CYCLOSPORINE IMPAIRS RELEASE OF ENDOTHELIUM-DERIVED RELAXING FACTORS IN EPICARDIAL AND RESISTANCE CORONARY-ARTERIES

Background Cyclosporin A is reported to impair endothelium-mediated va sorelaxation and induce endothelin release in some noncoronary vascula r beds. We wished to determine whether acute cyclosporine administrati on induces endothelial dysfunction in coronary conductance or resistan ce arteries. Methods and Results We examined the effect of intracorona ry acetylcholine, N-omega-nitro-L-arginine methyl ester (L-NAME), L-ar ginine, nitroglycerin, and adenosine before and after acute cyclospori ne administration (3 mg/kg IV over 30 minutes) in anesthetized dogs. F low velocity was measured with a 0.014-in Doppler wire to assess resis tance vessel responses, and epicardial coronary lumen area was simulta neously measured with a 4.3F, 30-MHz imaging catheter inserted over th e Doppler wire. In 6 dogs, acetylcholine-induced increase in how veloc ity was attenuated by cyclosporine in vehicle (137% to 55% at 10(-5) m ol/L, P<.001), as was acetylcholine-induced epicardial vasodilation (1 4.1% to 6.7% at 10(-5) mol/L, P<.001). Vasodilation in response to int racoronary nitroglycerin (200 mu g) and adenosine (6 mg) were unchange d by cyclosporine. Epicardial vasoconstriction with L-NAME (10(-4) mol /L) was reduced by cyclosporine (Pre, 7.4+/-0.9%; Post, 2.6+/-1.2%; P= .04), but L-arginine (10(-4) mol/L) had no effect after cyclosporine. In another 5 dogs, pure cyclosporine impaired acetylcholine-induced va sodilatation to the same degree as cyclosporine in vehicle (Cremophor) ; vehicle infusion did not impair endothelial function. In 5 more dogs , cyclosporine did not increase either arterial or coronary sinus conc entrations of endothelin-1. Conclusions The present study shows that c yclosporine acutely impairs release of endothelium-derived relaxing fa ctor in canine conductance and resistance coronary arteries and provid es evidence for decreased epicardial nitric oxide release after cyclos porine. The potential contribution of acute cyclo-sporine-induced coro nary endothelial dysfunction to posttransplant vasculopathy needs furt her study.