title: Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors.
abstract: From pharmacological investigations and clinical studies, it is known that ACE inhibitors exhibit additional local actions that are not related to hemodynamic changes and that cannot be explained only by interference with the renin-angiotensin system by means of an inhibition of ANG II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide BK and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. ACE inhibition, concentration, and time dependently increased the formation of NO and PGI2 in cultured endothelial cells of different origin and from different species, including humans. The specific B2 kinin receptor antagonist, icatibant, suppressed the ACE inhibitor-induced increase in endothelial cyclic GMP accumulation index for NO-formation and, in parallel, attenuated the increase in PGI2 release. In renovascular models of hypertension associated with a stimulated renin-angiotensin system (two-kidney, one-clip), blood pressure reduction by ACE inhibitors was attenuated by icatibant, whereas in rats with genetic hypertension with normal to low plasma renin, blood pressure reduction through ACE inhibitors was not affected. In experimental atherosclerosis in rabbits, ACE inhibitors were able to preserve endothelial function and vascular reactivity and to reduce surface involvement. In the balloon denudation model of carotid arteries in rats, it was found that ACE inhibition markedly reduced neointima formation. However, when the ACE inhibitor was given together with icatibant, its effect was significantly blunted. Perfusion with ACE inhibitors induced a reduction of the incidence, as well as of the duration, of ventricular fibrillation and improved cardiodynamics and myocardial metabolism. BK perfusion induced comparable cardioprotective effects. In addition, perfusion with ACE inhibitors markedly increased the outflow of BK and related kinins from isolated rat hearts. The antiischemic effect of ACE inhibitors and BK were abolished by the addition of L-NNA (1 x 10(-6) mol/l) or icatibant (1 x 10(-9) mol/l). Similar results were found in dogs and rabbits with myocardial infarction. BK and related kinins also seem to be involved in preconditioning and remodeling. The effect of ACE inhibition in LVH was investigated in rats made hypertensive by aortic banding. ACE inhibition with ramipril, in the antihypertensive dose of 1 mg/kg/day for 6 weeks, prevented the increase in blood pressure and the development of LVH. A lower, nonantihypertensive dose of the ACE inhibitor (10 micrograms/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but also prevented LVH after aortic banding.4+ off
authors.affiliation: Department of Pharmacology, Hoechst AG, Frankfurt/Main, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Linz
authors.forename: G
authors.initials: G
authors.lastname: Wiemer
authors.forename: P
authors.initials: P
authors.lastname: Gohlke
authors.forename: T
authors.initials: T
authors.lastname: Unger
authors.forename: B A
authors.initials: BA
authors.lastname: Schölkens
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000096:biosynthesis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy; D002319:Cardiovascular System / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy; D016234:Kallikrein-Kinin System / Q000502:physiology; D007705:Kinins / Q000737:chemistry / Q000502:physiology*; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000188:drug therapy; D009569:Nitric Oxide / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007705:Kinins; D000804:Angiotensin II; D009569:Nitric Oxide