Effects of the converting enzyme inhibitor cilazaprilat on endothelium-dependent responses.
The effects of cilazaprilat were assessed on endothelium-dependent relaxations and contractions in isolated canine arteries. In coronary arteries incubated with indomethacin, cilazaprilat potentiated endothelium-dependent relaxations to bradykinin. In superfusion-perfusion bioassay studies with femoral arteries, cilazaprilat augmented the release of nonprostanoid endothelium-derived relaxing factors caused by bradykinin. To verify whether this effect was solely due to inhibition of the converting enzyme, the effects of cilazaprilat on responses to a variety of endothelium-dependent vasoactive agents were assessed. Endothelium-dependent relaxations to acetylcholine, thrombin, and vasopressin were not altered significantly by cilazaprilat. However, those induced by ADP and aggregating platelets were enhanced significantly by the compound. Endothelium-dependent relaxations to ADP-beta-S were augmented significantly but to a lesser extent. Furthermore, in the presence of the nitric oxide synthase antagonist NG-nitro-L-arginine, ADP-beta-S still caused small relaxations that were possibly mediated by endothelium-derived hyperpolarizing factor. These relaxations were augmented by cilazaprilat. Thus, the augmentation of purinergic relaxations may involve an increased production of endothelium-derived relaxing factors in addition to the protection of ADP from breakdown. Cilazaprilat did not affect endothelium-dependent contractions to acetylcholine or the calcium ionophore A23187 in canine basilar arteries, previously shown to be mediated by superoxide anions. Thus, cilazaprilat is not a scavenger of superoxide anion. Because this agent potentiates endothelium-dependent relaxations to bradykinin, ADP, and aggregating platelets, the present study suggests that, in addition to the lowering of plasmatic levels of angiotensin II, the antihypertensive and cardioprotective effects of cilazaprilat are mediated through an increased production of endothelium-derived relaxing factors.
Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Tex. 77030.
J V
JV
Mombouli
M
M
Nephtali
P M
PM
Vanhoutte
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D017315:Cilazapril / Q000031:analogs & derivatives*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D011724:Pyridazines; D017315:Cilazapril; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D000109:Acetylcholine; D001920:Bradykinin; C045980:cilazaprilat