CHRONIC EXPOSURE TO CYCLOSPORINE AFFECTS ENDOTHELIAL AND SMOOTH-MUSCLE REACTIVITY IN THE RAT AORTA

Chronic exposure to cyclosporine affects vascular reactivity. Experime nts were designed to characterize the endothelium-dependent and endoth elium-independent vascular reactivity of rats exposed to oral cyclospo rin A (CyA). Two subsets of rats (n = 6) were treated with CyA (20 mg/ kg/day) and olive oil (cyclosporine vehicle), respectively, for a peri od of 8 weeks. Aortic rings (4-5 mm) were suspended for isometric forc e measurement in organ chambers containing Krebs Ringer solution (37 d egrees C, 95% O-2, 5% CO2). The maximal endothelium-dependent relaxati on to cumulative doses of acetylcholine was significantly decreased in the CyA-treated aortic rings compared to olive oil-treated ones (data expressed as percent of initial contraction; CyA, 50% +/- 3% versus o live oil, 37% +/- 7%; p < 0.05). However, endothelium-dependent relaxa tions to histamine and adenosine diphosphate and endothelium-independe nt relaxation to sodium nitroprusside were not affected in both groups . An endothelium-dependent contraction to serotonin and aggregating pl atelets were observed in the CyA group, but not in the control group. The endothelium-independent contraction to norepinephrine was enhanced in the CyA group (CyA ED(50), log -7.66 +/- 0.18 mol/L versus olive o il ED(50), log -7.01 +/- 0.11 mol/L; p < 0.01). These experiments sugg est that chronic exposure to cyclosporine A could contribute to augmen ting vascular tone by (1) decreased release of endothelial relaxing fa ctor mediated by muscarinic receptors, (2) increased production of end othelium-related constricting factor mediated by serotoninergic recept ors, and (3) greater vascular smooth muscle sensitivity to circulating catecholamine.