Renin and Angiotensin: Introduction

Renin and Angiotensin: Introduction The renin–angiotensin system (RAS) participates significantly in the pathophysiology of hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy. This realization has led to a thorough exploration of the RAS and the development of new approaches for inhibiting its actions. This chapter discusses the biochemistry, molecular and cellular biology, and physiology of the RAS; the pharmacology of drugs that interrupt the RAS; and the clinical utility of inhibitors of the RAS. Therapeutic applications of drugs covered in this chapter are also discussed in Chapters 27 and 28.

The Renin–Angiotensin System History In 1898, Tiegerstedt and Bergman found that crude saline extracts of the kidney contained a pressor substance that they named renin. In 1934, Goldblatt and his colleagues demonstrated that constriction of the renal arteries produced persistent hypertension in dogs. In 1940, Braun-Menéndez and his colleagues in Argentina and Page and Helmer in the U.S. reported that renin was an enzyme that acted on a plasma protein substrate to catalyze the formation of the actual pressor material, a peptide, that was named hypertensin by the former group and angiotonin by the latter. These two terms persisted for nearly 20 years until it was agreed to rename the pressor substance angiotensin and to call the plasma substrate angiotensinogen. In the mid-1950s, two forms of angiotensin were recognized, a decapeptide (angiotensin I [AngI]) and an octapeptide (angiotensin II [AngII]) formed by proteolytic cleavage of AngI by an enzyme termed angiotensin-converting enzyme (ACE). The octapeptide was shown to be the more active form, and its synthesis in 1957 by Schwyzer and by Bumpus made the material available for intensive study. It was later shown that the kidneys are important for aldosterone regulation and that angiotensin potently stimulates the production of aldosterone in humans. Moreover, renin secretion increased with depletion of Na+. Thus, the RAS came to be recognized as a mechanism to stimulate aldosterone synthesis and secretion and an important homeostatic mechanism in the regulation of blood pressure and electrolyte composition. In the early 1970s, polypeptides were discovered that either inhibited the formation of AngII or blocked AngII receptors. These inhibitors revealed important physiological and pathophysiological roles for the RAS and inspired the development of a new and broadly efficacious class of antihypertensive drugs: the orally active ACE inhibitors. Studies with ACE inhibitors uncovered roles for the RAS in the pathophysiology of hypertension, heart failure, vascular disease, and renal failure. Selective and competitive antagonists of AngII receptors were developed that yielded losartan, the first orally active, highly selective, and potent nonpeptide AngII receptor antagonist. Subsequently, many other AngII receptor antagonists have been developed. Recently aliskiren, a direct renin inhibitor, was approved for antihypertensive therapy (see Chapter 27). Components of the Renin–Angiotensin System Overview AngII, the most active angiotensin peptide, is derived from angiotensinogen in two proteolytic steps. First, renin, an enzyme released from the kidneys, cleaves the decapeptide AngI from the amino terminus of angiotensinogen (renin substrate). Then, ACE removes the carboxy-terminal dipeptide of AngI to produce the octapeptide AngII. These enzymatic steps are summarized in Figure 26–1. AngII acts by binding to two heptahelical GPCRs, AT1 and AT2. Figure 26–1. Components of the RAS. The heavy arrows show the classical pathway, and the light arrows indicate alternative pathways. ACE, angiotensin-converting enzyme; Ang, angiotensin; AP, aminopeptidase; E, endopeptidases; IRAP, insulin-regulated amino peptidases; PCP, prolylcarboxylpeptidase; PRR, (pro)renin receptor. Receptors involved: AT1, AT2, Mas, AT4, and PRR. *Exposure of the active site of renin can also occur non-proteolytically; see text and Figure 26–3. The understanding of the RAS has expanded in recent years. The current view of the RAS also includes a local (tissue) RAS, alternative pathways for AngII synthesis (ACE independent), formation of other biologically active angiotensin peptides (AngIII, AngIV, Ang[1–7]), and additional angiotensin binding receptors (angiotensin subtypes 1, 2, and 4 [AT1, AT2, AT4]; Mas) that participate in cell growth differentiation, hypertrophy, inflammation, fibrosis, and apoptosis. All components of the RAS are described in detail in a later section.

