Protective Effects of Angiotensin II Interruption: Evidence for Antiinflammatory Actions

Nigel J. Dagenais, B.Sc.(Pharm.); Fakhreddin Jamali, Ph.D.

Disclosures

Pharmacotherapy. 2005;25(9):1213-1229. 

In This Article

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

Clinically, interruption of angiotensin II activity can be achieved by using ACE inhibitors or ARBs. The ACE inhibitors act by inhibiting ACE that catalyzes the conversion of inactive angiotensin I to the active angiotensin II. The ARBs act by antagonizing the AT1 receptor. Both the ACE inhibitors and the ARBs have shown significant benefit by reducing mortality in patients with heart failure,[73,74,75] preventing diabetic nephropathy,[76,77] and reducing ischemia in cardiovascular disease.[78,79]

Despite these similarities in treatment of cardiovascular disease, important pharmacologic differences between the two drug classes may have clinical implications. Therapy with ACE inhibitors potentiates bradykinin half-life, since ACE is also involved in bradykinin breakdown.[80] In fact, ACE demonstrates a higher affinity for bradykinin than for angiotensin I, and therefore essentially acts as a kininase rather than an angiotensinase.[81] On the other hand, the ARBs do not affect ACE and therefore are not thought to elevate bradykinin concentrations.

The pharmacologic effects of bradykinin accumulation with ACE inhibitor therapy are multifarious. Most important, bradykinin is an important mediator in inducing endothelial nitric oxide production, resulting in vasorelaxation and reduced NF-κ B activity.[36,82] This induction of endothelial nitric oxide production is thought to orchestrate some of the antihypertensive effects of ACE inhibitor therapy. Furthermore, potentiation of nitric oxide release is also considered one of the mechanisms of bradykinin-induced cardioprotection after ischemia.[81] Other relevant bradykinin effects are the production of prostaglandins—most notably prostacyclin, which acts as a vasodilator and inhibitor of platelet aggregation[83]—and the release of tissue-type plasminogen activator, which acts as a fibrinolytic agent for the dissolution of clots.[84] Hence, elevated bradykinin concentrations may account for much of the benefit of ACE inhibitors in patients with cardiovascular disease.

Accumulation of bradykinin by antagonizing ACE is also thought to be responsible for many of the adverse effects of ACE inhibitors. Specifically, development of a persistent dry cough in patients receiving ACE inhibitor treatment is thought to be due primarily to bradykinin or substance P potentiation; the latter also is metabolized by ACE. All ACE inhibitors can cause varying degrees of cough, which is essentially a drug-class effect.[85] In addition, angioedema—a rare, potentially life-threatening condition due to localized edema of the skin—may also occur in approximately 0.1-0.5% of patients receiving ACE inhibitor therapy.[86] Bradykinin has also been implicated as the primary cause of angioedema development through direct action on cutaneous blood vessels, the mechanism of which, however, remains unknown.[85] Furthermore, ACE inhibitor therapy can result in induction or exacerbation of psoriasis, probably due to elevated bradykinin concentrations.[87]

Pharmacologically, ARB therapy can be considered quite distinct from ACE inhibitor treatment. First, ARBs leave the angiotensin II type 2 (AT2) receptor unopposed. The role of AT2 activation is still somewhat unclear. Some researchers believe that stimulation of the AT2 receptor has the opposite effect of that of the AT1 receptor to antiinflammatory activity.[88] For example, AT2 stimulation can increase endothelial nitric oxide production.[89]

Second, angiotensin II can be produced from pathways other than ACE. The most important alternative pathway is chymase, a tissue-specific enzyme originally discovered in mast cells that can make angiotensin II independent of ACE. Although the importance of these alternative pathways is still controversial, some researchers recognize that chymase is the major route of angiotensin II synthesis in tissues and may be more important in the pathogenesis of cardiovascular disease than previously thought.[90] Thus, ACE inhibitor therapy may only partially inhibit angiotensin II activity, whereas ARB treatment prevents its activity without regard to its origin.

Furthermore, ACE inhibitors induce a negative feedback pathway on ACE, resulting in increased ACE in circulation beyond the ability of therapeutic dosages of ACE inhibitors to prevent angiotensin II formation.[91] Since ARBs exert their effect on the AT1 receptor only, increased ACE has less impact on its therapeutic efficacy. In addition, ARB therapy may also induce antiinflammatory mechanisms through increased AT2 stimulation. However, many proponents of ACE inhibitors over ARBs argue that the benefits of bradykinin potentiation are blunted with ARB therapy. Nevertheless, increasing evidence indicates that ARBs also elevate bradykinin.

