan	Reduction in: - TNF—α and IL-1 concentration [33,93]; - IL-6 production [30]; - TGF-β1 concentration [90,91] - Th1 cell numbers [92]; - abolishes the inflammatory activation of macrophages and adipocytes [93]; - levels of monocyte/macrophage chemotactic proteins [94].
Candesartan	Reduction in: - IL-1beta [31], IL-6 and IL-8 concentration [31,32,85]; - CRP concentration [41]; - TNF-alfa concentration [41,113,124,125,126,127,128,129]; - lymphocyte proliferation and IFN-gamma production in vitro assays, and suppressed antigen-specific Th1 and Th2 lymphocytes in vivo [115]; - formation of ROIs by phagocytes [113,124,125,126,127,128,129]; - the expression of CD25 and IL-2 release by T cells [113,124,125,126,127,128,129]; - the general number of immune cells in bronchoalveolar lavage fluid [125]; - the release of Th2-lymphocyte (IL-4, IL-5 and IL-13) and Th1-lymphocyte (IL-2 and IFN-γ) cytokines [125]. No significant effect on: - the secretion of IL-10 [130].
Losartan	Reduction in: - IL-1beta [31], IL-6 and IL-8 concentration [31,32,85]; - the plasma concentration of TGF—β 1 [87]; - IFN-gamma, IL-6, IL-17F and IL-22 [89]; - TNF—α concentration [97,98]; - inhibits M1 macrophage polarization and promotes the shift towards M2 phenotype [99]; - inflammatory responses by inhibiting Th22 cell chemotaxis in IgA nephropathy [100]; - the maturation of dendritic cells accumulated in the respiratory tract, and blocks the Th1 and Th17 polarization of lymphocytes [101]; - the inflammatory response by inhibiting the MAPK and NF-κB pathways in B and T lymphocytes [102]. No significant effect on: - TGF—β 1 serum level and urinary excretion [88]. Increase in: - both TGF—β and IL-22 levels [39,40].
Olmesartan	Reduction in: - infiltration of CD8+ T cells and activated M1 macrophages [103]; - the release of TNF-alfa by macrophages [79,113,114]. - lymphocyte proliferation and IFN-gamma production in vitro assays, and suppressed antigen-specific Th1 and Th2 lymphocytes in vivo [115]; - the number of infiltrating macrophages [116]; - tubular TGFβ expression [119]; - IL-1β and TNF-α levels, down-regulating the expression of MMP-2, MMP-9, COX-2 and RANKL [120]; - IL-6 level [121]. Increase in: - in the number of M2 macrophages and upregulated production of anti-inflammatory cytokines [103]; - osteoprotegerin [120].
Eprosartan	Reduction in: - the neutrophil ability to generate peroxide anions as well as macrophage infiltration [122,123].
Telmisartan	Reduction in: - IL-6, IL-1beta, TNF—α, and MCP-1 levels [97,98,99,100,101,102,103]; - NADPH oxidase activity [104,105,106,107,108,109,110]; - ROI’s production [104,105,106,107,108,109,110]; - the infiltration of CD4+ T cells [104,105,106,107,108,109,110]; -IL-17 activity [112]; - lymphocyte proliferation and IFN-gamma production in vitro assays, and suppressed antigen-specific Th1 and Th2 lymphocytes in vivo [115]. No significant effect on: - IL-4, IL-13, and CRP levels in hypertensive patients [111]; Increase in: - concentration of anti-inflammatory IL-10 [111].
Irbesartan	Reduction in: - the general number of immune cells in bronchoalveolar lavage fluid [125]; - the release of Th2-lymphocyte (IL-4, IL-5 and IL-13) and Th1-lymphocyte (IL-2 and IFN-γ) cytokines [125]; - inhibiting the activation of microglia and macrophages [132]; - the production of IFN-beta and the expression of iNOS, and thus inhibits NO production [133]; - expression of MCP-1 mRNA in THP-1 monocyte cell line stimulated with TNF-α and activates PPARγ [134]; - macrophage infiltration [136].

4. The Most Recent Studies

Recent studies of antihypertensive drugs (diuretics (furosemide, hydrochlorothiazide), ACEI, and combination drugs (ACEI + diuretic) that were conducted in CBA mice showed that diuretics administered alone or with captopril increase the generation of Reactive Oxygen Intermediates, but reduce the formation of NO by macrophages and also increase the expression of surface markers important for the phagocytosis process (CD11b, CD16/32, CDC14) and antigen presentation (CD80, CD86, CD40, I-Ak). Furosemide and hydrochlorothiazide treatment increase generation of activated B cell SRBCs (early humoral response). Captopril does not affect the early response, but when added to furosemide it enhances the early humoral response, and when added to hydrochlorothiazide it reduces it. Captopril (such as furosemide and hydrochlorothiazide) enhances the maturation of antibodies through switching classes. Furosemide added to captopril enhances its effect, while hydrochlorothiazide added to captopril does not [142].

In the cellular response in the antigen presentation phase in the transfer of hapten-labeled macrophages, treatment with all single drugs reduces the presentation activity. Adding captopril to diuretics does not change the activity of the presentation. On the other hand, in the phase of induction of the cellular response in active sensitization with hapten, all drugs significantly reduce the contact hypersensitivity reaction in relation to the control. In the induction of a cellular response in the transfer of effector cells in the delayed-type hypersensitivity captopril and furosemide strongly inhibit the contact hypersensitivity reaction and hydrochlorothiazide has no influence on the reaction. Diuretics with or without captopril modulate humoral and allergic cellular responses by affecting macrophage function [143].

Most of diuretics change the immune response, modulating it towards the anti-inflammatory response [144].

Recommendations for the use of drugs from the appropriate drug groups depending on the diseases accompanying arterial hypertension are presented in Figure 1 [145].

5. Conclusions

ACEI and ARBs, the most commonly used antihypertensive drugs, significantly impact the functions of immune cells, and modulate the mechanisms of immune response not only in hypertensive patients, but also in people with immune-related and inflammatory diseases, and even in healthy subjects (Table 1). Therefore, the immunomodulatory properties of ACEI and ARBs are often used in other inflammatory diseases. The use of ACEI and ARB in combination with antihypertensive drugs from other classes multiplies the beneficial systemic therapeutic effect in relieving chronic inflammation. However, it is worth remembering to achieve a balance between the anti-inflammatory component and protection against cancer and microbes in the treatment of inflammatory diseases.

Author Contributions

Resources, P.B.; writing—original draft preparation, P.B.; writing—review and editing, P.B. and K.N.; visualization, P.B.; supervision, K.N. and J.M.; project administration, P.B.; funding acquisition, P.B. All authors have read and agreed to the published version of the manuscript.

