Endothelium-Derived Relaxing Factor and Muscle-Derived Relaxing Factor in Rat Aorta: Action of Cyclosporine A

Balligand, Jean-Luc;Godfraind, Theophile
(1991) SATELLITE SYMP OF THE INTERNATIONAL UNION OF PHARMACOLOGY : EDRF AND EDRF RELATED SUBSTANCES — Location: ANTWERP (Belgium) (28.June.1990)

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The aim of the present study was to characterize the toxicity of cyclosporine, a widely used immunosuppressant, toward vascular endothelial and smooth muscle cells. Rat aortic rings in classical organ baths and perfused rabbit thoracic aortas were exposed to cyclosporine or solvent in vitro. Cyclosporine reduced the maximum endothelium-dependent relaxation to acetylcholine and the ionophore A23187, but not to SIN-1, a metabolite of molsidomine that spontaneously releases nitric oxide (NO). L-Arginine, which is the precursor for the synthesis of NO from endothelial cells, relaxed rat aortic rings with or without endothelium that had been incubated for 8 h in physiological solution under O2 and CO2 at 37-degrees-C. Nitroarginine, a potent inhibitor of NO synthesis from L-arginine. and methylene blue, an inhibitor of guanylate cyclase, inhibited this relaxation in both types of rings, whereas cyclosporine did not. From these data, we conclude that the cells of the vascular wall synthesize not only an endothelium-derived relaxing factor (EDRF), but also a media-derived relaxing factor (MDRF), the nature of which is probably close to NO. Cyclosporine does not affect the synthesis of these two factors, but inhibits the endothelial cell mechanisms responsible for the stimulated EDRF release that follows muscarinic receptor activation and intracellular rise in calcium.
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Balligand, J.-L., & Godfraind, T. (1991). Endothelium-Derived Relaxing Factor and Muscle-Derived Relaxing Factor in Rat Aorta: Action of Cyclosporine A. Journal of Cardiovascular Pharmacology, 17(Suppl 3), S213-S221. https://doi.org/10.1097/00005344-199117003-00039 (Original work published 1991)