Although the ARB losartan was previously reported not to influence bradykinin concentrations,[92] more recent data concerning ARBs suggest elevated bradykinin action, possibly by AT2 stimulation[93] or ACE inhibition.[94] Recent data demonstrated that losartan significantly increased bradykinin concentrations (by approximately 2-fold) in patients with hypertension, similar to the increase reported for ACE inhibitors.[94] The authors also used the ARB eprosartan. Although the effect did not reach statistical significance, a trend was observed toward elevated bradykinin concentrations. The authors thought the effect of ARBs on potentiating bradykinin was a class effect, which they attributed to reduced bradykinin breakdown, possibly through ACE inhibition. This may explain some of the benefit for patients with cardiovascular disease; however, further study is required.

Many of the adverse effects of ACE inhibitors thought to be bradykinin mediated also occur in patients receiving ARB therapy. For example, angioedema has been reported with increasing frequency with many of the ARBs,[95,96,97,98] albeit with less frequency than reported with ACE inhibitors. Thus, clinicians now recommend caution when treatment is changed to an ARB after a patient experiences ACE inhibitor-induced angioedema because a significant portion of patients also develop angioedema with ARB therapy.[99] In addition, a rare case of pustular psoriasis was reported associated with candesartan, an ARB thought to be bradykinin mediated.[100] On the other hand, the frequency of cough is significantly less with ARB than ACE inhibitor therapy, suggesting reduced bradykinin or substance P activity.[85] Nevertheless, most experimental evidence suggests that ARBs are involved in increasing bradykinin actions and that combination therapy with ACE inhibitors and ARBs has synergistic effects.[101]

An additional pharmacologic aspect of both classes of angiotensin II disruption is inhibition of aldosterone secretion, resulting in reduced sodium, water retention and, subsequently, blood pressure. However, important evidence indicates that aldosterone secretion can be elevated independent of angiotensin II by means of a phenomenon referred to as aldosterone "escape."[102,103] Aldosterone antagonists, such as spironolactone, have improved morbidity and mortality in patients with heart failure already treated with an ACE inhibitor.[104] Thus, aldosterone antagonists have a complementary benefit in angiotensin II disruption.

In summary, ACE inhibitors and ARBs have many pharmacologic similarities, but with important pharmacologic differences. Whether these two drug classes are distinctly different forms of pharmacotherapy is still hotly debated; however, both classes have shown various antiinflammatory actions and are similar at least in that regard.

Cardiovascular Disease. The Heart Outcomes Prevention Evaluation (HOPE) trial[78] was the first major randomized, prospective study to demonstrate that patients treated with the ACE inhibitor ramipril had a 22% reduction in cardiovascular disease morbidity and mortality compared with placebo. This reduction in cardiovascular disease end points was approximately 3 times greater than what would be expected from the minor detectable reduction in blood pressure (3.3 mm Hg systolic) observed in the ramipril-treated group. Hence, this benefit seemed to be independent of blood pressure, or some different cardioprotective mechanism. Nonetheless, a substudy of the HOPE trial demonstrated a large difference in ambulatory blood pressure (-10/4 mm Hg) between the ramipril and placebo groups.[105] This obscured the issue as to whether the apparent ramipril benefit was due to blood pressure or other effects of angiotensin II interruption.

Other authors have questioned the work of the HOPE investigators, who did not find a relationship between ramipril and blood pressure.[106] Some patients took their ramipril at bedtime, and ambulatory blood pressure was measured 12-18 hours later, long after the antihypertensive effect of ramipril had waned. However, despite some speculation over the results of the HOPE trial, separate papers reported that the benefits of ramipril were not related to reduced blood pressure.[107,108]

Moreover, the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, which compared losartan with the β-blocker atenolol, demonstrated that losartan significantly reduced the relative risk of the primary end point (myocardial infarction, death, or stroke).[109] Blood pressure reductions were almost identical in both losartan- and atenolol-treated patients (30/17 and 29/17 mm Hg, respectively). Despite controversy over the mechanism of the cardioprotective effect of angiotensin II suppression, evidence accruing from in vitro, animal, and human studies indicates that both forms of angiotensin II disruption have significant antiinflammatory actions.