Funding

This study entitled “The influence of diuretics and combination drugs (diuretic + ACEI) on the immunological activity of mouse macrophages”, was supported by The Polish Ministry of Science and Higher Education under the “Diamond Grant” program (0168/DIA/2017/46).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data are included within the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

Yoon, S.S.; Gu, Q.; Nwankwo, T.; Wright, J.D.; Hong, Y.; Burt, V. Trends in Blood Pressure among Adults with Hypertension: United States, 2003 to 2012. Hypertension 2015, 65, 54–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Muntner, P.; Carey, R.M.; Gidding, S.; Jones, D.W.; Taler, S.J.; Wright, J.T.; Whelton, P.K. Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. Circulation 2018, 137, 109–118. [Google Scholar] [CrossRef] [PubMed]
Whelton, P.K.; Carey, R.M.; Aronow, W.S.; Casey, D.E.; Collins, K.J.; Dennison Himmelfarb, C.; DePalma, S.M.; Gidding, S.; Jamerson, K.A.; Jones, D.W.; et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018, 71, e13–e115. [Google Scholar] [CrossRef] [PubMed]
Forman, J.P.; Stampfer, M.J.; Curhan, G.C. Diet and Lifestyle Risk Factors Associated with Incident Hypertension in Women. JAMA 2009, 302, 401–411. [Google Scholar] [CrossRef] [Green Version]
Sonne-Holm, S.; Sørensen, T.I.; Jensen, G.; Schnohr, P. Independent Effects of Weight Change and Attained Body Weight on Prevalence of Arterial Hypertension in Obese and Non-Obese Men. BMJ 1989, 299, 767–770. [Google Scholar] [CrossRef] [Green Version]
Staessen, J.A.; Wang, J.; Bianchi, G.; Birkenhäger, W.H. Essential Hypertension. Lancet 2003, 361, 1629–1641. [Google Scholar] [CrossRef]
Wang, N.-Y.; Young, J.H.; Meoni, L.A.; Ford, D.E.; Erlinger, T.P.; Klag, M.J. Blood Pressure Change and Risk of Hypertension Associated with Parental Hypertension: The Johns Hopkins Precursors Study. Arch. Intern. Med. 2008, 168, 643–648. [Google Scholar] [CrossRef]
Selassie, A.; Wagner, C.S.; Laken, M.L.; Ferguson, M.L.; Ferdinand, K.C.; Egan, B.M. Progression Is Accelerated from Prehypertension to Hypertension in Blacks. Hypertension 2011, 58, 579–587. [Google Scholar] [CrossRef] [Green Version]
Carnethon, M.R.; Evans, N.S.; Church, T.S.; Lewis, C.E.; Schreiner, P.J.; Jacobs, D.R.; Sternfeld, B.; Sidney, S. Joint Associations of Physical Activity and Aerobic Fitness on the Development of Incident Hypertension: Coronary Artery Risk Development in Young Adults. Hypertension 2010, 56, 49–55. [Google Scholar] [CrossRef] [Green Version]
Warnes, C.A.; Williams, R.G.; Bashore, T.M.; Child, J.S.; Connolly, H.M.; Dearani, J.A.; Del Nido, P.; Fasules, J.W.; Graham, T.P.; Hijazi, Z.M.; et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults with Congenital Heart Disease). Developed in Collaboration with the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J. Am. Coll. Cardiol. 2008, 52, e143–e263. [Google Scholar] [CrossRef] [Green Version]
Mancia, G.; Fagard, R.; Narkiewicz, K.; Redón, J.; Zanchetti, A.; Böhm, M.; Christiaens, T.; Cifkova, R.; De Backer, G.; Dominiczak, A.; et al. 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J. Hypertens. 2013, 31, 1281–1357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Gibbs, J.; Gaskin, E.; Ji, C.; Miller, M.A.; Cappuccio, F.P. The Effect of Plant-Based Dietary Patterns on Blood Pressure: A Systematic Review and Meta-Analysis of Controlled Intervention Trials. J. Hypertens. 2021, 39, 23–37. [Google Scholar] [CrossRef] [PubMed]
Sacks, F.M.; Campos, H. Dietary Therapy in Hypertension. N. Engl. J. Med. 2010, 362, 2102–2112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Appel, L.J.; Champagne, C.M.; Harsha, D.W.; Cooper, L.S.; Obarzanek, E.; Elmer, P.J.; Stevens, V.J.; Vollmer, W.M.; Lin, P.-H.; Svetkey, L.P.; et al. Effects of Comprehensive Lifestyle Modification on Blood Pressure Control: Main Results of the PREMIER Clinical Trial. JAMA 2003, 289, 2083–2093. [Google Scholar] [CrossRef]
Nazimek, K.; Kozlowski, M.; Bryniarski, P.; Strobel, S.; Bryk, A.; Myszka, M.; Tyszka, A.; Kuszmiersz, P.; Nowakowski, J.; Filipczak-Bryniarska, I. Repeatedly Administered Antidepressant Drugs Modulate Humoral and Cellular Immune Response in Mice through Action on Macrophages. Exp. Biol. Med. 2016, 241, 1540–1550. [Google Scholar] [CrossRef] [PubMed]
Nazimek, K.; Strobel, S.; Bryniarski, P.; Kozlowski, M.; Filipczak-Bryniarska, I.; Bryniarski, K. The Role of Macrophages in Anti-Inflammatory Activity of Antidepressant Drugs. Immunobiology 2017, 222, 823–830. [Google Scholar] [CrossRef]
Migdalof, B.H.; Antonaccio, M.J.; McKinstry, D.N.; Singhvi, S.M.; Lan, S.J.; Egli, P.; Kripalani, K.J. Captopril: Pharmacology, Metabolism and Disposition. Drug Metab. Rev. 1984, 15, 841–869. [Google Scholar] [CrossRef]
Serreau, R.; Luton, D.; Macher, M.-A.; Delezoide, A.-L.; Garel, C.; Jacqz-Aigrain, E. Developmental Toxicity of the Angiotensin II Type 1 Receptor Antagonists during Human Pregnancy: A Report of 10 Cases. BJOG Int. J. Obstet. Gynaecol. 2005, 112, 710–712. [Google Scholar] [CrossRef]
Yusuf, S.; Teo, K.K.; Pogue, J.; Dyal, L.; Copland, I.; Schumacher, H.; Dagenais, G.; Sleight, P.; Anderson, C. Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events. N. Engl. J. Med. 2008, 358, 1547–1559. [Google Scholar] [CrossRef]
Israili, Z.H.; Hall, W.D. Cough and Angioneurotic Edema Associated with Angiotensin-Converting Enzyme Inhibitor Therapy. A Review of the Literature and Pathophysiology. Ann. Intern. Med. 1992, 117, 234–242. [Google Scholar] [CrossRef]
Wood, R. Bronchospasm and Cough as Adverse Reactions to the ACE Inhibitors Captopril, Enalapril and Lisinopril. A Controlled Retrospective Cohort Study. Br. J. Clin. Pharmacol. 1995, 39, 265–270. [Google Scholar] [CrossRef] [PubMed]
Bangalore, S.; Kumar, S.; Messerli, F.H. Angiotensin-Converting Enzyme Inhibitor Associated Cough: Deceptive Information from the Physicians’ Desk Reference. Am. J. Med. 2010, 123, 1016–1030. [Google Scholar] [CrossRef] [PubMed]
