Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3',5'-monophosphate.

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 mg/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 B2-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.

Effect of early onset angiotensin converting enzyme inhibition on myocardial capillaries.

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 angiogenesis in the heart.

Vascular remodeling in systemic hypertension.

It is now well accepted that treatment of hypertension must extend beyond the mere control of blood pressure. Among the objectives "beyond blood pressure control" is the remodeling of resistance and compliance vessels that have usually undergone a process of hypertrophy and/or hyperplasia. Salutary vascular remodeling by antihypertensive treatment not only implies structural changes of the vascular wall, but also functional improvements, including diminished contractile responses to endogenous vasoconstrictors and enhanced relaxation to endogenous vasodilators. We have treated spontaneously hypertensive rats with the angiotensin-converting enzyme (ACE) inhibitors zabicipril, perindopril, and ramipril at antihypertensive and sub-antihypertensive doses and have analyzed vascular morphology and function. Chronic oral treatment was begun before hypertension developed (prevention study). Remodeling of mesenteric vessels with, inter alia, a reduction of the media:lumen ratio was achieved by antihypertensive doses of the drugs. Further, vascular function was improved not only after high-dose, but also after low-dose ACE inhibitor treatment, as tested in the aortic vessels: an inhibition of vascular ACE was associated with attenuated vasoconstrictor responses to norepinephrine and enhanced dilator responses to acetylcholine. In addition, low and high doses significantly increased aortic cyclic guanosine monophosphate (cGMP) content, suggesting an improved vasodilator capacity. Our data demonstrate that improvements of vascular function can be achieved by ACE inhibitors, independently of structural changes and of the antihypertensive action exerted by these drugs.

Cardiac and vascular effects of chronic angiotensin converting enzyme inhibition at subantihypertensive doses.

AIM: We performed two sets of experiments in order to prevent or to regress cardiac and vascular hypertrophy, using antihypertensive and subantihypertensive doses of the angiotensin converting enzyme inhibitor zabicipril. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) begin to develop hypertension at less than 4 weeks of age and reach stable hypertension levels after 12-14 weeks. The blood pressure increase is accompanied by the development of cardiac and vascular hypertrophy. Treatment of SHR in utero and up to the age of 20 weeks with an antihypertensive dose of zabicipril (1 mg/kg per day) not only prevented the development of high blood pressure but also the development of cardiac and vascular hypertrophy. This effect was demonstrated by a significant decrease in left ventricular weight and the number of smooth muscle cell layers in the vascular media, media thickness and the media:lumen ratio in mesenteric arteries. In contrast, antihypertensive treatment with the Ca2+ antagonist verapamil (100 mg/kg per day) and the subantihypertensive dose of zabicipril (0.01 mg/kg per day) did not affect the development of cardiac and vascular hypertrophy. We found a significant increase in the length and surface density of myocardial capillaries after treatment with zabicipril at 1 mg/kg per day, indicating that the capillary density had improved and therefore that the oxygen supply of the heart was improved. Similar findings were observed with the low dose of zabicipril in SHR, although these rats had high blood pressure and cardiac and vascular hypertrophy. CONCLUSIONS: Treatment of adult SHR for 16 weeks with zabicipril at 1 mg/kg per day completely normalized their blood pressure levels. This effect was accompanied by a regression of left ventricular but not of vascular hypertrophy. Treatment with an antihypertensive dose of verapamil or with a subantihypertensive dose of zabicipril had no effect on cardiac and vascular hypertrophy.