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
E-mail: kwancy@mcmaster.ca
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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