The Pleiotropic Effects of Angiotensin Receptor Blockers

Abstract

The angiotensin receptor blockers (ARBs) are very effective and safe antihypertensive drugs. They exert their antihypertensive effect through blockage of the angiotensin II, type 1 receptor and quite possibly through stimulation by angiotensin II of the unoccupied type 2 receptor. Besides hypertension, the ARBs have been found recently to be of value in the treatment of heart failure and diabetic nephropathy. In addition, ARBs have emerged lately as being very effective and perhaps superior to other antihypertensive drugs in the prevention of de novo or recurrent strokes. Other actions that may account for their stroke‐protective effects include their antiatherogenic, antidiabetic, antiplatelet aggregating, hypouricemic, and atrial antifibrillatory actions. All these actions make the ARBs a true pleiotropic class of drugs. Each of the foregoing effects will be discussed briefly in this concise review.

The angiotensin receptor blockers (ARBs) were originally approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and although they were very effective and safe drugs, they were used initially as alternatives to angiotensin‐converting enzyme (ACE) inhibitors for patients intolerant to ACE inhibitors. As more experience has been gained with their use, ¹ , ² , ³ , ⁴ , ⁵ however, ARBs are now used as initial therapy for the treatment of hypertension. Recent studies have also shown that ARBs are quite effective for the treatment of heart failure (HF) ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² and nephropathy in patients with or without diabetes mellitus. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ Another significant benefit that has emerged from large clinical outcomes trials in hypertensive patients treated with ARBs is protection from new or recurrent stroke. ⁴ , ²⁰ , ²¹ , ²² , ²³ The findings from these trials are summarized in the Table, and will be discussed separately in this concise review. In addition, certain unique effects of ARBs, such as their antiatherogenic, antioxidant, antidiabetic, hypouricemic, antiplatelet aggregating, and atrial antifibrillatory actions will be presented, which will show that ARBs are truly a pleiotropic class of drugs.

ANTIHYPERTENSIVE EFFECTS OF ARBS

The ARBs exert their antihypertensive effects by interfering with the action of angiotensin II (Ang‐II) through selective blockade of the type 1 receptor (AT₁R) and, quite possibly, through stimulation by Ang‐II of the unoccupied type 2 receptor (AT₂R). The site of action of the ARBs together with the pathways of Ang‐II generation are depicted in the Figure. The figure shows that Ang‐II is produced by the classic pathway through the action of ACE, as well as by alternate pathways through the action of other enzymes and, especially, chymase. ² Several studies have shown that this pathway is quite important, since up to 40% of tissue Ang‐II in the blood vessels, heart, and kidneys is produced by chymase. ²⁴ , ²⁵ , ²⁶ The action of the chymase‐generated Ang‐II cannot be blocked by ACE inhibitors, but it can be blocked by ARBs, since their action is independent of the pathway by which Ang‐II is produced. Based on this mechanism of action, theoretically, the ARBs should be superior to ACE inhibitors with respect to blood pressure (BP) reduction, but this theoretic advantage has not materialized clinically. The ARBs are superior to ACE inhibitors, however, regarding their better tolerance and safety with respect to cough and the incidence of angioedema. ¹ , ² , ³ The antihypertensive action of ARBs, like that of the ACE inhibitors, is greatly enhanced by their combination with a low‐dose diuretic. ¹ , ² , ³ In addition, ARBs have been shown by several clinical trials to exert a beneficial effect, which is beyond BP control, when compared with other antihypertensive drugs. This additional benefit has been attributed to their blocking the action of Ang‐II. ²⁷ In the Losartan Intervention for End Point Reduction (LIFE) study, ⁴ losartan produced greater regression of left ventricular hypertrophy (LVH) than did atenolol for the same reduction of BP. Similar results were shown in the Swedish Irbesartan Left Ventricular Hypertrophy Investigation Versus Atenolol (SILVHIA) study, ²⁸ where the LVH regression was greater with irbesartan than atenolol for the same reduction of BP. In contrast, the Candesartan Assessment in the Treatment of Cardiac Hypertrophy (CATCH) study ²⁹ did not show any difference in LVH regression by either candesartan or enalapril, since both drugs block the action of Ang‐II.

