ENDOTHELIUM-MEDIATED VASODILATION DURING ACE-INHIBITION

ACE inhibitors are superior to other vasodilators in the treatment of congestive heart failure and may be advantageous in patients with myoc ardial infarction and hypertension. The mechanisms mediating these ben eficial effects are not clear. The present article discusses the mecha nisms lending 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 arterie s mounted in organ chambers for recording of isometric force. The ACE inhibitors captopril, enalaprilat, fosinoprilat, lisinopril, or ramipr ilat alone did not affect vascular tone in isolated coronary artery pr eparations with intact endothelium. However, in the presence of exogen ous Bk, kallidin, or one of the slowly degradable Bk-2-receptor agonis ts D-Arg(Hyp(3))-Bk or [Hyp(3)-Tyr(Me)(8)]-Bk they elicited potent con centration-dependent relaxations. Relaxations in response to lisinopri l were not observed in the presence of other vasodilators. They were p revented by mechanical removal of the endothelium, inhibition of nitri c oxide synthase or Bk-2-receptor blockade. The data indicate that ACE inhibitors potentiate the effects of Bk on endothelial cells by a loc al mechanism probably independent of the degradation of bradykinin. Th e chronic effects of ACE inhibitors on endothelial function were compa red with those of selective angiotensin(AT)(1)-receptor blockade in cy closporin A (CsA) treated rats. Chronic AT blockade alone does not aff ect endothelium-dependent relaxations and increases contractions to AT II in the rat aorta. Combination of CsA with either an ACE-inhibitor o r an AT(2) receptor antagonist prevented the endothelial dysfunction i n the rat arta observed after CsA alone. The data suggest a role for A TII in the development of chronic endothelial dysfunction.