Effects of FK506 in rat and human resistance arteries

Background FK506 is widely used in organ transplantation and causes hyperte nsion. However. little is known about the impact of the drug on the cardiov ascular system. Methods. We therefore investigated the effect of FK506 on resistance artery and blood pressure responsiveness to vasoconstrictors and vasodilators. St udies were conducted in vitro using human and murine resistance artery, ex vivo in resistance artery isolated from rats treated with FK506 (6 mg/kg/da y), and in vivo in conscious. treated animals. Results. In vitro exposure (24 hr) of human and rat resistance artery to FK 506 (1000 ng/ml) increased the sensitivity to norepinephrine (NE) and impai red the response to acetylcholine (Ach) and sodium nitroprusside (SNp). In contrast, arteries isolated from rats given FK506 for eight days showed a r educed sensitivity to NE (P < 0.05) and a normal endothelium-dependent rela xation. Their incubation with L-arginine caused a significant reduction in Ach sensitivity in the FK506 group (P < 0.05) but not in controls, suggesti ng enhancement of nitric oxide production by the drug. The sensitivity to S Np 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 al so presented signs of a compensatory response to excess vasodilation: tachy cardia (P < 0.01). reduced blood pressure sensitivity to NE and Ach. blunte d 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 deteri oration, with significant impairment of the maximum responses to Ach and to SNp. Conclusion. FK506 presents significant vascular toxicity affecting mainly s mooth muscle relaxation and alters vascular hemodynamics. The data suggest that similar cardiovascular changes may occur in transplant patients and re present the forerunner of hypertension often seen with more prolonged use o f the drug.