Chronic exposure to cyclosporine affects endothelial and smooth muscle reactivity in the rat aorta

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Chronic exposure to cyclosporine affects vascular reactivity. Experiments were designed to characterize the endothelium-dependent and endothelium-independent vascular reactivity of rats exposed to oral cyclosporin A (CyA). Two subsets of rats (n = 6) were treated with CyA (20 mg/kg/day) and olive oil (cyclosporine vehicle), respectively, for a period of 8 weeks. Aortic rings (4–5 mm) were suspended for isometric force measurement in organ chambers containing Krebs Ringer solution (37D°C, 95% O 2, 5% CO 2). The maximal endothelium-dependent relaxation 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 olive oil, 37% ± 7%; p < 0.05). However, endothelium-dependent relaxations to histamine and adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were not affected in both groups. An endothelium-dependent contraction to serotonin and aggregating platelets 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 oil ED 50, log −7.01 ± 0.11 mol/L; p < 0.01). These experiments suggest that chronic exposure to cyclosporine A could contribute to augmenting vascular tone by (1) decreased release of endothelial relaxing factor mediated by muscarinic receptors, (2) increased production of endothelium-related constricting factor mediated by serotoninergic receptors, and (3) greater vascular smooth muscle sensitivity to circulating catecholamine.