抄録
A newly discovered antifungal agent, pramanicin, within the therapeutically effective concentration range (4 - 100 μM), inhibits the tone of phenylephrine (PE)-precontracted dog carotid arterial rings in a concentration-dependent manner and leads to gradual development of relaxation. However, pramanicin had no effect on rings precontracted with 100 mM KCl or on endothelium-denuded rings. Thus, inhibition by pramanicin of PE-induced contraction was endothelium-dependent. Preincubation of 100 μM pramanicin with carotid arterial rings for 30 min did not significantly affect the concentration-contraction response to PE, but almost completely inhibited the endothelium-dependent relaxation response to subsequent addition of 3 μM carbachol or 100 μM pramanicin. This irreversible inhibition of endothelium-dependent relaxation, which is independent of extracellular Ca2+, suggests possible endothelial cell damage by pramanicin. Pretreatment of the endothelium-intact vascular rings with L-NG-nitro-arginine (100 μM) inhibited the relaxation of PE-precontracted rings induced by 3 μM carbachol or 100 μM pramanicin, suggesting that the generation of nitric oxide (NO) in endothelial cells mediates the slow vascular relaxation induced by pramanicin. We conclude that pramanicin has little direct effect on the contractility of smooth muscle cells, but causes an initial slow endothelium-dependent, NO-mediated vascular relaxation. This is followed by a cytotoxic effect on vascular endothelial cells, eventually resulting in the loss of vasorelaxant function.