Isles, C.G.; Hodsman, G.P.; Robertson, J.I. Side-Effects of Captopril. Lancet 1983, 1, 355. [Google Scholar] [CrossRef]
Kostis, J.B.; Packer, M.; Black, H.R.; Schmieder, R.; Henry, D.; Levy, E. Omapatrilat and Enalapril in Patients with Hypertension: The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) Trial. Am. J. Hypertens. 2004, 17, 103–111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Beltrami, L.; Zanichelli, A.; Zingale, L.; Vacchini, R.; Carugo, S.; Cicardi, M. Long-Term Follow-up of 111 Patients with Angiotensin-Converting Enzyme Inhibitor-Related Angioedema. J. Hypertens. 2011, 29, 2273–2277. [Google Scholar] [CrossRef] [PubMed]
Reardon, L.C.; Macpherson, D.S. Hyperkalemia in Outpatients Using Angiotensin-Converting Enzyme Inhibitors. How Much Should We Worry? Arch. Intern. Med. 1998, 158, 26–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Zhao, S.P.; Xie, X.M. Captopril Inhibits the Production of Tumor Necrosis Factor-Alpha by Human Mononuclear Cells in Patients with Congestive Heart Failure. Clin. Chim. Acta 2001, 304, 85–90. [Google Scholar] [CrossRef]
Schindler, R.; Dinarello, C.A.; Koch, K.M. Angiotensin-Converting-Enzyme Inhibitors Suppress Synthesis of Tumour Necrosis Factor and Interleukin 1 by Human Peripheral Blood Mononuclear Cells. Cytokine 1995, 7, 526–533. [Google Scholar] [CrossRef]
Sheikhi, A.; Jaberi, Y.; Esmaeilzadeh, A.; Khani, M.; Moosaeefard, M.; Shafaqatian, M. The Effect of Cardiovascular Drugs on Pro-Inflammatory Cytokine Secretion and Natural Killer Activity of Peripheral Blood Mononuclear Cells of Patients with Chronic Heart Failure in Vitro. Pak. J. Biol. Sci. 2007, 10, 1580–1587. [Google Scholar] [CrossRef]
Peeters, A.C.; Netea, M.G.; Kullberg, B.J.; Thien, T.; van der Meer, J.W. The Effect of Renin-Angiotensin System Inhibitors on pro- and Anti-Inflammatory Cytokine Production. Immunology 1998, 94, 376–379. [Google Scholar] [CrossRef]
Nemati, F.; Rahbar-Roshandel, N.; Hosseini, F.; Mahmoudian, M.; Shafiei, M. Anti-Inflammatory Effects of Anti-Hypertensive Agents: Influence on Interleukin-1β Secretion by Peripheral Blood Polymorphonuclear Leukocytes from Patients with Essential Hypertension. Clin. Exp. Hypertens. 2011, 33, 66–76. [Google Scholar] [CrossRef] [PubMed]
Haas, M.J.; Jurado-Flores, M.; Hammoud, R.; Feng, V.; Gonzales, K.; Onstead-Haas, L.; Mooradian, A.D. The Effects of Known Cardioprotective Drugs on Proinflammatory Cytokine Secretion From Human Coronary Artery Endothelial Cells. Am. J. Ther. 2019, 26, e321–e332. [Google Scholar] [CrossRef] [PubMed]
Miguel-Carrasco, J.L.; Zambrano, S.; Blanca, A.J.; Mate, A.; Vázquez, C.M. Captopril Reduces Cardiac Inflammatory Markers in Spontaneously Hypertensive Rats by Inactivation of NF-KB. J. Inflamm. 2010, 7, 21. [Google Scholar] [CrossRef] [Green Version]
Amirshahrokhi, K.; Ghazi-khansari, M.; Mohammadi-Farani, A.; Karimian, G. Effect of Captopril on TNF-α and IL-10 in the Livers of Bile Duct Ligated Rats. Iran. J. Immunol. 2010, 7, 247–251. [Google Scholar] [PubMed]
Albuquerque, D.; Nihei, J.; Cardillo, F.; Singh, R. The ACE Inhibitors Enalapril and Captopril Modulate Cytokine Responses in Balb/c and C57Bl/6 Normal Mice and Increase CD4(+)CD103(+)CD25(Negative) Splenic T Cell Numbers. Cell Immunol. 2010, 260, 92–97. [Google Scholar] [CrossRef] [PubMed]
Abdel-Wahab, B.A.; Metwally, M.E.; El-khawanki, M.M.; Hashim, A.M. Protective Effect of Captopril against Clozapine-Induced Myocarditis in Rats: Role of Oxidative Stress, Proinflammatory Cytokines and DNA Damage. Chem. Biol. Interact. 2014, 216, 43–52. [Google Scholar] [CrossRef] [PubMed]
Yan, W.; Li, J.; Chai, R.; Guo, W.; Xu, L.; Han, Y.; Bai, X.; Wang, H. Combining Use of Captopril and Losartan Attenuates the Progress of Streptococcus Pneumoniae-Induced Tympanosclerosis through the Suppression of TGF-Β1 Expression. PLoS ONE 2014, 9, e111620. [Google Scholar] [CrossRef]
Park, H.-S.; Han, A.; Yeo, H.-L.; Park, M.-J.; You, M.-J.; Choi, H.J.; Hong, C.-W.; Lee, S.-H.; Kim, S.H.; Kim, B.; et al. Chronic High Dose of Captopril Induces Depressive-like Behaviors in Mice: Possible Mechanism of Regulatory T Cell in Depression. Oncotarget 2017, 8, 72528–72543. [Google Scholar] [CrossRef] [Green Version]
Sepehri, Z.; Masoumi, M.; Ebrahimi, N.; Kiani, Z.; Nasiri, A.A.; Kohan, F.; Sheikh Fathollahi, M.; Kazemi Arababadi, M.; Asadikaram, G. Atorvastatin, Losartan and Captopril Lead to Upregulation of TGF-β, and Downregulation of IL-6 in Coronary Artery Disease and Hypertension. PLoS ONE 2016, 11, e0168312. [Google Scholar] [CrossRef]
Akbari, H.; Asadikaram, G.; Jafari, A.; Nazari-Robati, M.; Ebrahimi, G.; Ebrahimi, N.; Masoumi, M. Atorvastatin, Losartan and Captopril May Upregulate IL-22 in Hypertension and Coronary Artery Disease; the Role of Gene Polymorphism. Life Sci. 2018, 207, 525–531. [Google Scholar] [CrossRef]
Gong, X.; Zhou, R.; Li, Q. Effects of Captopril and Valsartan on Ventricular Remodeling and Inflammatory Cytokines after Interventional Therapy for AMI. Exp. Ther. Med. 2018, 16, 3579–3583. [Google Scholar] [CrossRef] [PubMed]
El-Ashmawy, N.E.; Khedr, N.F.; El-Bahrawy, H.A.; Hamada, O.B. Anti-Inflammatory and Antioxidant Effects of Captopril Compared to Methylprednisolone in L-Arginine-Induced Acute Pancreatitis. Dig. Dis. Sci. 2018, 63, 1497–1505. [Google Scholar] [CrossRef] [PubMed]
Wei, J.; Xu, H.; Liu, Y.; Li, B.; Zhou, F. Effect of Captopril on Radiation-Induced TGF-Β1 Secretion in EA.Hy926 Human Umbilical Vein Endothelial Cells. Oncotarget 2017, 8, 20842–20850. [Google Scholar] [CrossRef] [Green Version]
Abareshi, A.; Hosseini, M.; Beheshti, F.; Norouzi, F.; Khazaei, M.; Sadeghnia, H.R.; Boskabady, M.H.; Shafei, M.N.; Anaeigoudari, A. The Effects of Captopril on Lipopolysaccharide Induced Learning and Memory Impairments and the Brain Cytokine Levels and Oxidative Damage in Rats. Life Sci. 2016, 167, 46–56. [Google Scholar] [CrossRef] [PubMed]
