ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS, LEFT-VENTRICULAR HYPERTROPHY AND FIBROSIS

From pharmacological investigations and clinical studies, it is known that angiotensin converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained only by interference with the renin angiotensin system (RAS) by means of an inhibition of angiotensin II (ANG II) formation. Since ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK) and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. a) In rats made hypertensive by aortic banding, the effect of ramipril in left ventricular hypertrophy (LVH) was investigated. Ramipril in the antihypertensive dose of 1 mg/kg/day for 6 weeks prevented the increase in blood pressure and the development of LVH. The low dose of ramipril (10 mu g/kg/day for 6 weeks) had no effect on the increase in brood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and lower doses of ramipril, as well as the antihypertensive action of the higher dose of ramipril, was abolished by coadministration of the kinin receptor antagonist icatibant. In the regression study the antihypertrophic actions of ramipril were not blocked by the kinin receptor antagonist. Chronic administration of BK had similar beneficial effects in a prevention study which were abolished by icatibant and N-G-nitro-L-arginine (L-NNA). In a one year study the high and low dose of ramipril prevented LVH and fibrosis. Ramipril had an early direct effect in hypertensive rats on the mRNA expression for myocardial collagen I and III, unrelated to its blood pressure lowering effect. b) In spontaneously hypertensive rats (SHR) the preventive effects of chronic treatment with ramipril on myocardial LVH was investigated. SHR were treated in utero and, subsequently, up to 20 weeks of age with a high dose (1 mg/kg/day) or with a low dose (10 mu g/kg/day) of ramipril. Animals on a high dose remained normotensive, whereas those on a low dose developed hypertension in parallel to vehicle-treated controls. Left ventricular mass was reduced only in high-dose-treated, but not in low-dose treated animals but both groups revealed an increase in myocardial capillary length density. In SHR stroke prone animals cardiac function and metabolism was improved by ramipril and abolished by coadministration of icatibant. In contrast to the prevention studies, in a regression study ramipril reduced cardiac hypertrophy also by low dose treatment. c) In rats chronic nitric oxide (NO) inhibition by N-G-nitro-L-arginine-methyl ester (L-NAME) treatment induced hypertension and LVH. Ramipril protected against blood pressure increase and partially against myocardial hypertrophy. These experimental findings in different models of LVH characterise ACE inhibitors as remarkable antihypertrophic and antifibrotic substances.