Vasorelaxant effects of pramanicin, an anti-fungal agent: selective action on endothelial cells.
A newly discovered antifungal agent, pramanicin, within the therapeutically effective concentration range (4-100 microM), 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 microM 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 microM carbachol or 100 microM 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-N(G)-nitro-arginine (100 microM) inhibited the relaxation of PE-precontracted rings induced by 3 microM carbachol or 100 microM 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.
Kwan
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Department of Medicine, Faculty of Health Sciences, Faculty of Science, McMaster University, Hamilton, Ontario, Canada. kwancy@mcmaster.ca
Harrison
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Duspara
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Daniel
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D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000633:toxicity; D002217:Carbachol / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D007769:Lactams / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007769:Lactams; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C432807:pramanicin; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D002217:Carbachol; D019001:Nitric Oxide Synthase