Actions of cyclosporin A preparation and Cremophor-EL in rabbit mesenteric artery and thoracic aorta in vitro.
ABSTRACT 1. We studied the in vitro and direct effects of intravenous cyclosporin A preparation (Sandimmun) and its solvent (Cremophor-EL) on acetylcholine-induced endothelium-dependent relaxation, phenylephrine-induced contraction and drug-induced contraction of rabbit thoracic aorta and superior mesenteric artery segments. 2. At the lower concentration (5 micrograms/ml), cyclosporin A preparation inhibited endothelium-dependent relaxation of the superior mesenteric artery but not of the thoracic aorta. At this concentration cyclosporin A preparation augmented phenylephrine-induced contraction in both segments but by more in the superior mesenteric artery, and induced a slow increase in the tone of isolated superior mesenteric artery and thoracic aortic rings, which was greater in magnitude in the superior mesenteric artery than in the thoracic aorta. 3. Acetylcholine-induced endothelium-dependent relaxation was inhibited by cyclosporin A preparation (50 micrograms/ml) in both arteries but to a greater extent in the superior mesenteric artery. 4. The solvent of the intravenous cyclosporin A preparation (Cremophor-EL) in concentrations corresponding to those of the drug caused less inhibitory effects than cyclosporin A preparation on acetylcholine-induced endothelium-dependent relaxation, had comparable effects on phenylephrine-induced contraction, and produced similar contractions of both arteries. 5. The results indicate that Cremophor-EL may contribute to the inhibitory action of cyclosporin A preparation on acetylcholine-induced endothelium-dependent relaxation in the superior mesenteric artery, but is fully responsible for the smooth-muscle-contracting effect and the potentiation of phenylephrine-induced contraction in both arteries.