The haemodynamic effects of two angiotensin converting enzyme inhibitors, enalaprilat and zofenoprilat, in the rat: evidence for the involvement of bradykinin.
Since angiotensin converting enzyme (ACE) metabolizes bradykinin, the hypotensive effect of ACE inhibitors could be partly due to an increased bradykinin activity. We therefore investigated the influence of HOE K86-4321 [D-Arg-(Hyp2-Thi5,8-DPhe7)-bradykinin], a selective bradykinin-2 receptor antagonist, on the effects of enalaprilat (0.3 and 3.0 mg/kg) and zofenoprilat (0.1 and 1.0 mg/kg) on the heart rate, mean arterial blood pressure, cardiac output and total peripheral resistance in rats. Both enalaprilat and zofenoprilat reduced mean arterial pressure (from 110 +/- 7 to 85 +/- 6 and from 108 +/- 9 to 72 +/- 9 mmHg, respectively; P less than 0.05) and total peripheral resistance (from 515 +/- 35 to 413 +/- 29 and from 495 +/- 45 to 310 +/- 25 x 10(-3) mmHg/litre per min per kg, respectively; P less than 0.05); the heart rate and cardiac output changed little. In the presence of HOE K86-4321, which by itself did not affect the haemodynamic variables measured, the effects of the two ACE inhibitors were significantly reduced. These results suggest that bradykinin-2 receptor-mediated vasodilation, although not involved in blood pressure regulation, influences the reduction in blood pressure induced by enalaprilat and zofenoprilat in normotensive rats. Furthermore, at comparable ACE-inhibiting doses, zofenoprilat was more effective in reducing mean arterial pressure, which might be related to the presence of a sulphydryl group.
Tio
R A
RA
Department of Pharmacology and Clinical Pharmacology, University of Groningen, The Netherlands.
Heiligers
J P
JP
de Langen
C D
CD
van Gilst
W H
WH
König
W
W
Saxena
P R
PR
Wesseling
H
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D002216:Captopril / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015773:Enalaprilat / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; C058532:HOE k86-4321; D002216:Captopril; D015773:Enalaprilat; D001920:Bradykinin