Li, H.-Q.; Zhang, Q.; Chen, L.; Yin, C.-S.; Chen, P.; Tang, J.; Rong, R.; Li, T.-T.; Hu, L.-Q. Captopril Inhibits Maturation of Dendritic Cells and Maintains Their Tolerogenic Property in Atherosclerotic Rats. Int. Immunopharmacol. 2015, 28, 715–723. [Google Scholar] [CrossRef]
Abd Alla, J.; Langer, A.; Elzahwy, S.S.; Arman-Kalcek, G.; Streichert, T.; Quitterer, U. Angiotensin-Converting Enzyme Inhibition down-Regulates the pro-Atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis. J. Biol. Chem. 2010, 285, 23496–23505. [Google Scholar] [CrossRef] [Green Version]
Sugiyama, E.; Iwata, M.; Yamashita, N.; Yoshikawa, T.; Maruyama, M.; Yano, S. Immunosuppression by Captopril in Vitro: Inhibition of Human Natural Killer Activity by Copper-Dependent Generation of Hydrogen Peroxide. Jpn. J. Med. 1986, 25, 149–154. [Google Scholar] [CrossRef] [Green Version]
Fukuzawa, M.; Satoh, J.; Sagara, M.; Muto, G.; Muto, Y.; Nishimura, S.; Miyaguchi, S.; Qiang, X.L.; Sakata, Y.; Nakazawa, T.; et al. Angiotensin Converting Enzyme Inhibitors Suppress Production of Tumor Necrosis Factor-Alpha in Vitro and in Vivo. Immunopharmacology 1997, 36, 49–55. [Google Scholar] [CrossRef]
Sheth, T.; Parker, T.; Block, A.; Hall, C.; Adam, A.; Pfeffer, M.A.; Stewart, D.J.; Qian, C.; Rouleau, J.L.; IMPRESS Investigators. Comparison of the Effects of Omapatrilat and Lisinopril on Circulating Neurohormones and Cytokines in Patients with Chronic Heart Failure. Am. J. Cardiol. 2002, 90, 496–500. [Google Scholar] [CrossRef]
Suzuki, M.; Teramoto, S.; Katayama, H.; Ohga, E.; Matsuse, T.; Ouchi, Y. Effects of Angiotensin-Converting Enzyme (ACE) Inhibitors on Oxygen Radical Production and Generation by Murine Lung Alveolar Macrophages. J. Asthma 1999, 36, 665–670. [Google Scholar] [CrossRef]
Constantinescu, C.S.; Goodman, D.B.; Ventura, E.S. Captopril and Lisinopril Suppress Production of Interleukin-12 by Human Peripheral Blood Mononuclear Cells. Immunol. Lett. 1998, 62, 25–31. [Google Scholar] [CrossRef]
Stenvinkel, P.; Andersson, P.; Wang, T.; Lindholm, B.; Bergström, J.; Palmblad, J.; Heimbürger, O.; Cederholm, T. Do ACE-Inhibitors Suppress Tumour Necrosis Factor-Alpha Production in Advanced Chronic Renal Failure? J. Intern. Med. 1999, 246, 503–507. [Google Scholar] [CrossRef] [PubMed]
Navarro, J.F.; Milena, F.J.; Mora, C.; León, C.; Claverie, F.; Flores, C.; García, J. Tumor Necrosis Factor-Alpha Gene Expression in Diabetic Nephropathy: Relationship with Urinary Albumin Excretion and Effect of Angiotensin-Converting Enzyme Inhibition. Kidney Int. Suppl. 2005, S98–S102. [Google Scholar] [CrossRef] [Green Version]
Wang, C.-H.; Verma, S.; Hsieh, I.-C.; Chen, Y.-J.; Kuo, L.-T.; Yang, N.-I.; Wang, S.-Y.; Wu, M.-Y.; Hsu, C.-M.; Cheng, C.-W.; et al. Enalapril Increases Ischemia-Induced Endothelial Progenitor Cell Mobilization through Manipulation of the CD26 System. J. Mol. Cell. Cardiol. 2006, 41, 34–43. [Google Scholar] [CrossRef] [PubMed]
Almeida, L.C.; Muraro, L.S.; Albuquerque, D.A. Enhancement of Anti-OVA IgG2c Production in Vivo by Enalapril. Braz. J. Med. Biol. Res. 2016, 49. [Google Scholar] [CrossRef] [Green Version]
Keller, K.; Kane, A.; Heinze-Milne, S.; Grandy, S.A.; Howlett, S.E. Chronic Treatment with the ACE Inhibitor Enalapril Attenuates the Development of Frailty and Differentially Modifies Pro- and Anti-Inflammatory Cytokines in Aging Male and Female C57BL/6 Mice. J. Gerontol. A Biol. Sci. Med. Sci. 2019, 74, 1149–1157. [Google Scholar] [CrossRef]
Lee, C.; Chun, J.; Hwang, S.W.; Kang, S.J.; Im, J.P.; Kim, J.S. Enalapril Inhibits Nuclear Factor-ΚB Signaling in Intestinal Epithelial Cells and Peritoneal Macrophages and Attenuates Experimental Colitis in Mice. Life Sci. 2014, 95, 29–39. [Google Scholar] [CrossRef]
Hernández-Fonseca, J.P.; Durán, A.; Valero, N.; Mosquera, J. Losartan and Enalapril Decrease Viral Absorption and Interleukin 1 Beta Production by Macrophages in an Experimental Dengue Virus Infection. Arch. Virol. 2015, 160, 2861–2865. [Google Scholar] [CrossRef]
Cucak, H.; Nielsen Fink, L.; Højgaard Pedersen, M.; Rosendahl, A. Enalapril Treatment Increases T Cell Number and Promotes Polarization towards M1-like Macrophages Locally in Diabetic Nephropathy. Int. Immunopharmacol. 2015, 25, 30–42. [Google Scholar] [CrossRef] [Green Version]
Sueyoshi, R.; Ignatoski, K.M.W.; Daignault, S.; Okawada, M.; Teitelbaum, D.H. Angiotensin Converting Enzyme-Inhibitor Reduces Colitis Severity in an IL-10 Knockout Model. Dig. Dis. Sci. 2013, 58, 3165–3177. [Google Scholar] [CrossRef] [Green Version]
Salmenkari, H.; Pasanen, L.; Linden, J.; Korpela, R.; Vapaatalo, H. Beneficial Anti-Inflammatory Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker in the Treatment of Dextran Sulfate Sodium-Induced Colitis in Mice. J. Physiol. Pharmacol. 2018, 69, 4. [Google Scholar] [CrossRef]
Zamani, P.; Ganz, P.; Libby, P.; Sutradhar, S.C.; Rifai, N.; Nicholls, S.J.; Nissen, S.E.; Kinlay, S. Relationship of Antihypertensive Treatment to Plasma Markers of Vascular Inflammation and Remodeling in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis Study. Am. Heart J. 2012, 163, 735–740. [Google Scholar] [CrossRef]
Wang, S.; Yuan, B.; Dan, Q.; Yang, X.; Meng, B.; Zhang, Y. Effects of enalapril on IL-1beta, IL-6 expression in rat lung exposure to acrolein. Sichuan Da Xue Xue Bao Yi Xue Ban 2010, 41, 1003–1007, 1038. [Google Scholar] [PubMed]
Krysiak, R.; Okopień, B. Different Effects of Perindopril and Enalapril on Monocyte Cytokine Release in Coronary Artery Disease Patients with Normal Blood Pressure. Pharmacol. Rep. 2012, 64, 1466–1475. [Google Scholar] [CrossRef]
Shalkami, A.-G.S.; Hassan, M.I.A.; Abd El-Ghany, A.A. Perindopril Regulates the Inflammatory Mediators, NF-ΚB/TNF-α/IL-6, and Apoptosis in Cisplatin-Induced Renal Dysfunction. Naunyn Schmiedebergs Arch. Pharmacol. 2018, 391, 1247–1255. [Google Scholar] [CrossRef]