CARDIOPROTECTIVE EFFECTS OF ARBS

Several randomized, multicenter, clinical outcomes studies have shown that ARBs alone or in combination with ACE inhibitors are effective in improving the lifestyles of patients with cardiovascular (CV) disease and HF when added to background therapy. In the Evaluation of Losartan in the Elderly (ELITE II) study, ⁶ losartan was as effective as captopril in improving the symptoms of HF, but showed no difference from captopril in all‐cause mortality. Similar results were reported from the Optimal Trial in Myocardial Infarction With Angiotensin II Antagonist Losartan (OPTIMAAL) study, ⁹ which also compared losartan with captopril. Both studies have been criticized for underdosing the patients with losartan compared with captopril. Possibly, this question will be answered by the ongoing Heart Failure Endpoint Evaluation with Angiotensin II Antagonist Losartan (HEAAL). This study compares losartan 50 mg vs. 150 mg/d in patients with HF intolerant to ACE inhibitors. The Valsartan Heart Failure Trial (Val‐HeFT) ⁷ compared valsartan vs. placebo in patients with HF and a background therapy of ACE inhibitors for most patients. Valsartan lowered the combined mortality and morbidity by 13.2% compared with placebo, but there was no difference in overall mortality between the two groups. Similar results to those of Val‐HeFT were reported by the Candesartan in Heart Failure Assessment Reduction in Mortality and Morbidity (CHARM‐Added) trial, ¹⁰ which compared candesartan vs. placebo on a background of ACE inhibitors. The CHARM‐Alternative trial ¹¹ compared candesartan vs. placebo in patients with HF intolerant of ACE inhibitors. In this study, candesartan significantly reduced CV mortality and morbidity compared with placebo. In a similar substudy of Val‐HeFT, valsartan improved the structure and hemodynamic function of the heart compared with placebo. ⁸ The Valsartan in Acute Myocardial Infarction (VALIANT) study ¹² compared different doses of valsartan alone, captopril alone, and their combination in post‐myocardial infarction (MI) patients with left ventricular systolic dysfunction, HF, or both. There was no difference among the three groups in overall CV mortality, recurrent MI, or hospitalization for HF, although the combination group had the most drug‐related adverse events. All these studies failed to show superiority of ARBs over the ACE inhibitors and, for the time being, ACE inhibitors are still recommended as initial therapy in such patients, with ARBs recommended only for patients intolerant to ACE inhibitors.

RENOPROTECTIVE EFFECTS OF ARBS

Another group of patients who benefit from treatment with ARBs is hypertensive patients with diabetic nephropathy. In the Irbesartan in Diabetic Nephropathy Trial (IDNT), ¹³ irbesartan reduced urinary protein excretion, doubling of serum creatinine, end‐stage renal disease, and death compared with patients treated with amlodipine or placebo. In the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study, ¹⁴ which was similar to IDNT, losartan decreased the doubling of serum creatine, urinary protein excretion, and end‐stage renal disease compared with placebo but had no effect on all‐cause mortality. In another study of hypertensive patients with type‐2 diabetes mellitus and microalbuminuria (Irbesartan Microalbuminuria Type 2 Diabetes in hypertensive patients [IRMA‐2]), ¹⁵ irbesartan reduced urinary protein excretion and prevented the patients from developing diabetic nephropathy more than did placebo, and this effect was independent of BP control. In the Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study, ¹⁶ the renoprotective and antiproteinuric effects of telmisartan and enalapril were very similar in hypertensive type 2 diabetic patients. The renoprotective and antiproteinuric effects of ACE inhibitors and ARBs have also been tested in nondiabetic patients with renal failure and proteinuria. In the COOPERATE study, ¹⁷ the antiproteinuric effects of losartan and trandolapril were very similar, but their combination exerted much greater antiproteinuric effects. In contrast, the BP‐lowering effects were identical among the three treatment groups. Similar findings have been reported by other investigators. ¹⁸ In the ACE Inhibition in Progressive Renal Insufficiency (AIPRI) study, ¹⁹ which was similar to COOPERATE, treatment with benazepril resulted in a significant decrease of progression to end‐stage renal disease and of proteinuria compared with placebo. Based on these and similar findings, ARBs or ACEIs should be recommended as initial therapy for such patients. Their combination for the treatment of hypertension, however, is indicated only in the presence of proteinuria. ¹⁸