Angiotensin-Converting Enzyme Inhibitors

History

In the 1960s, Ferreira and colleagues found that the venoms of pit vipers contain factors that intensify vasodilator responses to bradykinin. These bradykinin-potentiating factors are a family of peptides that inhibit kininase II, an enzyme that inactivates bradykinin. Erdös and coworkers established that ACE and kininase II are the same enzyme, which catalyzes both the synthesis of AngII and the destruction of bradykinin. Based on these findings, the nonapeptide teprotide (snake venom peptide that inhibits kininase II and ACE) was later synthesized and tested in human subjects. It lowered blood pressure in many patients with essential hypertension and exerted beneficial effects in patients with heart failure.

The orally effective ACE inhibitor captopril was developed by a rational approach that involved analysis of the inhibitory action of teprotide, inference about the action of ACE on its substrates, and analogy with carboxypeptidase A, which was known to be inhibited by D-benzylsuccinic acid. Ondetti, Cushman, and colleagues argued that inhibition of ACE might be produced by succinyl amino acids that corresponded in length to the dipeptide cleaved by ACE. This led to the synthesis of a series of carboxy alkanoyl and mercapto alkanoyl derivatives that are potent competitive inhibitors of ACE. Most active was captopril (Vane, 1999).

Pharmacological Effects in Normal Laboratory Animals and Humans

The effect of ACE inhibitors on the RAS is to inhibit the conversion of AngI to the active AngII. Inhibition of AngII production will lower blood pressure and enhance natriuresis. ACE is an enzyme with many substrates, and inhibition of ACE may also induce effects unrelated to reducing the levels of AngII. ACE inhibitors increase bradykinin levels and bradykinin stimulates prostaglandin biosynthesis; both may contribute to the pharmacological effects of ACE inhibitors. ACE inhibitors increase by 5-fold the circulating levels of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline, which may contribute to the cardioprotective effects of ACE inhibitors (Rhaleb et al., 2001). In addition, ACE inhibitors will increase renin release and the rate of formation of AngI by interfering with both short- and long-loop negative feedbacks on renin release (Figure 26–2A). Accumulating AngI is directed down alternative metabolic routes, resulting in the increased production of vasodilator peptides such as Ang(1–7). In healthy, Na⁺-replete animals and humans, a single oral dose of an ACE inhibitor has little effect on systemic blood pressure, but repeated doses over several days cause a small reduction in blood pressure. By contrast, even a single dose of these inhibitors lowers blood pressure substantially in normal subjects depleted of Na⁺ (Figure 26-7).

Clinical Pharmacology

ACE inhibitors can be classified into three broad groups based on chemical structure: (1) sulfhydryl-containing ACE inhibitors structurally related to captopril; (2) dicarboxyl-containing ACE inhibitors structurally related to enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril, trandolapril, perindopril); and (3) phosphorus-containing ACE inhibitors structurally related to fosinopril. Many ACE inhibitors are ester-containing prodrugs that are 100- 1000 times less potent but have a better oral bioavailability than the active molecules. Currently, 11 ACE inhibitors are available for clinical use in the U.S. (Figure 26–9). They differ with regard to potency, whether ACE inhibition is primarily a direct effect of the drug itself or the effect of an active metabolite, and pharmacokinetics.

With the exceptions of fosinopril and spirapril (which display balanced elimination by the liver and kidneys), ACE inhibitors are cleared predominantly by the kidneys. Impaired renal function significantly diminishes the plasma clearance of most ACE inhibitors, and dosages of these drugs should be reduced in patients with renal impairment. Elevated plasma renin activity renders patients hyperresponsive to ACE inhibitor–induced hypotension, and initial dosages of all ACE inhibitors should be reduced in patients with high plasma levels of renin (e.g., patients with heart failure and salt-depleted patients).

All ACE inhibitors block the conversion of AngI to AngII and have similar therapeutic indications, adverse-effect profiles, and contraindications. Although captopril and enalapril are indistinguishable with regard to antihypertensive efficacy and safety, the Quality-of-Life Hypertension Study Group reported that captopril may have a more favorable effect on quality of life (Testa et al., 1993). Because hypertension usually requires lifelong treatment, quality-of-life issues are an important consideration in comparing antihypertensive drugs. ACE inhibitors differ markedly in tissue distribution, and it is possible that this difference could be exploited to inhibit some local (tissue) RAS while leaving others relatively intact.