Madej, A.; Buldak, L.; Basiak, M.; Szkrobka, W.; Dulawa, A.; Okopien, B. The Effects of 1 Month Antihypertensive Treatment with Perindopril, Bisoprolol or Both on the Ex Vivo Ability of Monocytes to Secrete Inflammatory Cytokines. Int. J. Clin. Pharmacol. Ther. 2009, 47, 686–694. [Google Scholar] [CrossRef] [PubMed]
Madej, A.; Dąbek, J.; Majewski, M.; Szuta, J. Effect of Perindopril and Bisoprolol on IL-2, INF-γ, Hs-CRP and T-Cell Stimulation and Correlations with Blood Pressure in Mild and Moderate Hypertension. Int. J. Clin. Pharmacol. Ther. 2018, 56, 393–399. [Google Scholar] [CrossRef]
Gilowski, W.; Krysiak, R.; Marek, B.; Okopień, B. The Effect of Short-Term Perindopril and Telmisartan Treatment on Circulating Levels of Anti-Inflammatory Cytokines in Hypertensive Patients. Endokrynol. Pol. 2018, 69, 667–674. [Google Scholar] [CrossRef]
Lizakowski, S.; Tylicki, L.; Renke, M.; Rutkowski, P.; Heleniak, Z.; Sławińska-Morawska, M.; Aleksandrowicz-Wrona, E.; Małgorzewicz, S.; Rutkowski, B. Aliskiren and Perindopril Reduce the Levels of Transforming Growth Factor-β in Patients with Non-Diabetic Kidney Disease. Am. J. Hypertens. 2012, 25, 636–639. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Tsai, M.-K.; Jan, R.-L.; Lin, C.-H.; Kuo, C.-H.; Yang, S.-N.; Chen, H.-N.; Huang, M.-Y.; Hung, C.-H. Suppressive Effects of Imidapril on Th1- and Th2-Related Chemokines in Monocytes. J. Investig. Med. 2011, 59, 1141–1146. [Google Scholar] [CrossRef]
Siragy, H.M.; Xue, C.; Webb, R.L. Beneficial Effects of Combined Benazepril-Amlodipine on Cardiac Nitric Oxide, CGMP, and TNF-Alpha Production after Cardiac Ischemia. J. Cardiovasc. Pharmacol. 2006, 47, 636–642. [Google Scholar] [CrossRef] [PubMed]
Li, H.; Wang, Y.; Zhou, Z.; Tian, F.; Yang, H.; Yan, J. Combination of Leflunomide and Benazepril Reduces Renal Injury of Diabetic Nephropathy Rats and Inhibits High-Glucose Induced Cell Apoptosis through Regulation of NF-ΚB, TGF-β and TRPC6. Ren Fail. 2019, 41, 899–906. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Yan, S.-H.; Zhao, N.-W.; Zhu, X.-X.; Wang, Q.; Wang, H.-D.; Fu, R.; Sun, Y.; Li, Q.-Y. Benazepril Inhibited the NF-ΚB and TGF-β Networking on LV Hypertrophy in Rats. Immunol. Lett. 2013, 152, 126–134. [Google Scholar] [CrossRef]
Wei, M.; Gu, S.; Zhang, Y.; Wu, Y.; Wu, Z. Effects of pravastatin, fosinopril and their combination on myocardium TNF-alpha expression and ventricular remodeling after myocardial infarction in rats. Zhonghua Xin Xue Guan Bing Za Zhi 2005, 33, 444–447. [Google Scholar]
Berezin, A.E. Effect of fosinopril on the rate of neurohumoral and proinflammatory activation in patients with heart failure. Klin. Med. 2004, 82, 29–32. [Google Scholar]
Shimozawa, M.; Naito, Y.; Manabe, H.; Uchiyama, K.; Katada, K.; Kuroda, M.; Nakabe, N.; Yoshida, N.; Yoshikawa, T. The Inhibitory Effect of Alacepril, an Angiotensin-Converting Enzyme Inhibitor, on Endothelial Inflammatory Response Induced by Oxysterol and TNF-Alpha. Redox Rep. 2004, 9, 354–359. [Google Scholar] [CrossRef]
Monti, M.; Terzuoli, E.; Ziche, M.; Morbidelli, L. H2S Dependent and Independent Anti-Inflammatory Activity of Zofenoprilat in Cells of the Vascular Wall. Pharmacol. Res. 2016, 113, 426–437. [Google Scholar] [CrossRef]
Scribner, A.W.; Loscalzo, J.; Napoli, C. The Effect of Angiotensin-Converting Enzyme Inhibition on Endothelial Function and Oxidant Stress. Eur. J. Pharmacol. 2003, 482, 95–99. [Google Scholar] [CrossRef]
Del Fiorentino, A.; Cianchetti, S.; Celi, A.; Pedrinelli, R. Aliskiren, a Renin Inhibitor, Downregulates TNF-α-Induced Tissue Factor Expression in HUVECS. J. Renin Angiotensin Aldosterone Syst. 2010, 11, 243–247. [Google Scholar] [CrossRef] [Green Version]
Gamboa, J.L.; Pretorius, M.; Todd-Tzanetos, D.R.; Luther, J.M.; Yu, C.; Ikizler, T.A.; Brown, N.J. Comparative Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin-Receptor Blockade on Inflammation during Hemodialysis. J. Am. Soc. Nephrol. 2012, 23, 334–342. [Google Scholar] [CrossRef] [Green Version]
Brili, S.; Tousoulis, D.; Antoniades, C.; Vasiliadou, C.; Karali, M.; Papageorgiou, N.; Ioakeimidis, N.; Marinou, K.; Stefanadi, E.; Stefanadis, C. Effects of Ramipril on Endothelial Function and the Expression of Proinflammatory Cytokines and Adhesion Molecules in Young Normotensive Subjects with Successfully Repaired Coarctation of Aorta: A Randomized Cross-over Study. J. Am. Coll. Cardiol. 2008, 51, 742–749. [Google Scholar] [CrossRef] [Green Version]
Sandmann, S.; Li, J.; Fritzenkötter, C.; Spormann, J.; Tiede, K.; Fischer, J.W.; Unger, T. Differential Effects of Olmesartan and Ramipril on Inflammatory Response after Myocardial Infarction in Rats. Blood Press. 2006, 15, 116–128. [Google Scholar] [CrossRef]
Janickova Zdarska, D.; Zavadova, E.; Kvapil, M. The Effect of Ramipril Therapy on Cytokines and Parameters of Incipient Diabetic Nephropathy in Patients with Type 1 Diabetes Mellitus. J. Int. Med. Res. 2007, 35, 374–383. [Google Scholar] [CrossRef] [Green Version]
Marcinkiewicz, J.; Witkowski, J.M.; Olszanecki, R. Dual role of the immune system in a course of COVID-19. The fatal impact of aging immune system. Cent. Eur. J. Immunol. 2021, 46, 1–9. [Google Scholar] [CrossRef] [PubMed]
An, J.; Nakajima, T.; Kuba, K.; Kimura, A. Losartan Inhibits LPS-Induced Inflammatory Signaling through a PPARgamma-Dependent Mechanism in Human THP-1 Macrophages. Hypertens. Res. 2010, 33, 831–835. [Google Scholar] [CrossRef] [Green Version]
Kaynar, K.; Ulusoy, S.; Ovali, E.; Vanizor, B.; Dikmen, T.; Gul, S. TGF-Beta and TNF-Alpha Producing Effects of Losartan and Amlodipine on Human Mononuclear Cell Culture. Nephrology 2005, 10, 478–482. [Google Scholar] [CrossRef] [PubMed]
El-Agroudy, A.E.; Hassan, N.A.; Foda, M.A.; Ismail, A.M.; El-Sawy, E.A.; Mousa, O.; Ghoneim, M.A. Effect of Angiotensin II Receptor Blocker on Plasma Levels of TGF-Beta 1 and Interstitial Fibrosis in Hypertensive Kidney Transplant Patients. Am. J. Nephrol. 2003, 23, 300–306. [Google Scholar] [CrossRef]