In Vitro and Animal Studies. Evidence of antiinflammatory properties from in vitro and animal studies for both the ACE inhibitors and ARBs is strong. In vitro, activated leukocytes treated with the ARB valsartan have shown a 40% reduction in generation of reactive oxygen species as well as reduced NF-κ B activation.[110] Valsartan also reduced TNF-α production in a rat model of diabetes, which was correlated with a renal protective effect.[111] Similar results were demonstrated in a rat model of endotoxemia in which ARB treatment significantly decreased IL-6 and TNF-α concentrations.[112]

In spontaneously hypertensive stroke-prone rats, ARB therapy increased survival, delayed brain damage, and significantly reduced kidney expression of monocyte chemoattractant protein-1, IL-1β, and TGF-β without a significant decrease in blood pressure.[113] In addition, the ACE inhibitor enalapril attenuated atherosclerosis development in angiotensin II-infused mice.[114] In this study, the atherosclerotic lesion was reduced by approximately 50% in the enalapril-treated mice, which prevented macrophage infiltration in the vessel wall with no reduction in blood pressure. However, enalapril did not significantly reduce the rate of aneurysm.

Angiotensin II interruption has also prevented experimental myocarditis in mice, probably due to prevention of leukocyte recruitment to the injury site.[115] Moreover, adhesion molecule expression and macrophage accumulation have been reversed in hypertensive rats treated with candesartan.[116] In the animal studies in which blood pressure was measured, angiotensin II disruption was not associated with a significant fall in blood pressure.[113,114] This suggests a protective mechanism independent of the antihypertensive effect, likely the result of antiinflammatory mechanisms, as indicated by reduced proinflammatory cytokines and adhesion molecules.

Some of the most persuasive work involved a rat model of myocardial infarction in which both ACE inhibitor and ARB treatment appeared to reverse the reduced adrenergic contractility response seen in heart failure.[117] Both valsartan and the ACE inhibitor temocapril not only improved heart contractility, but also reversed the reduced β-receptor density seen after myocardial infarction. This finding is important because in several studies inflammation has resulted in reduced response to some cardiovascular drugs.[118,119,120] In fact, this reduced drug response in inflammation was seen despite significantly elevated plasma concentrations compared with controls.[118,119] Hence, it may be possible to reverse the downregulation effect of inflammation by using an ACE inhibitor or ARB. This elevated adrenergic contractility may partly explain the extended benefit observed in heart failure with angiotensin II suppression. Of note, recent data from our laboratory suggest that AT1 receptors are not downregulated in rheumatoid arthritis, but may be upregulated.[121] Thus, ACE inhibitor and ARB therapy may be useful for exploiting this possible receptor upregulation as an effective antihypertensive in rheumatic conditions like rheumatoid arthritis.

The benefit seen in cardiovascular disease from angiotensin II interruption may be due to modulation of the Th1-Th2 balance. One study reported an imbalance of T-cell subsets in angiotensin II-infused rats toward a Th1 phenotype.[122] This was accompanied by elevated IFN-γ concentrations and decreased IL-4 concentrations. Furthermore, treatment of the angiotensin II-infused rats with candesartan ameliorated kidney disease and Th1 imbalance independent of antihypertensive effects. This ability of the ARB to modulate the Th1-Th2 imbalance not only may have cardiovascular implications but may influence autoimmune diseases as well.

Human Studies. Antiinflammatory actions by ACE inhibitor or ARB therapy in animal studies have shown similar results in human trials. A clinical trial involving a small sample of patients who had undergone coronary artery bypass surgery suggested that treatment with various ACE inhibitors significantly reduced IL-6 concentrations.[123] This may explain the benefit of ACE inhibitor therapy in such patients. In addition, enalapril or losartan treatment in patients with stable angina awaiting bypass graft surgery demonstrated reduced IL-1 and IL-6 concentrations.[124] Other studies, with larger samples of patients with cardiovascular disease, have documented numerous antiinflammatory effects with angiotensin II interruption.[125,126,127] Effects noted were significant reductions in IL-6, TNF-α, platelet activator inhibitor-1, monocyte chemotactic protein-1, and oxidative stress products.

One study demonstrated a significant reduction in C-reactive protein in response to both ARB and ACE inhibitor therapy.[128] Other studies, however, have not observed this effect.[125,126] Nevertheless, none of these documented reductions in inflammatory mediators were correlated with reduced blood pressure. Moreover, in patients with newly diagnosed hypertension, eprosartan was compared with hydrochlorothiazide regarding reduction of adhesion molecules and oxidative stress products.[129] Only eprosartan significantly reduced adhesion molecule concentrations and increased the lag time of oxLDL formation after 4 weeks of treatment. Both drugs demonstrated similar reductions in blood pressure.