Captopril

(CAPOTEN, others). Captopril, the first ACE inhibitor to be marketed, is a potent ACE inhibitor with a K_i of 1.7 nM. It is the only ACE inhibitor approved for use in the U.S. that contains a sulfhydryl moiety. Given orally, captopril is absorbed rapidly and has a bioavailability ~75%. Bioavailability is reduced by 25-30% with food, so captopril should be given 1 hour before meals. Peak concentrations in plasma occur within an hour, and the drug is cleared rapidly with a t_1/2 ~2 hours. Most of the drug is eliminated in urine, 40-50% as captopril and the rest as captopril disulfide dimers and captopril–cysteine disulfide. The oral dose of captopril ranges from 6.25-150 mg two to three times daily, with 6.25 mg three times daily or 25 mg twice daily being appropriate for the initiation of therapy for heart failure or hypertension, respectively. Most patients should not receive daily doses in excess of 150 mg, although the maximum labeled dose for heart failure is 450 mg/day.

Enalapril

(VASOTEC, others). Enalapril maleate is a prodrug that is hydrolyzed by esterases in the liver to produce the active dicarboxylic acid, enalaprilat. Enalaprilat is a highly potent inhibitor of ACE with a K_i of 0.2 nM. Although it also contains a "proline surrogate," enalaprilat differs from captopril in that it is an analog of a tripeptide rather than of a dipeptide. Enalapril is absorbed rapidly when given orally and has an oral bioavailability of ~60% (not reduced by food). Although peak concentrations of enalapril in plasma occur within an hour, enalaprilat concentrations peak only after 3-4 hours. Enalapril has a t_1/2 ~1.3 hours, but enalaprilat, because of tight binding to ACE, has a plasma t_1/2 of ~11 hours. Nearly all the drug is eliminated by the kidneys as either intact enalapril or enalaprilat. The oral dosage of enalapril ranges from 2.5-40 mg daily (single or divided dose), with 2.5 and 5 mg daily being appropriate for the initiation of therapy for heart failure and hypertension, respectively.

Enalaprilat

(VASOTEC INJECTION, others). Enalaprilat is not absorbed orally but is available for intravenous administration when oral therapy is not appropriate. For hypertensive patients, the dosage is 0.625-1.25 mg given intravenously over 5 minutes. This dosage may be repeated every 6 hours.

ACE Inhibitors in Hypertension

Inhibition of ACE lowers systemic vascular resistance and mean, diastolic, and systolic blood pressures in various hypertensive states except when high blood pressure is due to primary aldosteronism (see Chapter 27). The initial change in blood pressure tends to be positively correlated with plasma renin activity (PRA) and AngII plasma levels prior to treatment. Some patients may show a sizable reduction in blood pressure that correlates poorly with pretreatment values of PRA. It is possible that increased local (tissue) production of AngII or increased responsiveness of tissues to normal levels of AngII makes some hypertensive patients sensitive to ACE inhibitors despite normal PRA.

The long-term fall in systemic blood pressure observed in hypertensive individuals treated with ACE inhibitors is accompanied by a leftward shift in the renal pressure–natriuresis curve (Figure 26–7) and a reduction in total peripheral resistance in which there is variable participation by different vascular beds. The kidney is a notable exception: because the renal vessels are extremely sensitive to the vasoconstrictor actions of AngII, ACE inhibitors increase renal blood flow via vasodilation of the afferent and efferent arterioles. Increased renal blood flow occurs without an increase in GFR; thus, the filtration fraction is reduced.

ACE inhibitors cause systemic arteriolar dilation and increase the compliance of large arteries, which contributes to a reduction of systolic pressure. Cardiac function in patients with uncomplicated hypertension generally is little changed, although stroke volume and cardiac output may increase slightly with sustained treatment. Baroreceptor function and cardiovascular reflexes are not compromised, and responses to postural changes and exercise are little impaired. Even when a substantial lowering of blood pressure is achieved, heart rate and concentrations of catecholamines in plasma generally increase only slightly, if at all. This perhaps reflects an alteration of baroreceptor function with increased arterial compliance and the loss of the normal tonic influence of AngII on the sympathetic nervous system.

Aldosterone secretion is reduced, but not seriously impaired, by ACE inhibitors. Aldosterone secretion is maintained at adequate levels by other steroidogenic stimuli, such as ACTH and K⁺. The activity of these secretogogues on the zona glomerulosa of the adrenal cortex requires very small trophic or permissive amounts of AngII, which always are present because ACE inhibition never is complete. Excessive retention of K⁺ is encountered in patients taking supplemental K⁺, in patients with renal impairment, or in patients taking other medications that reduce K⁺ excretion.

