CLINICAL AND HORMONAL EFFECTS OF THE NEW ANGIOTENSIN-II RECEPTOR ANTAGONIST LRB081

The renin-angiotensin system is a major contributor to the pathophysio logy of cardiovascular diseases such as congestive heart failure and h ypertension. Antagonizing angiotensin (Ang) II at the receptor site ma y produce fewer side effects than inhibition of the promiscuous conver ting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT(1)-receptor ant agonist, on the presser action of exogenous Ang II. At the same lime, plasma hormones and drug levels were monitored. At 1-week intervals an d in a double-blind randomized Fashion, 8 male volunteers received thr ee doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP ) was measured at a finger by pholoplethysmograph. The peak BP respons e to intravenous injection of a standard dose of Ang II was determined before and for less than or equal to 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood B P response to Ang II was expressed in percent of the response before d rug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by hig h-performance liquid chromatography) were monitored. After LRB081 admi nistration, a dose-dependent inhibition of the BP response to Ang II w as observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB0 81. respectively. The time to peak was 3 h for 6 subjects and 3 and 6 h for 2 others. Preliminary plasma half-life (t1/2) was calculated at 2 h, With the highest dose, the inhibition remained significant for 24 h (31 +/- 5%. p < 0.05). Maximal BP-blocking effect and maximal plasm a drug level coincided, suggesting that the unmetabolized LRB081 is re sponsible for the antagonistic effect. PRA and Ang II increased dose d ependently after LRB081 intake. Aldosterone, epinephrine. and norepine phrine concentrations remained unchanged. No clinically significant ad verse reaction was observed during the study. LRB081 is a well-tolerat ed, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has be en shown to be responsible for the main effects.