Hemodynamic effects of new angiotensin converting enzyme inhibitors during continuous angiotensin I infusion on conscious dogs

The effects of a 6 h infusion of 50 ng/kg.min angiotensin I on hemodynamic parameters were recorded in conscious male beagle dogs. Mean arterial pressure was elevated from 107 +/- 3 mmHg to 152 +/- 5 mmHg (mean +/- SEM, n = 5) within the first hour, followed by a slow decrease to 145 +/- 5 mmHg after 6 h. Cardiac output fell from 2.3 +/- 0.2 l/min to 1.6 +/- 0.2 l/min followed by an increase to 2.5 +/- 0.3 l/min. The peripheral resistance showed an exceeding increase from 2.9 +/- 0.2 mmHg.s/ml to 5.7 +/- 0.7 mmHg.s/ml and a slow decrease to 3.5 +/- 0.5 mmHg.s/ml. Heart rate was found to be decreased from 62 +/- 7 min-1 to 58 +/- 7 min-1 after 1 h. The angiotensin converting Enzyme (ACE)-inhibitor enalapril caused a complete reduction of the angiotensin induced hypertension. Three new non-sulfhydryl containing ACE-inhibitors ((S)-N-[N-[1-[ethoxycarbonyl]-3-phenylpropyl]-L-alanyl]-N- [1-pyrrolidinyl]-glycine (REV 6207), (S)-N-[N-[1-[ethoxycarbonyl]-3-phenylpropyl]-L-alanyl]-N- [2-ethoxyethoxy]-glycine (REV 6134), (S)-N-[N-[1-[ethoxycarbonyl]-3-phenylporpyl]-L-alanyl]-N- [phenylmethyl]-glycine (REV 5975] were found to show a partial reduction of the angiotensin I effect. The duration of action which was found to be similar after oral and intravenous administration ranged from 83 +/- 33 min (n = 3) for REV 5975 to more than 360 min for enalapril. A correlation of the arterial pressure lowering and the percentage of the ACE-inhibition suggests that a considerable blood pressure effect can only be observed when more than about 80% of the ACE-activity is inhibited.