Comparative study of the cardiovascular effects of losartan in normal and in water- and salt-depleted sheep

The cardiovascular effects of losartan, a non-peptidic angiotensin II (ANG II) receptor antagonist, were studied in sheep. Eight normotensive, conscious sheep were tested twice: first under normal conditions and second when subjected to water and electrolytic depletion (furosemide 5 mg/kg twice a day for 3 days). Intravenous injection of 30 mg/kg losartan lowered the mean arterial blood pressure (MABP) in both control and water- and electrolyte-depleted sheep alike. The maximal decrease in MABP was significantly greater in diuretic-treated sheep than in controls (20.0 +/- 2.7 vs 9.3 +/- 1.1 mmHg) and occurred earlier (8.0 +/- 3.3 min vs 12.1 +/- 2.9 min). The decrease in blood pressure was associated with tachycardia in both controls and diuretic-treated sheep (+5.5 +/- 1.8 vs +11.3 +/- 3.9 beats/min). The vasopressor response to 0.1 microg/kg ANG II administered 30 min after losartan was completely antagonized. Two hours after losartan administration, MABP was on the increase in all animals and ANG II receptor blockade was partially obliterated in control sheep. The more marked cardiovascular effects recorded in diuretic-treated sheep as compared to control animals were associated with an increased activation of the renin-angiotensin system (plasma renin concentration: 6.51 +/- 1.33 vs 1.42 +/- 0.37 ng angiotensin I/ml/hr).