STROKE‐PROTECTIVE EFFECTS OF ARBS

Recent multicenter, randomized, clinical outcomes trials have shown that ARBs are emerging as superior drugs for stroke prevention in high‐risk hypertensive patients compared with other antihypertensive drugs. ³⁰ In the LIFE study, ⁴ for the same reduction of BP, losartan decreased the incidence of stroke by 25% compared with atenolol. In a sub‐study ²⁰ of the LIFE trial in patients with isolated systolic hypertension, stroke reduction was 40% in the losartan treatment group compared with the atenolol treatment group. Similar results were reported by the Study on Cognition and Prognosis in the Elderly (SCOPE), ²¹ where in elderly hypertensive patients treated with candesartan vs. conventional drugs, the stroke reduction was 23.4% in the candesartan‐treated group. The percentage of stroke reduction increased to 40% in a substudy of elderly patients with isolated systolic hypertension treated with candesartan vs. conventional drugs. ²² The recently published Morbidity and Mortality After Stroke—Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) trial ²³ showed a 25% reduction of recurrent stroke in hypertensive patients with previous stroke treated with eprosartan vs. nitrendipine for the same decrease in BP. In the Valsartan Antihypertensive Long‐term Use Evaluation (VALUE) study ⁵ of high‐risk hypertensive patients, the incidence of stroke was higher in the valsartan‐treated patients compared with amlodipine‐treated patients in the early phase of the study, and this difference was attributed to the poor BP control by valsartan. As the study progressed and the BP difference was narrowed, the stroke incidence was decreased, and by the end of the study it was 25% lower in the valsartan‐treated group, although the systolic BP was 1.7 mm Hg higher in this group. The overall stroke incidence at the end of the study was, however, 15% higher in the valsartan‐treated group, most likely due to the lag in early BP reduction.

These superior stroke‐protective effects of ARBs have been attributed to the simultaneous blockade of the AT₁R and stimulation of the unoccupied AT₂R by Ang‐II. This dual action of ARBs decreases the local vasoconstriction mediated by the AT₁R and increases local vasodilation and blood flow to the ischemic brain area, through stimulation of AT₂R. Several animal studies have shown strong support for this concept. ³¹ , ³² Additional studies have provided evidence that the AT₂Rs are up‐regulated in the ischemic areas of the brain ³³ and that treatment with ARBs up‐regulates these receptors. ³⁴ Although there is no controversy with the finding of the stroke‐protective effects of ARBs, there is some controversy regarding their CV protective effects. A recent editorial has questioned their protective action on the CV system, suggesting that long‐term treatment with ARBs for high‐risk patients increases the incidence of MI. ³⁵ This editorial created a great controversy among physicians and anxiety among patients and prompted some scientists to review the various actions of AT₂R. ³⁶ Both AT₁R and AT₂R belong to the superfamily of G‐protein‐coupled receptors and have different signaling pathways with opposite functions. The AT₁R is ubiquitously expressed in the adult, whereas the AT₂R is a fetal receptor and its expression decreases markedly after birth, remaining in small concentrations in the CV and renal tissues, but its expression is increased with tissue injury. ³⁶ Most of the experimental and clinical evidence indicates that the AT₂Rs have vasodilatory, vascular antiremodeling, and antigrowth effects. Some recent animal studies, however, indicate that overstimulation of AT₂R leads to CV hypertrophy, impairment of neoangiogenesis, and worsening of local ischemia, which may lead to MI. ³⁶

The findings of these experimental studies are in contrast to the clinical studies, which have shown that treatment with ARBs decreases LVH, slows deterioration of renal function, and decreases CV and stroke mortality. In addition, a recent systematic review of 19 clinical trials involving 31,569 high‐risk patients did not find any increased CV mortality in these patients after long‐term treatment with either ACE inhibitors, ARBs, or their combination. ³⁶

