ACE inhibitors are superior to other vasodilators in the treatment of congestive heart failure and may be advantageous in patients with myocardial infarction and hypertension. The mechanisms mediating these beneficial effects are not clear. The present article discusses the mechanisms leading to augmented release of endothelium-derived nitric oxide during ACE inhibition. Acute potentiation of bradykinin (Bk)-induced vasodilation was studied in rings of bovine and human coronary arteries mounted in organ chambers for recording of isometric force. The ACE inhibitors captopril, enalaprilat, fosinoprilat, lisinopril, or ramiprilat alone did not affect vascular tone in isolated coronary tone in isolated coronary artery preparations with intact endothelium. However, in the presence of exogenous Bk, kallidin, or one of the slowly degradable Bk2-receptor agonists D-Arg(Hyp3)-Bk or [Hyp3-Tyr(Me)8]-Bk they elicited potent concentration-dependent relaxations. Relaxations in response to lisinopril were not observed in the presence of other vasodilators. They were prevented by mechanical removal of the endothelium, inhibition of nitric oxide synthase or Bk2-receptor blockade. The data indicate that ACE inhibitors potentiate the effects of Bk on endothelial cells by a local mechanism, probably independent of the degradation of bradykinin. The chronic effects of ACE inhibitors on endothelial function were compared with those of selective angiotensin(AT)1-receptor blockade in cyclosporin A (CsA) treated rats. Chronic AT blockade alone does not affect endothelium-dependent relaxation and increases contractions to ATII in the rot aorta. Combination of CsA with either an ACE-Inhibitor or an AT2 receptor antagonist prevented the endothelial dysfunction in the rat arta observed after CsA alone.(ABSTRACT TRUNCATED AT 250 WORDS)
In normotensive Wistar rats, cyclosporine A causes a significant decrease in cardiac beta 1-adrenoceptors without affecting beta 2-adrenoceptors. This can be prevented by diltiazem or angiotensin-converting enzyme inhibitors. In heart transplant recipients, who undergo long-term treatment with cyclosporine A, there is a very similar beta 1-adrenoceptor down-regulation with time after transplantation. Thus, administration of cyclosporine A may cause these beta-adrenoceptor subtype alterations.
Chronic angiotensin-converting enzyme (ACE) inhibition prevents endothelial dysfunction in hypertension and hypercholesterolemia. Long-term treatment with cyclosporin A impairs endothelium-dependent relaxations and augments contractions to angiotensin II in the rat aorta. The present study compares vasomotor responses to several vasoconstrictor and dilator stimuli after 6 weeks of oral treatment with either the angiotensin-converting enzyme inhibitor lisinopril (10 mg/kg per day), the angiotensin subtype 1 receptor antagonist D 8731 (10 mg/kg per day), cyclosporin A (15 mg/kg per day), or a combination of cyclosporin A with lisinopril or D 8731 (n=15 rats per group). Twenty-four hours after the last treatment, aortic rings were mounted in organ chambers for measurement of isometric force. Endotheliumdependent relaxations to acetylcholine and calcium ionophore were impaired by cyclosporin A but not affected by the vasodilators. Cyclosporin A-induced endothelial dysfunction was prevented by cotreatment with lisinopril or D 8731. C hronic angiotensin-converting enzyme (ACE)inhibition prevents endothelial dysfunction in animal models with hypertension and hypercholesterolemia. 13 Even in hypertensive animals the modulation of endothelial function is not exclusively explained by the reduction of blood pressure, since treatment with hydralazine does not modify endothelium-dependent relaxations to the same extent, if at all. 1Considering additional studies showing reduced intima formation after endothelial injury and reduced development of atherosclerosis during ACE inhibition, 46 it has been hypothesized that chronic ACE inhibition protects or restores endothelial function. Both reduced angiotensin II (Ang II) formation and bradykinin accumulation during ACE inhibition have been discussed as mechanisms contributing to these effects.Long-term treatment with cyclosporin A (CsA) impairs endothelium-dependent relaxations in rats and humans.7 " In the rat this effect is not a consequence of increased blood pressure, since CsA does not significantly increase blood pressure in normotensive rats. 10 -12 We chose this model to determine possible protective effects of chronic ACE inhibition on endothelial function, since CsA has been shown to augment selectively the effects of Ang II in rat vascular smooth muscle. cidate the contribution of Ang II to these effects. In addition, we assessed the modulation of vascular smooth muscle contractions to Ang II and other vasoconstrictors by these treatments. CsA dosage was reduced compared with previous studies to reduce toxic side effects and to reach blood concentrations close to the therapeutic range.7 ' 10
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