CORONARY VASOMOTOR RESPONSES IN CYCLOSPORINE-TREATED PIGLETS

Chronic treatment with cyclosporine A (Cx) seems to produce a decrease d ability of the endothelium to secrete nitric oxide. However, its eff ect on the coronary arterial system remains controversial. Therefore, coronary arteries isolated from piglets treated by intramuscular injec tions of Cx (10 mg/kg/day, IM, for 22 days) were studied in organ bath s and compared with those isolated from control animals (IM injections of the Cx solvent). Depolarization-induced contractions (KCl 120 mM) were similar in both groups, whereas the acetylcholine-induced contrac tions (percent of 120 mM KCl) were enhanced: The area under the curve (AUC) was 245 +/- 51 in the Cx group versus 110 +/- 15 in the control group (p < 0.05). Removal of the endothelium did not significantly mod ify the acetylcholine-induced contractions in both groups and, therefo re, did not attenuate the enhanced responsiveness to acetylcholine in the Cx group. On unrubbed rings contracted with prostaglandin F-2 alph a, the endothelium-dependent relaxations from serotonin (in the presen ce of 1 mu M ketanserin) were reduced: The AUC was 479 +/- 24 in the C x group versus 385 +/- 22 in the control group (p < 0.02). Larger AUC values were also found for bradykinin and substance P in the Cx group: 158 +/- 18 versus 55 +/- 17 (in the control group, p < 0.01) and 198 +/- 8 versus 145 +/- 12 (p < 0.01), respectively. Nevertheless, no alt eration in calcium ionophore-induced relaxations was observed: The AUC was 217 +/- 10 in the Cx group and 224 +/- 18 in the control group (N S). Indomethacin incubation (10 mu M) did not prevent the impairment i n endothelium-dependent relaxations and did not attenuate the cyclospo rine-induced augmentation of acetylcholine-induced contractions. Thus, chronic administration of cyclosporine to piglets impairs the coronar y endothelial function and produces functional changes in smooth muscl e cells. These alterations may play a role in the occurrence of cardia c graft vasculopathy.