Antiatherogenic Effects

Recent studies have shown that up to 40% of Ang‐II in human blood vessels is generated by chymase—and more so in the atherosclerotic blood vessels. ²⁴ , ²⁵ The generation of this tissue Ang‐II was blocked by only 10% by the ACE inhibitor lisinopril and by 90% from chymostatin and a‐antitrypsin, enzymes that inactivate the action of chymase. ²⁴ Other studies have also shown that Ang‐II increases the expression of a lectin‐like receptor in human endothelial cells, the LOX‐1 receptor, that binds to oxidized low‐density lipoprotein and is responsible for its transfer and deposition in the vessel wall, ³⁸ and that the expression of this receptor was significantly suppressed with the administration of losartan. The suppression of generation of tissue Ang‐II and, consequently, the decrease in the expression of LOX‐1, could have accounted for the decrease by olmesartan of atherosclerotic plaque formation in monkeys fed high‐cholesterol diets. ³⁹ In addition, the reduction of inflammatory and growth factors could have played a role.

Antioxidant Effects

Ang‐II increases nicotinamide adenine dinucleotide phosphate oxidase activity, via the AT₁Rs, which, in turn, increases the production of reactive oxygen species (ROS). Ang‐II, in combination with ROS, leads to endothelial cell dysfunction and endothelial cell apoptosis in the CV tissues through inhibition of the antiapoptotic effects of protein Bcl‐2. ⁴⁰ The Bcl‐2 protein is also inhibited through a complex mechanism of inactivation of the extracellular signal‐regulated kinase and up‐regulation of the mitogen‐ activated protein kinase phosphatase 3, which decreases the action of the antiapoptopic protein Bcl‐2. ⁴⁰ Experimental studies in both animals and humans have demonstrated that the ACE inhibitors and ARBs possess antioxidant effects ⁴¹ , ⁴² through their action on the AT₁R and AT₂R. ROS have been implicated in the development and progression of atherosclerosis, diabetic nephropathy, endothelial cell dysfunction, and microvascular permeability. Superoxide anion is the most potent member of ROS and is inactivated by superoxide dismutase, and both ACE inhibitors and ARBs have been shown to stimulate superoxide dismutase. ⁴³ It is, therefore, quite possible that the beneficial effects of ACE inhibitors and ARBs on CV remodeling, LVH regression, HF, CV mortality, renal disease progression, and stroke prevention could be due in part to their antioxidant effects.

Antidiabetic Effects

Like ACE inhibitors, ARBs exert favorable effects on glucose metabolism and prevent new‐onset diabetes mellitus. ⁴ , ⁵ The antidiabetic effects of ARBs are very important because diabetes mellitus increases the CV and stroke consequences of hypertension. ⁴⁴ , ⁴⁵ The beneficial effects of ARBs on glucose metabolism and prevention of new‐onset diabetes mellitus have been attributed to their blockade of Ang‐II action, since Ang‐II impairs glucose metabolism through its adverse effects on insulin signaling pathways, tissue blood flow, oxidative stress, sympathetic activity, and adipogenesis. ⁴⁶ Certain ARBs, however, like irbesartan, telmisartan, and to a lesser extent losartan, increase insulin sensitivity independently of the renin–angiotensin system by stimulating the transcriptional activity of peroxisome proliferator‐activated receptor γ, which plays an important role in the regulation of insulin sensitivity. ⁴⁷ , ⁴⁸ Additionally, the molecule of certain ARBs, like telmisartan, has been shown to have a structural similarity with the molecule of pioglitazone, a ligand of peroxisome proliferator‐activated receptor γ, which stimulates insulin sensitivity and has been approved by the FDA for the treatment of diabetes mellitus. In studies in rats fed a high‐carbohydrate, high‐fat diet, telmisartan given in doses similar to those used for the treatment of hypertension reduced serum levels of glucose, insulin, and triglycerides. ⁴⁸

