Coronary vasomotor responses in cyclosporine-treated piglets

Abstract

Chronic treatment with cyclosporine A (Cx) seems to produce a decreased ability of the endothelium to secrete nitric oxide. However, its effect on the coronary arterial system remains controversial. Therefore, coronary arteries isolated from piglets treated by intramuscular injections of Cx (10 mg/kg/day, IM, for 22 days) were studied in organ baths 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 contractions (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 modify the acetylcholine-induced contractions in both groups and, therefore, did not attenuate the enhanced responsiveness to acetylcholine in the Cx group. On unrubbed rings contracted with prostaglandin F2 alpha, the endothelium-dependent relaxations from serotonin (in the presence of 1 microM ketanserin) were reduced: The AUC was 479 +/- 24 in the Cx 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 alteration in calcium ionophore-induced relaxations was observed: The AUC was 217 +/- 10 in the Cx group and 224 +/- 18 in the control group (NS). Indomethacin incubation (10 microM) did not prevent the impairment in endothelium-dependent relaxations and did not attenuate the cyclosporine-induced augmentation of acetylcholine-induced contractions. Thus, chronic administration of cyclosporine to piglets impairs the coronary endothelial function and produces functional changes in smooth muscle cells. These alterations may play a role in the occurrence of cardiac graft vasculopathy.