Jpn. J. Pharmacol. 85 (3), 234-240 (2001)

Vasorelaxant Effects of Pramanicin, an Anti-fungal Agent: Selective Action on Endothelial Cells

Chiu-Yin Kwan1,*, Paul H.M. Harrison2, Petra A. Duspara2 and Edwin E. Daniel1

1Department of Medicine, Faculty of Health Sciences and 2Department of Chemistry, Faculty of Science, McMaster Univeresity, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada
*Corresponding author. FAX: +1-905-522-3114

Abstract: A newly discovered antifungal agent, pramanicin, within the therapeutically effective concentration range (4-100 mM), 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 mM 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 mM carbachol or 100 mM 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 mM) inhibited the relaxation of PE-precontracted rings induced by 3 mM carbachol or 100 mM 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.

Keywords: Antifungal agent, Pramanicin, Endothelial cell, Nitric oxide, Vascularsmooth muscle

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