Antiplatelet Effects

ARBs have been shown to possess antiplatelet aggregating effects. Activation of platelets within the arterial lumen releases several substances including adenosine diphosphate, serotonin, thromboxane A₂, and P‐selectin, which all cause platelet aggregation. Recent experimental studies have shown that losartan interacts with the thromboxane A₂/prostaglandin H₂ receptor in human platelets and inhibits platelet activation by the thromboxane A₂ agonist UA46619 in a dose‐dependent manner. ⁴⁹ Losartan also blocks the action of P‐selectin on platelet adhesion. Treatment with losartan of platelets from spontaneously hypertensive stroke‐prone rats decreased their adhesiveness to surfaces, in comparison with candesartan and valsartan, which had a weaker effect on platelet adhesiveness. ⁵⁰ P‐selectin is an adhesion protein that is stored in the α granules of platelets, and platelets from such rats have a higher expression of p‐selectin and a higher ability to adhere to synthetic and endothelial surfaces than platelets from normotensive Wistar‐Kyoto rats. This is, perhaps, the reason for the increased thrombogenicity and the higher incidence of strokes seen in these animals. ⁵¹

Hypouricemic Effects

The role of uric acid as a risk factor for CV diseases and strokes has been widely debated over the years. Recent studies, however, have provided fresh evidence that high serum uric acid levels could be related to the higher incidence of hypertension, CV diseases, and stroke. ⁵² , ⁵³ , ⁵⁴ Although the mechanism by which uric acid exerts its pathogenetic effect is not clear, high uric acid levels have been shown to induce inflammation, endothelial dysfunction, and platelet adhesion and aggregation. ⁵⁵ , ⁵⁶ It is, therefore, conceivable that drugs like losartan which lower uric acid levels could decrease the incidence of these complications. In fact, the results of the LIFE study showed that the baseline uric acid level was significantly associated with the incidence of CV complications and strokes, especially in women, and that its lowering with losartan accounted for a 29% stroke reduction compared with atenolol. ⁵⁷

Atrial Antifibrillatory Effects

Several recent studies have demonstrated that ARBs decrease the recurrence of atrial fibrillation (AF) or prevent the new onset of AF. ⁵⁸ , ⁵⁹ In a prospective randomized study, ⁵⁸ 79 patients with chronic AF, after conversion to sinus rhythm, were treated with irbesartan 150–300 mg/d in combination with amiodarone 400 mg/d and compared with 75 similar patients treated with amiodarone 400 mg/d. After a median observation period of 254 days, 79.5% of patients treated with the combination regimen and 55.9% of those treated with amiodarone alone remained in sinus rhythm (p=0.007). In a subanalysis of the LIFE study, ⁵⁹ 8851 patients of 9193 with hypertension and LVH did not have AF at baseline. After a follow‐up of 4.8±1 years, 150 patients of 4298 randomized to the losartan treatment group developed new‐onset AF vs. 221 of 4182 patients randomized to the atenolol treatment group (p=0.001). The preventive effects of losartan on new‐onset AF have been attributed by the investigators to structural remodeling of the atria. Support for this concept has been provided from experimental studies in dogs, where the administration of another ARB, candesartan, shortened the duration of experimentally induced AF and, in addition, reduced the interstitial fibrosis of the atria compared with the control group (p<0.001). These positive effects of candesartan were attributed to its prevention of atrial remodeling. ⁶⁰

SUMMARY

In this concise review, clinical and experimental evidence was presented attesting to the pleiotropic effects of ARBs. These drugs, besides being effective and safe antihypertensive agents, have shown clinical usefulness for the treatment of HF and diabetic nephropathy in patients with high CV risk. One other significant action of these drugs, which is becoming increasingly evident, is their protection against de novo or recurrent stroke. In this respect, they appear to be unique drugs, because their stroke‐protective effect is the result of a dual action of blockade of the AT₁R and simultaneous stimulation of AT₂R, thus decreasing local vasoconstriction and increasing local vasodilation. This action prevents the extension of brain damage and hastens recovery. This unique action can be exerted only by ARBs, and in this respect ARBs are emerging as superior to other antihypertensive drugs, including ACE inhibitors. AT₂R plays a key role in stroke protection and lately has come of age as a significant mediator to the pleiotropic action of ARBs. The other ancillary actions of ARBs with respect to atherosclerosis, oxidative stress, new‐onset diabetes mellitus, platelet aggregation, and new‐onset or recurrent AF are also clinically important and quite possibly add to their cardioprotective, renoprotective, and stroke‐protective effects.