CONTRIBUTION OF KININS TO THE CARDIOVASCU LAR ACTIONS OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS .1.

From pharmacological investigations and clinical studies, it is known that ACE inhibitors exhibit additional local actions that are not rela ted to hemodynamic changes and that cannot be explained only by interf erence with the renin-angiotensin system by means of an inhibition of ANG II formation. Because ACE is identical to kininase II, which inact ivates the nonapeptide BK and related kinins, potentiation of kinins m ight be responsible for these additional effects of ACE inhibitors. AC E inhibition, concentration, and time dependently increased the format ion of NO and PGI(2) in cultured endothelial cells of different origin and from different species, including humans. The specific B-2 kinin receptor antagonist, icatibant, suppressed the ACE inhibitor-induced i ncrease in endothelial cyclic GMP accumulation index for NO-formation and, in parallel, attenuated the increase in PGI(2) release. In renova scular models of hypertension associated with a stimulated renin-angio tensin system (two-kidney, one-clip), blood pressure reduction by ACE inhibitors was attenuated by icatibant, whereas in rats with genetic h ypertension with normal to low plasma renin, blood pressure reduction through ACE inhibitors was not affected. In experimental atheroscleros is in rabbits, ACE inhibitors were able to preserve endothelial functi on and vascular reactivity and to reduce surface involvement. In the b alloon denudation model of carotid arteries in rats, it was found that ACE inhibition markedly reduced neointima formation. However, when th e ACE inhibitor was given together with icatibant, ifs effect was sign ificantly blunted. Perfusion with ACE inhibitors induced a reduction o f the incidence, as well as of the duration, of ventricular fibrillati on and improved cardiodynamics and myocardial metabolism. BK perfusion induced comparable cardioprotective effects. In addition, perfusion w ith ACE inhibitors markedly increased the outflow of BK and related ki nins from isolated rat hearts. The antiischemic effect of ACE inhibito rs and BK were abolished by the addition of L-MVA (1 x 10(-6) mol/l) o r icatibant (1 x 10(-9) mol/l). Similar results were found in dogs and rabbits with myocardial infarction, BK and related kinins also seem t o be involved in preconditioning and remodeling, The effect of ACE inh ibition in LVH was investigated in rats made hypertensive by aortic ba nding, ACE inhibition with ramipril, in the antihypertensive dose of 1 mg/kg/day for 6 weeks, prevented the increase in blood pressure and t he development of LVH, A lower, nonantihypertensive dose of the ACE in hibitor (10 mu g/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, The antihypertrophic effect of the higher and lower d oses of the ACE inhibitor, as well as the antihypertensive action of t he higher dose of ramipril, was abolished by coadministration of the B -2 kinin receptor antagonist icatibant, Chronic administration of BK h ad similar beneficial effects that were abolished by icatibant and L-N NA. In SHR, the preventive effects of chronic treatment,vith ramipril on myocardial LVH was investigated, SHR were treated in utero and subs equently, up to 20 weeks of age, with either a high (1 mg/kg/day) or l ow dose (10 mu g/kg/day) of the ACE inhibitor. Animals on a high dose remained normotensive, whereas those on a low dose developed hypertens ion in parallel to vehicle-treated controls, Left ventricular mass was reduced only in high-dose treated (and not in low-dose treated) anima ls, but both groups revealed an increase in myocardial capillary lengt h density, In SHSP animals, cardiac function and metabolism were impro ved by the ACE inhibitor and abolished by coadministration of icatiban t, In contrast to the prevention studies, in a regression study, ramip ril reduced cardiac hypertrophy also by low-dose treatment, Chronic in hibition of NO generation by oral L-NAME administration to rats induce d hypertension and LVH, Concomitant treatment with an ACE inhibitor pr otected against the blood pressure increase and protected partially ag ainst myocardial hypertrophy, On the basis of these experimental findi ngs in different pathophysiological situations, evidence is accumulati ng that kinins are participating in the cardiovascular actions of ACE inhibitors.