Angiotensin II Receptor Blockade in Normotensive Subjects

Abstract

Abstract-Use of angiotensin (Ang) II AT 1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (PϽ0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects. (Hypertension. 1999;33:850-855.)Key Words: angiotensin II Ⅲ receptors, angiotensin II Ⅲ human Ⅲ irbesartan Ⅲ losartan Ⅲ valsartan F or the past 15 years, angiotensin-converting enzyme (ACE) inhibitors have been widely used to block the renin-angiotensin system and to treat hypertension and congestive heart failure. Despite their recognized clinical efficacy, ACE inhibitors have some weaknesses. First, ACE is a nonspecific enzyme that uses bradykinin as a substrate in addition to angiotensin I (Ang I). Thus, ACE inhibition results in both Ang I and bradykinin accumulation, the latter being a potential source of side effects such as angioedema. 1,2 The occurrence of cough, the most frequent side effect of ACE inhibitors, has also been attributed to the lack of specificity of ACE inhibition. 1 Second, during long-term ACE inhibition, plasma angiotensin II (Ang II) levels decrease, but some Ang II is still circulating at measurable levels. 3 The reactive rise in plasma renin activity and plasma Ang I levels may account for the persistence of measurable Ang II levels, particularly if ACE activity is not fully inhibited around the clock. More recently, it has also been postulated that besides being generated through the primary ACE pathway, Ang II can be generated through non-ACE pathways that are not affected by ACE inhibitors. 4 To overcome the drawbacks of ACE inhibitors, substantial effort has been put into development of new compounds that block the renin-angiotens...

Comprehensive overview: efficacy, tolerability, and cost-effectiveness of irbesartan

“…Irbesartan has the ability to inhibit the pressor response to exogenously administered angiotensin II in normotensive subjects and had a dose-related BP response as shown in several studies 39–41. Irbesartan inhibited the pressor response by up to 100% at peak after 4 hours of oral doses at 25–300 mg 40,41.…”

“…Irbesartan inhibited the pressor response by up to 100% at peak after 4 hours of oral doses at 25–300 mg 40,41. Compared with losartan and valsartan in a double-blind, placebo-controlled, randomized, four-way crossover study, the degree and duration of angiotensin II receptor blockade induced by 150 mg of irbesartan was significantly greater than with either 50 mg of losartan or 80 mg of valsartan 39. Furthermore, in studies evaluating its efficacy in hypertensive patients, chronic doses of up to 300 mg had no effect of clinical importance on renal plasma flow, glomerular filtration rate, filtration fraction, or urinary excretion of sodium and potassium 42–44.…”

Effects of AT1 Receptor Blockade on Plasma Thromboxane A₂ (TXA₂) Level and Skin Microcirculation in Young Healthy Women on Low Salt Diet

“…In addition to their effect on blood pressure, long-term administration of AT1 receptor blockers results in a several-fold increase in plasma ANG II and thus a possible overstimulation of AT2 receptors [40,41,42,43]. Therefore, the effect of AT2 receptor stimulation is becoming increasingly important in both physiological and pathological situations, for example, hypertension.…”

Angiotensin Receptor Antagonists to Prevent Sudden Death in Heart Failure: Does the Dose Matter?

“…In their experience on normotensive healthy volunteers, Mazzolai et al [29] found that oral administration of losartan 50 mg provides only 35 to 45% blockade of AT 1 receptors. This is consistent with findings from Maillard et al [30], who reported on the effects of losartan, valsartan, and candesartan dosing on AT 1 receptor blockade.…”