Enhancement of the vasorelaxant potency of nicorandil by metabolic inhibition and adenosine in the pig coronary artery

Abstract

Nicorandil produced a dose-dependent relaxation with a mean pEC50 (-log EC50, M) of 4.76 +/- 0.02. Inhibition of metabolism with carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 100 nM) or by removal of extracellular glucose significantly increased the potency of nicorandil (pEC50s of 5.11 +/- 0.08 and 5.08 +/- 0.06, p < 0.05 in each case). The adenosine analogue 2-chloroadenosine (2-CA, 300 nM) had a similar effect (pEC50 = 5.17 +/- 0.06, p < 0.05). Reducing extracellular pH to 6.8 also significantly increased the potency of nicorandil, but to a smaller extent. Glibenclamide reduced the potency of nicorandil (pEC50 = 3.81 +/- 0.01, n = 7), and abolished its enhancement by CCCP, zero glucose, 2-CA or pH 6.8 solution. 2-CA did not affect the potency of nicorandil in relaxing contractions to 80 mM K+ or the potency of glyceryl trinitrate. We conclude that the potency of nicorandil to cause coronary vasorelaxation is increased under conditions of metabolic inhibition. This effect appears to result from the K+ channel opening action of the drug, and may have significant consequences for its therapeutic effectiveness.

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries

“…Evidence that this is the case for levcromakalim has been obtained by Randall & Gri th (1993) and Randall et al (1994), who showed that hypoxia, inhibition of oxidative phosphorylation, or adenosine increased the potency of the drug in causing vasorelaxation in the rabbit ear artery, though the potency of pinacidil was una ected. In porcine coronary arteries, we have recently shown that nicorandil relaxations were enhanced by metabolic inhibition, decreased pH, or adenosine receptor activation, so in this respect the K + channel opening action of nicorandil appears to resemble that of levcromakalim rather than pinacidil (Davie & Standen, 1998). Our present results suggest that this is also so in rat small mesenteric arteries, since both inhibition of oxidative phosphorylation with CCCP and removal of glucose potentiated nicorandil-induced relaxations.…”

Effects of ketamine on nicorandil induced ATP-sensitive potassium channel activity in cell line derived from rat aortic smooth muscle

“…The exact mechanisms of these effects have not been clearly identified. A recent study, however, indicated that metabolic inhibition significantly increased the potency of nicorandil on pig coronary artery relaxation (20). These results suggest that MgADP may enhance nicorandil induced KATP channel activities.…”

ATP-Sensitive Potassium Channels

“…Its effectiveness as an anti-anginal may be increased by a synergistic action with the intrinsic metabolic sensitivity of the K ATP channel, so that it preferentially activates channels in ischaemic tissue. In vitro studies on coronary arteries suggest that it may have such a self-targeting action [171]. A further incentive to consider K ATP channel openers as anti-anginal drugs may be an added benefit of a cardiprotective effect that is probably mediated by cardiac rather than vascular channels [169,170].…”