A prospective observational study involved 507 patients after a first stroke who were treated with ACE inhibitors or alternative antihypertensive therapy and were followed for 2 years after hospital discharge.[130] Primary outcomes were vascular mortality and subsequent nonfatal cardiovascular events. The ACE inhibitor therapy resulted in significantly reduced concentrations of C-reactive protein compared with other blood-pressure-lowering regimens. Furthermore, ACE inhibitor therapy reduced the 2-year cardiovascular risk (hazard ratio [HR] 0.39, p<0.0001) compared with other antihypertensives. This reduced risk was apparent even after multivariate analysis (HR 0.43, p<0.0001), suggesting that the benefit was independent of lowered blood pressure. Reduction in antiinflammatory markers with improved survival was correlated with angiotensin II interruption in this study.

Of note, however, most clinical trials measuring proinflammatory mediators in patients with cardiovascular disease are not randomized controlled studies. Rather, they are observational studies of short duration that focus on cytokine expression and not on clinical end points. Larger, prospective, randomized studies are needed to confirm these antiinflammatory actions in patients with cardiovascular diseases, and to confirm whether this results in reduced cardiovascular morbidity and mortality. Nevertheless, the available data are persuasive.

The ability of angiotensin II disruption to modulate the Th1-Th2 imbalance in atherosclerosis is evident from human studies. One group of investigators monitored various serum inflammatory markers in patients with hypertension after coronary angioplasty.[131] Three months of ACE inhibitor or ARB therapy resulted in significantly increased IL-10 concentrations and reduced matrix metalloproteinase protein level and activity, suggesting an elevated Th2 polarization. Similar reductions in Th1 cytokines have been noted in patients with heart failure treated with an ACE inhibitor and β-blockers.[132] Since elevated IL-10 levels have been protective after coronary syndromes,[30] this may help explain the benefit of angiotensin II disruption in cardiovascular disease.

Few studies have directly compared the antiinflammatory effects of ACE inhibitors with those of ARBs in patients with cardiovascular disease. However, most evidence tends to suggest that additional benefits may result from ARB therapy. In one recent study, irbesartan reduced serum IL-6 and C-reactive protein concentrations in patients after angioplasty, whereas no reductions in these mediators were observed with enalapril.[131] Furthermore, only irbesartan reduced platelet aggregation in these patients; enalapril had no significant effect.

In a clinical study comparing candesartan with enalapril in patients with non-insulin-dependent diabetes mellitus, candesartan was significantly more effective in reducing albuminuria.[133] Candesartan also was more effective in reducing vascular cell adhesion molecules and platelet-activator inhibitor-1, despite equal reductions in blood pressure with both drugs.

In these comparison trials, the ACE inhibitor used was enalapril, which has poor tissue penetration compared with other ACE inhibitors, such as quinapril, fosinopril, and trandolopril. In a study comparing enalapril with quinapril regarding C-reactive protein concentrations in patients after myocardial infarction, only quinapril significantly reduced C-reactive protein.[134] Thus, trials comparing ARBs and ACE inhibitors with drugs that have higher tissue penetration, such as quinapril, are needed to confirm the other results.

Another argument in favor of ARBs over ACE inhibitors is that ARB therapy is consistently associated with a significantly lower frequency of adverse effects requiring discontinuation of treatment.[135] Nevertheless, clinical trials have not demonstrated any survival advantages with ARBs over ACE inhibitors in patients with cardiovascular disease, suggesting that both offer similar benefit.[135,136,137,138]

The synergistic effects on bradykinin activity from ACE inhibitor and ARB therapy have motivated researchers to assess combination therapy in clinical trials. Whether combination therapy translates to increased cardiovascular protection is still unclear, although small human trials using combination therapy suggest some synergistic benefit. The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study demonstrated improved blood pressure control and ejection fraction with combination therapy compared with either ACE inhibitor or ARB therapy alone.[139]

The most compelling data are from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Added trial[140] and the Combination Treatment of Angiotensin-II Receptor Blocker and ACE Inhibitor in Non-Diabetic Renal Disease (COOPERATE) trial.[141] The CHARM-Added randomized trial assessed the effect of candesartan compared with placebo in patients with heart failure taking an ACE inhibitor.[140] Over 1000 patients were followed for more than 3 years; primary end points were cardiovascular death or unplanned hospital admission due to worsening heart failure. Candesartan therapy significantly reduced each primary end point and total number of hospitalizations (HR 0.85, p=0.011). This benefit was demonstrated across all subgroups, including patients taking β-blockers. However, candesartan also significantly lowered blood pressure from baseline levels compared with placebo; therefore, the antihypertensive effect may explain some of the apparent benefit.

