We investigated the preventive effects of long-term treatment with the angiotensin converting enzyme inhibitor ramipril on myocardial left ventricular hypertrophy and capillary length density in spontaneously hypertensive rats. Rats were treated in utero and subsequently up to 20 weeks of age with a high dose (1 mg/kg per day) or with a low dose (0.01 mg/kg per day) of ramipril. Animals given a high dose of ramipril remained normotensive, whereas those given a low dose developed hypertension in parallel to vehicle-treated controls. At the end of the treatment period, converting enzyme activity in heart tissue was inhibited dose-dependently in the treated groups. Both groups revealed an increase in myocardial capillary length density together with increased myocardial glycogen and reduced citric acid concentrations. Left ventricular mass was reduced only in high dose-but not in low dose-treated animals. Our results demonstrate that early onset treatment with a converting enzyme inhibitor can induce myocardial capillary proliferation, even at doses too low to antagonize the development of hypertension or left ventricular hypertrophy. We hypothesize that potentiation of kinins is responsible for this effect, probably by augmenting myocardial blood flow, which is a well-known trigger mechanism of angjogenesis in the heart (Hypertension 1992^20:478-482) KEY WORDS • angiotensin converting enzyme inhibitors • hypertrophy • capillaries • rats, inbred SHR C ardiac left ventricular hypertrophy (LVH), a frequent consequence of arterial hypertension, is increasingly considered an independent cardiovascular risk factor giving rise to cardiac failure, ischemia, and arrhythmias. Spontaneously hypertensive rats (SHR) develop hypertension during their first 12 weeks of life. As in human hypertension, the increase in blood pressure is accompanied by vascular and cardiac hypertrophy. Whereas LVH induced by physical exercise or chronic hypoxia is associated with normal or even increased capillary density, hypertension-induced LVH usually features a reduced capillary supply that may eventually lead to cardiac ischemia. recently reported that long-term treatment with a low or sub-antihypertensive dose of the ACE inhibitor ramipril (0.01 mg/kg per day) prevented LVH in rats with renal hypertension due to aortic banding, suggesting that early onset treatment with ACE inhibitors can induce structural changes of the heart independent of the blood pressure-lowering actions of these drugs. The question of whether a sub-antihypertensive dose of an From the Departments of Pharmacology (T.U., V.L., P.G.) and Pathology (T.M., P.B., G.M.), University of Heidelberg, and Hoechst AG (W.L., B.A.S.), Franltfurt/Main, FRG.

We investigated functional changes in aortic preparations of spontaneously hypertensive rats treated in utero and subsequently up to 20 weeks of age with the angiotensin converting enzyme (ACE) inhibitors ramipril (0.01 and 1 mg/kg per day) and perindopril (0.01 nig/kg per day). Early-onset treatment with the high dose of ramipril inhibited aortic ACE activity, prevented the development of hypertension, increased aortic vasodilator responses to acetylcholine (10~8 to 10~6 mol/L), decreased vasoconstrictor responses to norepinephrine (10~8 mol/L), and increased aortic cyclic GMP content by 160%. Low-dose ramipril inhibited aortic ACE activity and attenuated the aortic vasoconstrictor response to norepinephrine but had no effect on blood pressure. Low-dose treatment with ramipril and perindopril resulted in a significant increase in aortic cyclic GMP content by 98% and 77%, respectively. Long-term coadministration of the bradykinin B 2 -receptor antagonist Hoe 140 abolished the ACE inhibitor-induced increase in aortic cyclic GMP. Our data demonstrate that long-term treatment with ACE inhibitors can alter vascular function of compliance vessels independently of the antihypertensive action. The increase in aortic cyclic GMP was due to bradykinin potentiating the action of the ACE inhibitors. (Hypertension. 1993;22:682-687.) KEY WORDS • angiotensin converting enzyme inhibitors • guanosine cyclic monophosphate • perindopril • ramipril • rats, inbred SHR • bradykininS pontaneously hypertensive rats (SHR) and strokeprone SHR (SHRSP) develop hypertension during their first 12 weeks of life. The increase in blood pressure is associated with functional changes of the vascular wall. It has been reported that the endothelium-dependent relaxation of blood vessels to different agonists is impaired in hypertensive compared with normotensive animals.16 Endothelium-derived relaxing factor (EDRF) can be released by the endothelium in response to a number of agonists, including acetylcholine, bradykinin, and norepinephrine (for review, see References 7 and 8). EDRF causes vascular relaxation by stimulation of soluble guanylate cyclase, leading to a rise in the intracellular cyclic GMP (cGMP) content. The formation of cGMP in rabbit aortic segments and bovine endothelial cells can be stimulated in a concentration-dependent fashion by the angiotensin converting enzyme (ACE) inhibitor ramipril.9 This effect may be the result of an ACE inhibitor-induced potentiation of endogenous kinins, leading to enhanced EDRF release and, subsequently, cGMP formation.

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