The sensitivity of coronary vascular tone to glibenclamide: a study on the isolated perfused guinea pig heart

Abstract

Objective: The aim was to obtain an estimate of the affinity of glibenclamide binding to ATP sensitive potassium channels of coronary smooth muscle cells in the intact guinea pig heart, in order to assess possible cardiovascular risks for diabetic patients receiving sulphonylurea drugs.

Methods: The arrested isolated perfused heart was used as a bioassay for KATP channels in coronary resistance vessels. The decrease of coronary perfusion pressure induced by hypoxia and by various concentrations of the potassium channel opener levcromakalim was measured and the inhibitory effect of glibenclamide on hypoxic and drug induced vasodilatation was analysed.

Results: The delay between application of hypoxic solution and half maximum vasodilatation was on average 105(SEM 4) s. It was increased by 17.6(2.0) s in the presence of 5 nM glibenclamide. The dose-response curve of the effects of levcromakalim on coronary perfusion pressure was shifted to the right in the presence of 20 nM to 1 microM glibenclamide. The concentrations of levcromakalim required to produce half maximum vasodilatation in the presence and absence of glibenclamide were determined, and the data were analysed using a Schild plot. The measured concentration ratios could be fitted by a straight line with a slope of 0.93(SD 0.04), which was not significantly different from 1. This is consistent with competitive inhibition of the vasodilator effects of levcromakalim by glibenclamide. The apparent dissociation constant of glibenclamide binding to KATP channels in coronary smooth muscle cells was 35 nM.

Conclusions: The KATP channels in coronary resistance arteries are almost as sensitive to inhibition by glibenclamide as the KATP channels in pancreatic beta cells. It is likely that the plasma concentrations reached after oral ingestion of glibenclamide may inhibit a fraction of the KATP channels in coronary smooth muscle cells and thus impair hypoxic dilatation of coronary resistance arteries.