Park, H.C.; Xu, Z.G.; Choi, S.; Goo, Y.S.; Kang, S.W.; Choi, K.H.; Ha, S.K.; Lee, H.Y.; Han, D.S. Effect of Losartan and Amlodipine on Proteinuria and Transforming Growth Factor-Beta1 in Patients with IgA Nephropathy. Nephrol. Dial. Transplant. 2003, 18, 1115–1121. [Google Scholar] [CrossRef] [Green Version]
Cardoso, P.R.G.; Matias, K.A.; Dantas, A.T.; Marques, C.D.L.; Pereira, M.C.; Duarte, A.L.B.P.; de Melo Rego, M.J.B.; da Rocha Pitta, I.; da Rocha Pitta, M.G. Losartan, but Not Enalapril and Valsartan, Inhibits the Expression of IFN-γ, IL-6, IL-17F and IL-22 in PBMCs from Rheumatoid Arthritis Patients. Open Rheumatol. J. 2018, 12, 160–170. [Google Scholar] [CrossRef] [PubMed]
Subeq, Y.-M.; Ke, C.-Y.; Lin, N.-T.; Lee, C.-J.; Chiu, Y.-H.; Hsu, B.-G. Valsartan Decreases TGF-Β1 Production and Protects against Chlorhexidine Digluconate-Induced Liver Peritoneal Fibrosis in Rats. Cytokine 2011, 53, 223–230. [Google Scholar] [CrossRef]
Jiao, B.; Wang, Y.S.; Cheng, Y.N.; Gao, J.J.; Zhang, Q.Z. Valsartan Attenuated Oxidative Stress, Decreased MCP-1 and TGF-Β1 Expression in Glomerular Mesangial and Epithelial Cells Induced by High-Glucose Levels. Biosci. Trends 2011, 5, 173–181. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Li, X.; Hu, H.; Wang, Y.; Xue, M.; Li, X.; Cheng, W.; Xuan, Y.; Yin, J.; Yang, N.; Yan, S. Valsartan Attenuates KIR2.1 by Downregulating the Th1 Immune Response in Rats Following Myocardial Infarction. J. Cardiovasc. Pharmacol. 2016, 67, 252–259. [Google Scholar] [CrossRef]
Iwashita, M.; Sakoda, H.; Kushiyama, A.; Fujishiro, M.; Ohno, H.; Nakatsu, Y.; Fukushima, T.; Kumamoto, S.; Tsuchiya, Y.; Kikuchi, T.; et al. Valsartan, Independently of AT1 Receptor or PPARγ, Suppresses LPS-Induced Macrophage Activation and Improves Insulin Resistance in Cocultured Adipocytes. Am. J. Physiol. Endocrinol. Metab. 2012, 302, E286–E296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Xie, Q.; Wang, Y.; Sun, Z.; Yang, T. Effects of Valsartan and Indapamide on Plasma Cytokines in Essential Hypertension. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2006, 31, 629–634. [Google Scholar] [PubMed]
Hepworth, M.L.; Passey, S.L.; Seow, H.J.; Vlahos, R. Losartan Does Not Inhibit Cigarette Smoke-Induced Lung Inflammation in Mice. Sci. Rep. 2019, 9, 15053. [Google Scholar] [CrossRef] [Green Version]
Wang, F.; Huang, L.; Peng, Z.-Z.; Tang, Y.-T.; Lu, M.-M.; Peng, Y.; Mel, W.-J.; Wu, L.; Mo, Z.-H.; Meng, J.; et al. Losartan Inhibits LPS + ATP-Induced IL-1beta Secretion from Mouse Primary Macrophages by Suppressing NALP3 Inflammasome. Pharmazie 2014, 69, 680–684. [Google Scholar]
Suganuma, E.; Niimura, F.; Matsuda, S.; Ukawa, T.; Nakamura, H.; Sekine, K.; Kato, M.; Aiba, Y.; Koga, Y.; Hayashi, K.; et al. Losartan Attenuates the Coronary Perivasculitis through Its Local and Systemic Anti-Inflammatory Properties in a Murine Model of Kawasaki Disease. Pediatr. Res. 2017, 81, 593–600. [Google Scholar] [CrossRef]
Kim, E.; Hwang, S.-H.; Kim, H.-K.; Abdi, S.; Kim, H.K. Losartan, an Angiotensin II Type 1 Receptor Antagonist, Alleviates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain by Inhibiting Inflammatory Cytokines in the Dorsal Root Ganglia. Mol. Neurobiol. 2019, 56, 7408–7419. [Google Scholar] [CrossRef]
Yamamoto, S.; Zhong, J.; Yancey, P.G.; Zuo, Y.; Linton, M.F.; Fazio, S.; Yang, H.; Narita, I.; Kon, V. Atherosclerosis Following Renal Injury Is Ameliorated by Pioglitazone and Losartan via Macrophage Phenotype. Atherosclerosis 2015, 242, 56–64. [Google Scholar] [CrossRef] [Green Version]
Xiao, C.; Zhou, Q.; Li, X.; Li, H.; Zhong, Y.; Meng, T.; Zhu, M.; Sun, H.; Liu, S.; Tang, R.; et al. Losartan and Dexamethasone May Inhibit Chemotaxis to Reduce the Infiltration of Th22 Cells in IgA Nephropathy. Int. Immunopharmacol. 2017, 42, 203–208. [Google Scholar] [CrossRef]
Liu, J.; Zhang, P.-S.; Yu, Q.; Liu, L.; Yang, Y.; Guo, F.-M.; Qiu, H.-B. Losartan Inhibits Conventional Dendritic Cell Maturation and Th1 and Th17 Polarization Responses: Novel Mechanisms of Preventive Effects on Lipopolysaccharide-Induced Acute Lung Injury. Int. J. Mol. Med. 2012, 29, 269–276. [Google Scholar] [CrossRef]
Wang, X.; Chen, X.; Huang, W.; Zhang, P.; Guo, Y.; Körner, H.; Wu, H.; Wei, W. Losartan Suppresses the Inflammatory Response in Collagen-Induced Arthritis by Inhibiting the MAPK and NF-ΚB Pathways in B and T Cells. Inflammopharmacology 2019, 27, 487–502. [Google Scholar] [CrossRef] [PubMed]
Aki, K.; Shimizu, A.; Masuda, Y.; Kuwahara, N.; Arai, T.; Ishikawa, A.; Fujita, E.; Mii, A.; Natori, Y.; Fukunaga, Y.; et al. ANG II Receptor Blockade Enhances Anti-Inflammatory Macrophages in Anti-Glomerular Basement Membrane Glomerulonephritis. Am. J. Physiol. Renal Physiol. 2010, 298, F870–F882. [Google Scholar] [CrossRef] [PubMed]
Takagi, H.; Mizuno, Y.; Yamamoto, H.; Goto, S.; Umemoto, T.; All-Literature Investigation of Cardiovascular Evidence Group. Effects of Telmisartan Therapy on Interleukin-6 and Tumor Necrosis Factor-Alpha Levels: A Meta-Analysis of Randomized Controlled Trials. Hypertens. Res. 2013, 36, 368–373. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Li, W.; Zhang, J.; Lu, F.; Ma, M.; Wang, J.; Suo, A.; Bai, Y.; Liu, H. Effects of telmisartan on the level of Aβ1-42, interleukin-1β, tumor necrosis factor α and cognition in hypertensive patients with Alzheimer’s disease. Zhonghua Yi Xue Za Zhi 2012, 92, 2743–2746. [Google Scholar]
Justin, A.; Sathishkumar, M.; Sudheer, A.; Shanthakumari, S.; Ramanathan, M. Non-Hypotensive Dose of Telmisartan and Nimodipine Produced Synergistic Neuroprotective Effect in Cerebral Ischemic Model by Attenuating Brain Cytokine Levels. Pharmacol. Biochem. Behav. 2014, 122, 61–73. [Google Scholar] [CrossRef]
Pang, T.; Wang, J.; Benicky, J.; Sánchez-Lemus, E.; Saavedra, J.M. Telmisartan Directly Ameliorates the Neuronal Inflammatory Response to IL-1β Partly through the JNK/c-Jun and NADPH Oxidase Pathways. J. Neuroinflamm. 2012, 9, 102. [Google Scholar] [CrossRef] [Green Version]
