title: The haemodynamic effects of two angiotensin converting enzyme inhibitors, enalaprilat and zofenoprilat, in the rat: evidence for the involvement of bradykinin.
abstract: 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.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Groningen, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: Tio
authors.forename: J P
authors.initials: JP
authors.lastname: Heiligers
authors.forename: C D
authors.initials: CD
authors.lastname: de Langen
authors.forename: W H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: W
authors.initials: W
authors.lastname: König
authors.forename: P R
authors.initials: PR
authors.lastname: Saxena
authors.forename: H
authors.initials: H
authors.lastname: Wesseling
mesh_terms: 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
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; C058532:HOE k86-4321; D002216:Captopril; D015773:Enalaprilat; D001920:Bradykinin