Effects of FK506 in rat and human resistance arteries

Abstract

FK506 is widely used in organ transplantation and causes hypertension. However, little is known about the impact of the drug on the cardiovascular system. We therefore investigated the effect of FK506 on resistance artery and blood pressure responsiveness to vasoconstrictors and vasodilators. Studies were conducted in vitro using human and murine resistance artery, ex vivo in resistance artery isolated from rats treated with FK506 (6 mg/kg/day), and in vivo in conscious, treated animals. In vitro exposure (24 hr) of human and rat resistance artery to FK506 (1000 ng/ml) increased the sensitivity to norepinephrine (NE) and impaired the response to acetylcholine (Ach) and sodium nitroprusside (SNp). In contrast, arteries isolated from rats given FK506 for eight days showed a reduced sensitivity to NE (P < 0.05) and a normal endothelium-dependent relaxation. Their incubation with L-arginine caused a significant reduction in Ach sensitivity in the FK506 group (P < 0.05) but not in controls, suggesting enhancement of nitric oxide production by the drug. The sensitivity to SNp was reduced, as in the in vitro experiments (P < 0.05). Rats given FK506 for eight days presented blood pressure similar to that in controls but also presented signs of a compensatory response to excess vasodilation: tachycardia (P < 0.01), reduced blood pressure sensitivity to NE and Ach, blunted heart rate response to both agonists, and exaggerated hypotension at high doses of Ach. After 21 days of treatment, blood pressure remained similar to that in controls, but resistance artery showed further functional deterioration, with significant impairment of the maximum responses to Ach and to SNp. FK506 presents significant vascular toxicity affecting mainly smooth muscle relaxation and alters vascular hemodynamics. The data suggest that similar cardiovascular changes may occur in transplant patients and represent the forerunner of hypertension often seen with more prolonged use of the drug.