Walcher, D.; Hess, K.; Heinz, P.; Petscher, K.; Vasic, D.; Kintscher, U.; Clemenz, M.; Hartge, M.; Raps, K.; Hombach, V.; et al. Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-Gamma. Hypertension 2008, 51, 259–266. [Google Scholar] [CrossRef] [Green Version]
Matsumura, T.; Kinoshita, H.; Ishii, N.; Fukuda, K.; Motoshima, H.; Senokuchi, T.; Taketa, K.; Kawasaki, S.; Nishimaki-Mogami, T.; Kawada, T.; et al. Telmisartan Exerts Antiatherosclerotic Effects by Activating Peroxisome Proliferator-Activated Receptor-γ in Macrophages. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 1268–1275. [Google Scholar] [CrossRef] [Green Version]
Huang, S.-S.; He, S.-L.; Zhang, Y.-M. The Effects of Telmisartan on the Nuclear Factor of Activated T Lymphocytes Signalling Pathway in Hypertensive Patients. J. Renin Angiotensin Aldosterone Syst. 2016, 17, 1470320316655005. [Google Scholar] [CrossRef] [Green Version]
Guerra, G.C.B.; Araújo, A.A.; Lira, G.A.; Melo, M.N.; Souto, K.K.O.; Fernandes, D.; Silva, A.L.; Araújo Júnior, R.F. Telmisartan Decreases Inflammation by Modulating TNF-α, IL-10, and RANK/RANKL in a Rat Model of Ulcerative Colitis. Pharmacol. Rep. 2015, 67, 520–526. [Google Scholar] [CrossRef] [PubMed]
Chang, H.-Y.; Li, X.; Tian, Y. Telmisartan Reduces Arrhythmias through Increasing Cardiac Connexin43 by Inhibiting IL-17 after Myocardial Infarction in Rats. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 5283–5289. [Google Scholar] [CrossRef] [PubMed]
Kataoka, H.; Murakami, R.; Numaguchi, Y.; Okumura, K.; Murohara, T. Angiotensin II Type 1 Receptor Blockers Prevent Tumor Necrosis Factor-Alpha-Mediated Endothelial Nitric Oxide Synthase Reduction and Superoxide Production in Human Umbilical Vein Endothelial Cells. Eur. J. Pharmacol. 2010, 636, 36–41. [Google Scholar] [CrossRef] [PubMed]
de Araújo, A.A.; Borba, P.B.; de Souza, F.H.D.; Nogueira, A.C.; Saldanha, T.S.; Araújo, T.E.F.; da Silva, A.I.; de Araújo Júnior, R.F. In a Methotrexate-Induced Model of Intestinal Mucositis, Olmesartan Reduced Inflammation and Induced Enteropathy Characterized by Severe Diarrhea, Weight Loss, and Reduced Sucrose Activity. Biol. Pharm. Bull. 2015, 38, 746–752. [Google Scholar] [CrossRef] [Green Version]
Sagawa, K.; Nagatani, K.; Komagata, Y.; Yamamoto, K. Angiotensin Receptor Blockers Suppress Antigen-Specific T Cell Responses and Ameliorate Collagen-Induced Arthritis in Mice. Arthritis Rheum. 2005, 52, 1920–1928. [Google Scholar] [CrossRef] [PubMed]
Uramatsu, T.; Nishino, T.; Obata, Y.; Sato, Y.; Furusu, A.; Koji, T.; Miyazaki, T.; Kohno, S. Involvement of Apoptosis Inhibitor of Macrophages in a Rat Hypertension Model with Nephrosclerosis: Possible Mechanisms of Action of Olmesartan and Azelnidipine. Biol. Pharm. Bull. 2013, 36, 1271–1277. [Google Scholar] [CrossRef] [Green Version]
de Araújo, R.F.; Reinaldo, M.P.O.D.; Brito, G.A.D.; Cavalcanti, P.D.; Freire, M.A.D.; de Medeiros, C.A.X.; de Araújo, A.A. Olmesartan Decreased Levels of IL-1β and TNF-α, down-Regulated MMP-2, MMP-9, COX-2, RANK/RANKL and up-Regulated SOCs-1 in an Intestinal Mucositis Model. PLoS ONE 2014, 9, e114923. [Google Scholar] [CrossRef]
Nagib, M.M.; Tadros, M.G.; ElSayed, M.I.; Khalifa, A.E. Anti-Inflammatory and Anti-Oxidant Activities of Olmesartan Medoxomil Ameliorate Experimental Colitis in Rats. Toxicol. Appl. Pharmacol. 2013, 271, 106–113. [Google Scholar] [CrossRef]
Suh, S.H.; Choi, H.S.; Kim, C.S.; Kim, I.J.; Ma, S.K.; Scholey, J.W.; Kim, S.W.; Bae, E.H. Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ. Int. J. Mol. Sci. 2019, 20, 3843. [Google Scholar] [CrossRef] [Green Version]
Araújo, A.A.; Lopes de Souza, G.; Souza, T.O.; de Castro Brito, G.A.; Sabóia Aragão, K.; Xavier de Medeiros, C.A.; Lourenço, Y.; do Socorro Costa Feitosa Alves, M.; Fernandes de Araújo, R. Olmesartan Decreases IL-1β and TNF-α Levels; Downregulates MMP-2, MMP-9, COX-2, and RANKL and Upregulates OPG in Experimental Periodontitis. Naunyn Schmiedebergs Arch. Pharmacol. 2013, 386, 875–884. [Google Scholar] [CrossRef] [PubMed]
Li, Z.-C.; Yu, H.-Y.; Wang, X.-X.; Zhang, M.; Wang, J.-P. Olmesartan Medoxomil Reverses Left Ventricle Hypertrophy and Reduces Inflammatory Cytokine IL-6 in the Renovascular Hypertensive Rats. Eur. Rev. Med. Pharmacol. Sci. 2013, 17, 3318–3322. [Google Scholar] [PubMed]
Rahman, S.T.; Lauten, W.B.; Khan, Q.A.; Navalkar, S.; Parthasarathy, S.; Khan, B.V. Effects of Eprosartan versus Hydrochlorothiazide on Markers of Vascular Oxidation and Inflammation and Blood Pressure (Renin-Angiotensin System Antagonists, Oxidation, and Inflammation). Am. J. Cardiol. 2002, 89, 686–690. [Google Scholar] [CrossRef] [PubMed]
Behr, T.M.; Willette, R.N.; Coatney, R.W.; Berova, M.; Angermann, C.E.; Anderson, K.; Sackner-Bernstein, J.D.; Barone, F.C. Eprosartan Improves Cardiac Performance, Reduces Cardiac Hypertrophy and Mortality and Downregulates Myocardial Monocyte Chemoattractant Protein-1 and Inflammation in Hypertensive Heart Disease. J. Hypertens. 2004, 22, 583–592. [Google Scholar] [CrossRef]
Yu, Y.; Jiang, H.; Niu, Y.; Zhang, X.; Zhang, Y.; Liu, X.I.; Qi, T.; Yu, C. Candesartan Inhibits Inflammation through an Angiotensin II Type 1 Receptor Independent Way in Human Embryonic Kidney Epithelial Cells. An. Acad. Bras. Cienc. 2019, 91, e20180699. [Google Scholar] [CrossRef]
Kim, M.-J.; Im, D.-S. Suppressive Effects of Type I Angiotensin Receptor Antagonists, Candesartan and Irbesartan on Allergic Asthma. Eur. J. Pharmacol. 2019, 852, 25–33. [Google Scholar] [CrossRef] [PubMed]
Khuman, M.W.; Harikumar, S.K.; Sadam, A.; Kesavan, M.; Susanth, V.S.; Parida, S.; Singh, K.P.; Sarkar, S.N. Candesartan Ameliorates Arsenic-Induced Hypertensive Vascular Remodeling by Regularizing Angiotensin II and TGF-Beta Signaling in Rats. Toxicology 2016, 374, 29–41. [Google Scholar] [CrossRef]
Tawinwung, S.; Petpiroon, N.; Chanvorachote, P. Blocking of Type 1 Angiotensin II Receptor Inhibits T-Lymphocyte Activation and IL-2 Production. In Vivo 2018, 32, 1353–1359. [Google Scholar] [CrossRef] [Green Version]