ACE inhibitors alone normalize blood pressure in ~50% of patients with mild to moderate hypertension. Ninety percent of patients with mild to moderate hypertension will be controlled by the combination of an ACE inhibitor and either a Ca²⁺ channel blocker, a adrenergic receptor blocker, or a diuretic. Diuretics augment the antihypertensive response to ACE inhibitors by rendering the patient's blood pressure renin dependent. Several ACE inhibitors are marketed in fixed-dose combinations with a thiazide diuretic or Ca²⁺ channel blocker for the management of hypertension

Adverse Effects of ACE Inhibitors

In general, ACE inhibitors are well tolerated. Metabolic side effects are rare during long-term therapy with ACE inhibitors. The drugs do not alter plasma concentrations of uric acid or Ca²⁺ and may improve insulin sensitivity in patients with insulin resistance and decrease cholesterol and lipoprotein (a) levels in proteinuric renal disease.

Hypotension

A steep fall in blood pressure may occur following the first dose of an ACE inhibitor in patients with elevated PRA. Care should be exercised in patients who are salt depleted, are on multiple antihypertensive drugs, or who have congestive heart failure.

Cough

In 5-20% of patients, ACE inhibitors induce a bothersome, dry cough mediated by the accumulation in the lungs of bradykinin, substance P, and/or prostaglandins. Thromboxane antagonism, aspirin, and iron supplementation reduce cough induced by ACE inhibitors. ACE dose reduction or switching to an ARB is sometimes effective. Once ACE inhibitors are stopped, the cough disappears, usually within 4 days.

Hyperkalemia

Significant K⁺ retention is rarely encountered in patients with normal renal function. However, ACE inhibitors may cause hyperkalemia in patients with renal insufficiency or diabetes or in patients taking K⁺-sparing diuretics, K⁺ supplements, receptor blockers, or NSAIDs.

Acute Renal Failure

AngII, by constricting the efferent arteriole, helps to maintain adequate glomerular filtration when renal perfusion pressure is low. Inhibition of ACE can induce acute renal insufficiency in patients with bilateral renal artery stenosis, stenosis of the artery to a single remaining kidney, heart failure, or volume depletion owing to diarrhea or diuretics.

Fetopathic Potential

The fetopathic effects may be due in part to fetal hypotension. Once pregnancy is diagnosed, it is imperative that ACE inhibitors be discontinued as soon as possible.

Skin Rash

ACE inhibitors occasionally cause a maculopapular rash that may itch, but that may resolve spontaneously or with antihistamines. Although initially attributed to the presence of the sulfhydryl group in captopril, a rash also may occur with other ACE inhibitors, albeit less frequently.

Angioedema

In 0.1-0.5% of patients, ACE inhibitors induce a rapid swelling in the nose, throat, mouth, glottis, larynx, lips, and/or tongue. Once ACE inhibitors are stopped, angioedema disappears within hours; meanwhile, the patient's airway should be protected, and if necessary, epinephrine, an antihistamine, and/or a glucocorticoid should be administered. African-Americans have a 4.5 times greater risk of ACE inhibitor–induced angioedema than Caucasians (Brown et al., 1996). Although rare, angioedema of the intestine (visceral angioedema) characterized by emesis, watery diarrhea, and abdominal pain also has been reported.

Other Side Effects

Extremely rare but reversible side effects include dysgeusia (an alteration in or loss of taste), neutropenia (symptoms include sore throat and fever), glycosuria (spillage of glucose into the urine in the absence of hyperglycemia), and hepatotoxicity.

Drug Interactions

Antacids may reduce the bioavailability of ACE inhibitors; capsaicin may worsen ACE inhibitor–induced cough; NSAIDs, including aspirin, may reduce the antihypertensive response to ACE inhibitors; and K⁺-sparing diuretics and K⁺ supplements may exacerbate ACE inhibitor–induced hyperkalemia. ACE inhibitors may increase plasma levels of digoxin and lithium and may increase hypersensitivity reactions to allopurinol.

Non-Peptide Angiotensin II Receptor Antagonists

History

Attempts to develop therapeutically useful AngII receptor antagonists date to the early 1970s, and these initial endeavors concentrated on angiotensin peptide analog. Saralasin, 1-sarcosine, 8-isoleucine AngII, and other 8-substituted angiotensins were potent AngII receptor antagonists but were of no clinical value because of lack of oral bioavailability and unacceptable partial agonist activity.

