EFFECTS OF LOSARTAN ON BLOOD-PRESSURE, PLASMA-RENIN ACTIVITY, AND ANGIOTENSIN-II IN VOLUNTEERS

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 11 were from 4.3+/-1.7 to 72.4+/-33.3 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.