Dose-ranging study of the angiotensin II receptor antagonist irbesartan (SR 47436/BMS-186295) on blood pressure and neurohormonal effects in salt-deplete men.
We characterised the blood pressure (BP) and hormonal responses to the oral angiotensin II (Ang II) receptor antagonist irbesartan (SR47436/BMS-186295) or placebo in normal men with an activated renin-angiotensin system (RAS) during salt depletion. We also evaluated safety and tolerability. Twelve healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Six different single oral doses of irbesartan (1, 5, 10, 25, 50, and 100 mg) were administered double-blind in a three-panel, dose escalation with placebo randomised in each panel. Supine and erect BP and heart rate (HR), serum and urinary electrolytes: plasma renin activity (PRA), and Ang II were measured at intervals. Urinary electrolytes were measured for the 24-h period before dosing (to confirm salt depletion) and for 24 h afterward. No drug-related side effects were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with irbesartan from 10 mg and beyond, with no change in HR. Supine mean arterial pressure (MAP) decreased by 18.8 mm Hg. There was a dose-related reactive increase in PRA (to 35 ng/ml/h) and Ang II (to 450 pg/ml) with irbesartan. Irbesartan is an orally active AT1 receptor antagonist. In salt-deplete normal men, it has a dose-related haemodynamic, hormonal, and electrolyte profile characteristic of AT1 antagonists. The dose range studied did not show a plateau or maximum effect.
McIntyre
M
M
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.
MacFadyen
R J
RJ
Meredith
P A
PA
Brouard
R
R
Reid
J L
JL
D000328:Adult; D000804:Angiotensin II / Q000097:blood*; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004039:Diet, Sodium-Restricted; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D000077405:Irbesartan; D008297:Male; D012083:Renin / Q000097:blood*; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D012083:Renin; D000077405:Irbesartan