A breakthrough came in the early 1980s with the synthesis and testing of a series of imidazole-5-acetic acid derivatives that attenuated pressor responses to AngII in rats. Two compounds, S-8307 and S-8308, were found to be highly specific, albeit very weak, non-peptide AngII receptor antagonists that were devoid of partial agonist activity. Through a series of stepwise modifications, the orally active, potent, and selective non-peptide AT₁ receptor antagonist losartan was developed (Timmermans et al., 1993) and approved for clinical use in the U.S. in 1995. Since then, six additional AT₁ receptor antagonists (Figure 26–10) have been approved. Although these AT₁ receptor antagonists are devoid of partial agonist activity, structural modifications as minor as a methyl group can transform a potent antagonist into an agonist (Perlman et al., 1997).

Pharmacological Effects

The AngII receptor blockers bind to the AT₁ receptor with high affinity and are more than 10,000-fold selective for the AT₁ receptor over the AT₂ receptor. The rank-order affinity of the AT₁ receptor for ARBs is candesartan = olmesartan > irbesartan = eprosartan > telmisartan = valsartan = EXP 3174 (the active metabolite of losartan) > losartan. Although binding of ARBs to the AT₁ receptor is competitive, the inhibition by ARBs of biological responses to AngII often is insurmountable (the maximal response to AngII cannot be restored in the presence of the ARB regardless of the concentration of AngII added to the experimental preparation).

The mechanism of insurmountable antagonism by ARBs may be due to slow dissociation kinetics of the compounds from the AT₁ receptor; however, a number of other factors may contribute, such as ARB-induced receptor internalization and alternative binding sites for ARBs on the AT₁ receptor (McConnaughey et al., 1999). Insurmountable antagonism has the theoretical advantage of sustained receptor blockade even with increased levels of endogenous ligand and with missed doses of drug. Whether this advantage translates into an enhanced clinical performance remains to be determined.

ARBs potently and selectively inhibit most of the biological effects of AngII (Timmermans et al., 1993; Csajka et al., 1997), including AngII–induced (1) contraction of vascular smooth muscle, (2) rapid pressor responses, (3) slow pressor responses, (4) thirst, (5) vasopressin release, (6) aldosterone secretion, (7) release of adrenal catecholamines, (8) enhancement of noradrenergic neurotransmission, (9) increases in sympathetic tone, (10) changes in renal function, and (11) cellular hypertrophy and hyperplasia. ARBs reduce arterial blood pressure in animals with renovascular and genetic hypertension, as well as in transgenic animals overexpressing the renin gene. ARBs, however, have little effect on arterial blood pressure in animals with low-renin hypertension (e.g., rats with hypertension induced by NaCl and deoxycorticosterone).

Do ARBs have therapeutic efficacy equivalent to that of ACE inhibitors? Although both classes of drugs block the RAS, they differ in several important aspects:

• ARBs reduce activation of AT₁ receptors more effectively than do ACE inhibitors. ACE inhibitors reduce the biosynthesis of AngII by the action of ACE, but do not inhibit alternative non-ACE AngII-generating pathways. ARBs block the actions of AngII via the AT₁ receptor regardless of the biochemical pathway leading to AngII formation.
• In contrast to ACE inhibitors, ARBs permit activation of AT₂ receptors. ACE inhibitors increase renin release, but block the conversion of AngI to AngII. ARBs also stimulate renin release; however, with ARBs, this translates into a several-fold increase in circulating levels of AngII. Because ARBs block AT₁ receptors, this increased level of AngII is available to activate AT₂ receptors.
• ACE inhibitors may increase Ang(1–7) levels more than do ARBs. ACE is involved in the clearance of Ang(1–7), so inhibition of ACE may increase Ang(1–7) levels more so than do ARBs.
• ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin and Ac-SDKP.

Whether the pharmacological differences between ARBs and ACE inhibitors result in significant differences in therapeutic outcomes is an open question.

Clinical Pharmacology

Oral bioavailability of ARBs generally is low (<50%, except for irbesartan, with 70% available), and protein binding is high (>90%).

