Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers.

Abstract

Losartan is an orally active, nonpeptide angiotensin II (Ang II) (site-1) receptor antagonist. We conducted a multiple-dose study in healthy male volunteers to investigate the tolerability, blood pressure effects, and changes in plasma renin activity (PRA) and plasma Ang II concentration associated with once-daily administration of 100 mg losartan for a week. Subjects were studied on a standardized sodium diet (24-hour urinary sodium excretion, 98±37 [SD] mEq per 24 hours on the placebo run-in day). Measurements of blood pressure, heart rate, PRA, Ang II, and aldosterone were taken during a placebo run-in day and after single and multiple (7 days) daily doses of losartan (100 mg, n = 10) or placebo (n=4). Ang II was measured specifically by high performance liquid chromatography coupled with radioimmunoassay. In subjects given losartan, respective decreases (systolic/diastolic) from run-in in supine blood pressure 6 hours after dosing were (mean±SD), compared with the placebo run-in day, first dose: -8.8±9.6/-6.8±5.0, last dose: -11.6±8.9/-7.0±4.8 mm Hg (p<0.05 for all changes). At this 6-hour time point, corresponding increases from run-in in PRA were from 1.2±0.6 to 12.0±6.3 (first dose) and 9.6±4.9 (last dose) ng angiotensin I per milliliter per hour and in Ang II were from 4.3±1.7 to 72.4±33J and 45.7± 14.1 pg/mL. All changes in PRA and Ang II were statistically significant within the losartan-treated group, and the biochemical changes were significantly greater than those in the placebo-treated group. The increment in Ang II was less after the last dose than after the first (p<0.05). The drug was well tolerated by all subjects. These data indicate that, under the conditions of this study, losartan administration (100 mg/day for eight doses over 9 days) results in treatment-related decreases in blood pressure and increases in PRA and Ang II octapeptide. The drug is being investigated as therapy for hypertension and heart failure and is anticipated to be a more specific mechanism for inhibiting the renin-angiotensin system than angiotensin converting enzyme inhibitors. Early clinical investigation of losartan has shown single and multiple doses up to 40 mg to be well tolerated and pharmacologically active, with doses of 10 mg or greater blocking pressor responses to exogenous angiotensin I (Ang I) and Ang II.5 -6 Also, through blockade of Ang II receptors in the juxtaglomerular apparatus, which inhibits renin release, losartan administration results in dose-related increases in plasma renin activity (PRA) and immunoreactive Ang II. 56 Studies have also been completed that demonstrate the tolerability of single doses up to 300 mg and more than 90% blockade of responses to exogenous Ang II by oral doses of 80-120 mg (unpub-

Effect of losartan, an Angiotensin II receptor antagonist, on portal pressure in cirrhosis

“…For example, the decrease in blood pressure induced by angiotensin II blockade is more prominent in a standing than in a sitting position. 33 In this study, blood pressure was measured with the patient in a sitting position; unfortunately, nothing is reported about the conditions of measurement in the abstract by Girgrah et al Acute administration of captopril, which as an angiotensinconverting enzyme inhibitor blocks the production of angiotensin II, caused a more pronounced decrease of arterial pressure in patients with cirrhosis than observed in the present study, but a high dosage of captopril was used. 34 Long-term treatment with captopril or enalapril did not induce a reduction in blood pressure in patients with cirrhosis.…”

The potential role of angiotensin II in the vasculature

“…The finding that treatment of normotensive rats with losartan alone had no effect on BP, but induced medial hypertrophy that was prevented by additional treatment with PD123319, could be related to an already demonstrated increase in plasma Ang II concentration secondary to AT 1 receptor long term blockade. 45 Under our experimental conditions in Ang II-induced hypertension, we suggested that the AT 2 receptors were activated and induced vascular trophic effects. The trophic effect of AT 2 receptor stimulation appeared specific to VSMC and independent of arterial type (ie, conductive or resistive).…”

TRV120027, a Novel β-Arrestin Biased Ligand at the Angiotensin II Type I Receptor, Unloads the Heart and Maintains Renal Function When Added to Furosemide in Experimental Heart Failure

“…This could, in part, be due to the reduction in renal perfusion pressure but also due to antagonizing the inhibitory action of angiotensin II on renin secretion by TRV120027. 42,43 Although there was a trend for angiotensin II to increase in the furosemide-alone group, we were not able to assess the angiotensin II levels in the furosemide+TRV120027 group because the angiotensin II assay cross-reacts with TRV120027. Importantly, given that aldosterone, the secretion of which is stimulated by angiotensin II, decreased with TRV120027 suggests that downstream signaling of renin was effectively blocked, which would mean that the increase in plasma renin activity with TRV120027 would be of little consequence.…”