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 s ystem (RAS) by means of an inhibition of angiotensin II (ANG II) forma tion. Since ACE is identical to kininase II, which inactivates the non apeptide bradykinin (BK) and related kinins, potentiation of kinins mi ght 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 increas e in blood pressure and the development of LVH. The low dose of ramipr il (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 aorti c banding. The antihypertrophic effect of the higher and lower doses o f ramipril, as well as the antihypertensive action of the higher dose of ramipril, was abolished by coadministration of the kinin receptor a ntagonist icatibant. In the regression study the antihypertrophic acti ons of ramipril were not blocked by the kinin receptor antagonist. Chr onic administration of BK had similar beneficial effects in a preventi on 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, unrela ted to its blood pressure lowering effect. b) In spontaneously hyperte nsive rats (SHR) the preventive effects of chronic treatment with rami pril 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) o r 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 hyperten sion in parallel to vehicle-treated controls. Left ventricular mass wa s reduced only in high-dose-treated, but not in low-dose treated anima ls 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 icatiban t. In contrast to the prevention studies, in a regression study ramipr il reduced cardiac hypertrophy also by low dose treatment. c) In rats chronic nitric oxide (NO) inhibition by N-G-nitro-L-arginine-methyl es ter (L-NAME) treatment induced hypertension and LVH. Ramipril protecte d against blood pressure increase and partially against myocardial hyp ertrophy. These experimental findings in different models of LVH chara cterise ACE inhibitors as remarkable antihypertrophic and antifibrotic substances.