DOSE-RANGING STUDY OF THE ANGIOTENSIN TYPE-I RECEPTOR ANTAGONIST LOSARTAN (DUP753 MK954), IN SALT-DEPLETE NORMAL MAN/

In a dose-ranging study, the angiotensin type I receptor antagonist lo sartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low so dium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days befor e study. On the fourth day, subjects (n = 12) received placebo and thr ee active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-bli nd, three-panel, dose-ranging design. On the study day, 24-h urinary s odium excretion was approximately 10-20 mmol Na, with an increase in r enin and aldosterone levels at baseline. Dose-dependent decreases in s upine and erect blood pressures (BP) were statistically significant fo r 50 and 100 mg and were associated with a modest increase in supine h eart rate (HR) at the higher dose. The peak BP decreases observed sugg ested that the highest dose studied (100 mg) was not necessarily the m aximal response. Active treatments caused no increase in the sodium lo ss on the study day. Renin was significantly increased by doses >10 mg in a dose-dependent fashion but there was little change in plasma ald osterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms we re uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.