Clinical and Hormonal Effects of the New Angiotensin II Receptor Antagonist LRB081

Abstract

The renin-angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. Antagonizing angiotensin (Ang) II at the receptor site may produce fewer side effects than inhibition of the promiscuous converting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT1-receptor antagonist, on the pressor action of exogenous Ang II. At the same time, plasma hormones and drug levels were monitored. At 1-week intervals and in a double-blind randomized fashion, 8 male volunteers received three doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP) was measured at a finger by photoplethysmograph. The peak BP response to intravenous injection of a standard dose of Ang II was determined before and for < or = 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood BP response to Ang II was expressed in percent of the response before drug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by high-performance liquid chromatography) were monitored. After LRB081 administration, a dose dependent inhibition of the BP response to Ang II was observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB081, respectively. The time to peak was 3 h for 6 subjects and 4 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 plasma drug level coincided, suggesting that the unmetabolized LRB081 is responsible for the antagonistic effect. PRA and Ang II increased dose dependently after LRB081 intake. Aldosterone, epinephrine, and norepinephrine concentrations remained unchanged. No clinically significant adverse reaction was observed during the study. LRB081 is a well-tolerated, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has been shown to be responsible for the main effects.

Angiotensin Type 2 Receptor-Mediated Hypotension in Angiotensin Type-1 Receptor-Blocked Rats

“…Increased circulating Ang II has been observed after AT 1 receptor blockade in several studies. [23][24][25] The further reduction in BP when Ang II or CGP was added indicates that despite high circulating Ang II, AT 2 receptors were not fully occupied, such that additional agonist elicited a biological response.…”

Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin‐angiotensin system

“…Angiotensin receptor antagonists demonstrated a dose‐dependent blockade of the blood pressure response to exogenous angiotensin II, reaching close to maximal effect at the high doses [ 21–31]. Time to maximal effect varied between antagonists, ranging from 1 to 8 h and some inhibition was still visible at 24 h. The maximal inhibitory effect of valsartan and losartan was reached with a dose of 80 mg and for losartan, the intensity and duration remain unchanged from 80 to 120 mg [ 27, 30, 31].…”