The COOPERATE trial studied the addition of losartan in comparison with placebo in patients with nondiabetic renal disease taking the ACE inhibitor trandolapril.[141] A total of 263 patients were randomized to receive losartan alone, trandolapril alone, or a combination of the two drugs; patients were followed for 3 years. The primary end points were the time to doubling of serum creatinine level and end-stage renal disease. Only 11% of the patients receiving combination therapy reached the combined primary end points versus 23% of those receiving the monotherapy regimens (p=0.02). Systolic blood pressure levels were not significantly different among the three groups, suggesting an independent mechanism. Although combination therapy seems to provide a benefit for patients with heart failure and renal disease, whether combination treatment is beneficial for those with cardiovascular disease remains unknown.

The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)-Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) long-term trial[142] and the Valsartan in Acute Myocardial Infarction Trial (VALIANT)[143] are assessing monotherapy and combination therapy with primary end points of mortality and cardiovascular events in over 20,000 and 14,500 patients, respectively. In addition, both trials will involve substudies to determine the effects of different therapies on biologic markers, cytokine profiling, and other markers of inflammation. These studies should provide more information regarding any antiinflammatory effects of angiotensin II suppression and whether this translates to reduced cardiovascular end points.

Captopril was the first ACE inhibitor to be marketed. Its structure is distinctive in that it contains a sulfhydryl moiety (-SH group) with structural characteristics similar to those of the immunosuppressant penicillamine. This sulfhydryl group is thought to be responsible for many of the characteristic adverse effects frequently seen with captopril, such as rash, oral ulceration, taste disturbances and, more rarely, blood dyscrasias, which are seen less frequently or not at all with other ACE inhibitors.[144] This immunosuppressant structure of captopril was assessed for disease-modifying activity in an open trial involving 15 patients with rheumatoid arthritis who were followed for 48 weeks.[145] Of the 15 patients, 10 reported moderate (3 patients) to good (7 patients) improvement in all clinical symptoms. Laboratory data also supported an antiinflammatory effect, with significant reductions in C-reactive protein, serum viscosity, and immunoglobulin at 24 and 48 weeks.

To determine whether the disease-modifying activity of ACE inhibitors is a class effect, an open study was conducted using the nonthiol-ACE inhibitor pentopril.[146] This study reported a lack of efficacy in clinical symptoms with pentopril therapy; however, a significant reduction in C-reactive protein was noted at 16 weeks. A lack of clinical effect with pentopril led the authors to conclude that captopril is unique in its disease-modifying effect, possibly due to the thiol group.[144,146] However, the pentopril study[146] may have been inadequately powered to detect significant differences due to its small sample size.

Animal data suggest that clinical trials with nonthiol ACE inhibitors for patients with rheumatoid arthritis should be revisited. The most compelling data yet to establish the antiinflammatory actions of angiotensin II interruption were reported in a study using a murine model of rheumatoid arthritis termed collagen-induced arthritis.[147] Quinapril 10 mg/kg/day was administered to assess disease progression and production of TNF-α, as compared with placebo. Of interest, quinapril given as prophylactic therapy from the start of arthritis induction and as treatment at the onset of mild arthritis diminished the arthritic index significantly compared with placebo. In the prophylactic protocol, quinapril-treated mice had a median maximal paw arthritis score of 3, compared with 10 in the control group. Quinapril reduced both the number of paws affected and the maximum individual paw score. Similar results were noted in the treatment protocol group after the onset of arthritis.

Histologic examination of the paws confirmed the clinical data; the quinapril-treated mice demonstrated reduced inflammatory infiltrate, bone erosion, and cartilage damage. Furthermore, quinapril suppressed serum collagen-induced antibody production and paw TNF-α concentration, suggesting an antiinflammatory action. Parallel results were demonstrated with candesartan in this study to confirm these effects through angiotensin II suppression, rather than other effects of ACE inhibition. Hence, ACE inhibitor or ARB therapy may represent a disease-modifying treatment for patients with rheumatoid arthritis or other inflammatory conditions.

