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 II 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.
Merck Research Laboratories, West Point, PA 19486.
M R
MR
Goldberg
W
W
Tanaka
A
A
Barchowsky
T E
TE
Bradstreet
J
J
McCrea
M W
MW
Lo
E J
EJ
McWilliams
T D
TD
Bjornsson
D000293:Adolescent; D000328:Adult; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000097:blood*; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D009994:Osmolar Concentration; D011863:Radioimmunoassay; D012016:Reference Values; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000009:adverse effects / Q000494:pharmacology*
D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D012083:Renin; D019808:Losartan