Systemic and regional hemodynamic effects of a new angiotensin converting enzyme and neutral endopeptidase mixed inhibitor, alatriopril, in the dog
Richard, V.; Lecomte, J.M.; Thuillez, C.
Archives des Maladies du Coeur et des Vaisseaux 86(8): 1275-1279
1993
ISSN/ISBN: 0003-9683 PMID: 8129543 Document Number: 7718
Alatriopril is a dual inhibitor of two cell surface metallopeptidases which play important roles in the regulation of arterial blood pressure and renal function : the angiotensin I converting enzyme (ACE) which catalyses transformation of angiotensin Ito angiotensin II, and the neutral endopeptidase (NEP; EC 3.4.24.11; atriopeptidase), responsible for the degradation of the atrial natriuretic factor (ANF). The purpose of the present study was to evaluate the systemic and regional hemodynamic effects of alatrioprilat, the active part of alatriopril, in 6 anesthetized, closed-chest beagle dogs instrumented for the measurement of arterial pressure (aortic catheter), cardiac output (thermodilution), as well as femoral and renal artery flows (Doppler). Animal received alatrioprilat at the doses of 1 and 10 mg/kg (i.v. bolus). Hemodynamic parameters were measured at baseline, then 15, 30, 45 and 60 min after administration of each dose. In addition, plasma ANF and ACE activity were determined at baseline and 30 min after administration. At the dose of 1 mg/kg, alatrioprilat dit not induce marked hemodynamic effects, except a transient hypotension which appeared within the first 10 min after administration and lasted less than 10 min. Neither plasma ANF nor angiotensin converting enzyme activity were affected by this dose. In contrast, at the dose of 10 mg/kg, alatrioprilat induced a sustained decreased in arterial pressure (average decrease after 30 min : - 15±5 %; p<0,05 vs baseline), total peripheral resistance (- 17±8 %; p<0,05), as well as femoral (- 15±7 %; p<0,05) and renal resistance (- 13±15 %; p<0,05). Cardiac output and heart rate were not modified by alatrioprilat at any time. These hemodynamic effects were accompanied by a marked inhibition of angiotensin converting enzyme activity (- 59±12 %; p<0,05) and a modest increase in plasma ANF (9±4 %; p=NS). Thus, in this dog model, dual ACE and NEP inhibition by alatrioprilat induced a sustained decrease in arterial blood pressure which could entirely be accounted for by a decrease in total peripheral resistance. This peripheral vasodilating effect was present both at the femoral and renal levels. Such a hemodynamic profile suggests that alatriopril could be beneficial in the treatment of hypertension or heart failure.
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