Asthma. Extending angiotensin II interruption to other inflammatory diseases, such as asthma, may have promise. Treatment with ARBs has reduced antigen-induced bronchoconstriction reactions and eosinophil accumulation in guinea pig airway.[148] Accordingly, two studies demonstrated that ARB therapy in patients with asthma can increase geometric mean values of forced expiratory volume in the presence of the bronchoconstricting agent methacholine, suggesting improved airway dilation.[149,150] Although the ARB-treated patients in these studies had slight reductions in blood pressure, there was no correlation with the antihypertensive effect and improvement in forced expiratory volume. In addition to improved airway dilation, airway remodeling can be prevented, as demonstrated with valsartan in a rat model of asthma.[151] Therefore, angiotensin II suppression may represent a novel adjunctive therapy for asthmatic patients.

Fibrosis. Much of the benefit provided by ACE inhibitors and ARBs in reducing mortality in patients with heart failure is thought to be due to reduced production of TGF-β, a critical messenger involved in progressive myocardial hypertrophy and collagen disposition after infarction.[17,152] Both ACE inhibitors and ARBs have suppressed pancreatitis and fibrosis in rats by reducing TGF-β production.[153,154] In addition, ARBs can significantly reduce formation of gastric ulcers in rat models,[155,156] as well as bleomycin-induced lung fibrosis[157] and doxorubicin-induced cardiomyopathy.[158] This indicates that angiotensin II blockade may be useful in preventing drug-related adverse effects, such as gastric ulcers induced by nonsteroidal antiinflammatory drugs. Similar reductions in fibrosis and collagen disposition were shown in a rat model of liver fibrosis treated with an ARB. This was correlated with reductions in TGF-β and connective tissue growth factor.[159] Furthermore, angiotensin II interruption can attenuate liver fibrosis in vivo with no antihypertensive effect.[160]

Clinically, these actions may help explain the benefit of ARB treatment in patients with hepatitis C early in the course of the disease.[161] In addition, a 50% reduction in TGF-β has been demonstrated in renal transplant recipients treated with an ACE inhibitor or ARB. This finding is relevant because elevated TGF-β is thought to be critical in the development of chronic allograft nephropathy.[162] Thus, angiotensin II disruption may be a valuable adjunctive therapy in organ transplant recipients and patients with other fibrotic conditions.

Cancer. Angiotensin II interruption may extend to antitumor effects. The ability of angiotensin II to induce cell proliferation in numerous tissues may explain its role in tumor growth. For example, in vitro studies have shown that ARB therapy reduces oncogenic proliferation and metastasis in oncogenic cell lines.[163] In addition, a synergistic effect was reported with cyclooxygenase inhibition and ARB treatment in reducing tumor growth in a mouse model of colon cancer.[164] Regarding angiogenesis, angiotensin II disruption seems to consistently inhibit vessel growth and therefore prevent tumor spread in cancer models.[165,166]

However, this effect has been inconsistent in cardiovascular and other models.[59] The reason for the inconsistency is unclear, but it may be due to specific cell signaling present in oncogenic cells and absent in healthy cells. Furthermore, oncogenesis has been linked to reactive oxygen species generation and chronic inflammation,[167] which suggests that angiotensin II interruption may play a role in cancer treatment and prevention.

A few clinical studies suggest this may be the case.[168,169] A retrospective cohort study of nearly 5000 patients with hypertension in Scotland compared ACE inhibitors with other antihypertensive agents. The ACE inhibitor therapy resulted in significantly less relative risk (RR) of cancer (RR 0.72, 95% confidence interval [CI] 0.55-0.92) and cancer fatality (RR 0.65, 95% CI 0.44-0.93) than other antihypertensive agents (RR 1.1).[168] The greatest benefit of ACE inhibitor therapy regarding cancer prevention in this cohort was seen at follow-up 3 or more years later, which suggests a long-term effect.

Furthermore, in a case report of a patient who developed Kaposi's sarcoma after kidney transplantation, the sarcoma was resistant to radiotherapy and chemotherapy but responded to captopril treatment.[169] The result was more than 50% and 25%, respectively, of total and partial remission of the patient's lesions. The effect of captopril was attributed to the inhibition of angiogenesis. Nevertheless, despite retrospective evidence and an isolated case report, randomized prospective trials are needed to confirm the anticancer effects of ACE inhibitors and ARBs.

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