Barakat, W.; Safwet, N.; El-Maraghy, N.N.; Zakaria, M.N.M. Candesartan and Glycyrrhizin Ameliorate Ischemic Brain Damage through Downregulation of the TLR Signaling Cascade. Eur. J. Pharmacol. 2014, 724, 43–50. [Google Scholar] [CrossRef]
Benicky, J.; Sánchez-Lemus, E.; Honda, M.; Pang, T.; Orecna, M.; Wang, J.; Leng, Y.; Chuang, D.-M.; Saavedra, J.M. Angiotensin II AT1 Receptor Blockade Ameliorates Brain Inflammation. Neuropsychopharmacology 2011, 36, 857–870. [Google Scholar] [CrossRef] [Green Version]
Larrayoz, I.M.; Pang, T.; Benicky, J.; Pavel, J.; Sánchez-Lemus, E.; Saavedra, J.M. Candesartan Reduces the Innate Immune Response to Lipopolysaccharide in Human Monocytes. J. Hypertens. 2009, 27, 2365–2376. [Google Scholar] [CrossRef] [Green Version]
Zhao, L.-Q.; Huang, J.-L.; Yu, Y.; Lu, Y.; Fu, L.-J.; Wang, J.-L.; Wang, Y.-D.; Yu, C. Candesartan Inhibits LPS-Induced Expression Increase of Toll-like Receptor 4 and Downstream Inflammatory Factors Likely via Angiotensin II Type 1 Receptor Independent Pathway in Human Renal Tubular Epithelial Cells. Sheng Li Xue Bao 2013, 65, 623–630. [Google Scholar] [PubMed]
Xing, G.; Wei, M.; Xiu, B.; Ma, Y.; Liu, T. Irbesartan reduces inflammatory response of central nervous system in a rat model of fluid percussion brain injury. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2016, 32, 917–920. [Google Scholar]
Kato, Y.; Kamiya, H.; Koide, N.; Odkhuu, E.; Komatsu, T.; Watarai, A.; Kondo, M.; Kato, K.; Nakamura, J.; Yokochi, T. Irbesartan Attenuates Production of High-Mobility Group Box 1 in Response to Lipopolysaccharide via Downregulation of Interferon-β Production. Int. Immunopharmacol. 2015, 26, 97–102. [Google Scholar] [CrossRef]
Zhao, Y.; Watanabe, A.; Zhao, S.; Kobayashi, T.; Fukao, K.; Tanaka, Y.; Nakano, T.; Yoshida, T.; Takemoto, H.; Tamaki, N.; et al. Suppressive Effects of Irbesartan on Inflammation and Apoptosis in Atherosclerotic Plaques of ApoE-/- Mice: Molecular Imaging with 14C-FDG and 99mTc-Annexin A5. PLoS ONE 2014, 9, e89338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Ni, J.; Huang, H.-Q.; Lü, L.-L.; Zheng, M.; Liu, B.-C. Influence of Irbesartan on the Urinary Excretion of Cytokines in Patients with Chronic Kidney Disease. Chin. Med. J. 2012, 125, 1147–1152. [Google Scholar] [PubMed]
Tu, X.; Chen, X.; Xie, Y.; Shi, S.; Wang, J.; Chen, Y.; Li, J. Anti-Inflammatory Renoprotective Effect of Clopidogrel and Irbesartan in Chronic Renal Injury. J. Am. Soc. Nephrol. 2008, 19, 77–83. [Google Scholar] [CrossRef]
Kabel, A.M.; Salama, S.A.; Alghorabi, A.A.; Estfanous, R.S. Amelioration of Cyclosporine-Induced Testicular Toxicity by Carvedilol and/or Alpha-Lipoic Acid: Role of TGF-Β1, the Proinflammatory Cytokines, Nrf2/HO-1 Pathway and Apoptosis. Clin. Exp. Pharmacol. Physiol. 2020, 47, 1169–1181. [Google Scholar] [CrossRef]
Ye, X.-L.; Huang, W.-C.; Zheng, Y.-T.; Liang, Y.; Gong, W.-Q.; Yang, C.-M.; Liu, B. Irbesartan ameliorates cardiac inflammation in type 2 diabetic db/db mice. Nan Fang Yi Ke Da Xue Xue Bao 2016, 37, 505–511. [Google Scholar]
Zhao, X.; Yang, D.; Xu, W.; Xu, W.; Guo, Z. Effect of Irbesartan on Oxidative Stress and Serum Inflammatory Factors in Renal Tissues of Type 2 Diabetic Rats. J. Coll. Physicians Surg. Pak. 2019, 29, 422–425. [Google Scholar] [CrossRef]
Jiang, Y.; Jiang, L.-L.I.; Maimaitirexiati, X.-M.Z.Y.; Zhang, Y.; Wu, L. Irbesartan Attenuates TNF-α-Induced ICAM-1, VCAM-1, and E-Selectin Expression through Suppression of NF-ΚB Pathway in HUVECs. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 3295–3302. [Google Scholar]
Tsuruoka, S.; Kai, H.; Usui, J.; Morito, N.; Saito, C.; Yoh, K.; Yamagata, K. Effects of Irbesartan on Inflammatory Cytokine Concentrations in Patients with Chronic Glomerulonephritis. Intern. Med. 2013, 52, 303–308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Bryniarski, P.; Nazimek, K.; Marcinkiewicz, J. Anti-Inflammatory Activities of Captopril and Diuretics on Macrophage Activity in Mouse Humoral Immune Response. Int. J. Mol. Sci. 2021, 22, 11374. [Google Scholar] [CrossRef] [PubMed]
Bryniarski, P.; Nazimek, K.; Marcinkiewicz, J. Captopril Combined with Furosemide or Hydrochlorothiazide Affects Macrophage Functions in Mouse Contact Hypersensitivity Response. Int. J. Mol. Sci. 2021, 23, 74. [Google Scholar] [CrossRef]
Bryniarski, P.; Nazimek, K.; Marcinkiewicz, J. Immunomodulatory Potential of Diuretics. Biology 2021, 10, 1315. [Google Scholar] [CrossRef]
Wożakowska-Kapłon, B.; Filipiak, K.J.; Czarnecka, D.; Dzida, G.; Mamcarz, A.; Tykarski, A.; Widecka, K.; Narkiewicz, K. Combination therapy in the management of hypertension—current problem in Poland. Expert consensus statement of the Polish Society of Hypertension and Polish Cardiac Society Working Group on Cardiovascular Pharmacotherapy. Kardiol. Pol. 2013, 71, 433–438. [Google Scholar] [CrossRef] [PubMed] [Green Version]

Figure 1. Recommendations for the use of drugs from the appropriate drug groups depending on the diseases accompanying hypertension. Abbreviation: RAA blocker—renin-angiotensin-aldosterone system blocker.

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Bryniarski, P.; Nazimek, K.; Marcinkiewicz, J. Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers. Int. J. Mol. Sci. 2022, 23, 1772. https://doi.org/10.3390/ijms23031772

AMA Style

Bryniarski P, Nazimek K, Marcinkiewicz J. Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers. International Journal of Molecular Sciences. 2022; 23(3):1772. https://doi.org/10.3390/ijms23031772

Chicago/Turabian Style

Bryniarski, Paweł, Katarzyna Nazimek, and Janusz Marcinkiewicz. 2022. "Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers" International Journal of Molecular Sciences 23, no. 3: 1772. https://doi.org/10.3390/ijms23031772

APA Style

Bryniarski, P., Nazimek, K., & Marcinkiewicz, J. (2022). Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers. International Journal of Molecular Sciences, 23(3), 1772. https://doi.org/10.3390/ijms23031772

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