Vasomotor responses in cyclosporin A-treated rats after chronic angiotensin blockade.

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. Endothelium-dependent 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. Relaxations to nitroglycerin, SIN-1, and forskolin were not affected by any treatment. Contractions to phenylephrine and serotonin were reduced by lisinopril but not by D 8731. In contrast, contractions to angiotensin II were augmented by cyclosporin A, lisinopril, and the combination of both but not by D 8731 or D 8731 plus cyclosporin A. The data suggest a role for angiotensin II in cyclosporin A-induced endothelial dysfunction. Chronic ACE inhibition reduces overall smooth muscle contractility. The selective augmentation of angiotensin II effects by ACE inhibition and cyclosporin A suggests upregulation of angiotensin receptors in the aortic smooth muscle by these treatments. Chronic angiotensin subtype 1 receptor blockade does not appear to affect angiotensin receptor function.