Losartan (Cozaar)

Approximately 14% of an oral dose of losartan is converted to the 5-carboxylic acid metabolite EXP 3174, which is more potent than losartan as an AT₁ receptor antagonist. The metabolism of losartan to EXP 3174 and to inactive metabolites is mediated by CYP2C9 and CYP3A4. Peak plasma levels of losartan and EXP 3174 occur ~1-3 hours after oral administration, respectively, and the plasma half-lives are 2.5 and 6-9 hours, respectively. The plasma clearances of losartan and EXP 3174 are due to renal clearance and hepatic clearance (metabolism and biliary excretion). The plasma clearance of losartan and EXP 3174 is affected by hepatic but not renal insufficiency. Losartan should be administered orally once or twice daily for a total daily dose of 25-100 mg. In addition to being an ARB, losartan is a competitive antagonist of the thromboxane A₂ receptor and attenuates platelet aggregation (Levy et al., 2000). Also, EXP 3179, a metabolite of losartan without angiotensin receptor effects, reduces COX-2 mRNA upregulation and COX-dependent prostaglandin generation (Krämer et al., 2002).

Therapeutic Uses of AngII Receptor Antagonists

All ARBs are approved for the treatment of hypertension. In addition, irbesartan and losartan are approved for diabetic nephropathy, losartan is approved for stroke prophylaxis, and valsartan is approved for heart failure and to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction. The efficacy of ARBs in lowering blood pressure is comparable with that of ACE inhibitors and other established antihypertensive drugs, with a favorable adverse-effect profile. ARBs also are available as fixed-dose combinations with hydrochlorothiazide or amlodipine (Chapters 27 and 28).

Losartan is well tolerated in patients with heart failure and is comparable to enalapril with regard to improving exercise tolerance (Lang et al., 1997). The Evaluation of Losartan in the Elderly (ELITE) study reported that in elderly patients with heart failure, losartan was as effective as captopril in improving symptoms and better in reducing mortality (Pitt et al., 1997). However, the greater reduction in mortality by losartan was not confirmed in the larger Losartan Heart Failure Survival Study (ELITE II) trial (Pitt et al., 2000). The Valsartan in Acute Myocardial Infarction (VALIANT) trial demonstrated that valsartan is as effective as captopril in patients with myocardial infarction complicated by left ventricular systolic dysfunction with regard to all-cause-mortality (Pfeffer et al., 2003). Both valsartan and candesartan reduce mortality and morbidity in heart failure patients (Maggioni et al., 2002; Granger et al., 2003). Current recommendations are to use ACE inhibitors as first-line agents for the treatment of heart failure and to reserve ARBs for treatment of heart failure in patients who cannot tolerate or have an unsatisfactory response to ACE inhibitors.

At present, there is conflicting evidence regarding the advisability of combining an ARB and an ACE inhibitor in heart failure patients. The Candesartan in Heart Failure Assessment of Reduction in Mortality (CHARM-additive) and the Valsartan in Heart Failure (ValHeFt) studies indicate that a combination of ARB and ACE inhibitors decrease morbidity and mortality in patients with heart failure (McMurray et al., 2003; Cohn and Tognoni, 2001). In contrast, the VALIANT and ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint) findings show no added benefits with combination therapy, which was associated with more adverse effects (Pfeffer et al., 2003; ONTARGET Investigators, 2008).

ARBs are renoprotective in type 2 diabetes mellitus, in part via blood pressure–independent mechanisms (Viberti et al., 2002). Based on these results, many experts now consider them the drugs of choice for renoprotection in diabetic patients. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study demonstrated the superiority of an ARB compared with a ₁ adrenergic receptor antagonist with regard to reducing stroke in hypertensive patients with left ventricular hypertrophy (Dahlöf et al., 2002). Also, irebesartan appears to maintain sinus rhythm in patients with persistent, long-standing atrial fibrillation (Madrid et al., 2002). Losartan is reported to be safe and highly effective in the treatment of portal hypertension in patients with cirrhosis and portal hypertension (Schneider et al., 1999) without compromising renal function.

Adverse Effects

ARBs are generally well tolerated. The incidence of angioedema and cough with ARBs is less than that with ACE inhibitors. As with ACE inhibitors, ARBs have teratogenic potential and should be discontinued in pregnancy. In patients whose arterial blood pressure or renal function is highly dependent on the RAS (e.g., renal artery stenosis), ARBs can cause hypotension, oliguria, progressive azotemia, or acute renal failure. ARBs may cause hyperkalemia in patients with renal disease or in patients taking K⁺ supplements or K⁺-sparing diuretics. ARBs enhance the blood pressure–lowering effect of other antihypertensive drugs, a desirable effect but one that may necessitate dosage adjustment. There are rare postmarketing reports of anaphylaxis, abnormal hepatic function, hepatitis, neutropenia, leukopenia, agranulocytosis, pruritus, urticaria, hyponatremia, alopecia, and vasculitis, including Henoch-Schönlein purpura.