ENHANCEMENT OF THE VASORELAXANT POTENCY OF NICORANDIL BY METABOLIC INHIBITION AND ADENOSINE IN THE PIG CORONARY-ARTERY

Objective: Nicorandil is used clinically to treat angina and acts in p art by opening ATP-sensitive K+ channels whose opening is also enhance d by metabolic compromise. We have therefore investigated whether trea tments that mimic conditions in ischaemia can increase the potency of nicorandil to dilate coronary arteries. Methods: Ring segments from pi g small coronary arteries were mounted on a myograph, contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 6844, and relaxations t o cumulative doses of nicorandil were measured. Results and Conclusion s: Nicorandil produced a dose-dependent relaxation with a mean pEC(50) (-log EC50, M) of 4.76 +/- 0.02. Inhibition of metabolism with carbon yl cyanide m-chlorophenyl hydrazone (CCCP, 100 nM) or by removal of ex tracellular glucose significantly increased the potency of nicorandil (pEC(50)s 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 (pEC(50) = 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 (pEC (50) = 3.81 +/- 0.01, n = 7), and abolished its enhancement by CCCP, z ero 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 g lyceryl trinitrate. We conclude that the potency of nicorandil to caus e coronary vasorelaxation is increased under conditions of metabolic i nhibition. This effect appears to result from the K+ channel opening a ction of the drug, and may have significant consequences for its thera peutic effectiveness. (C) 1998 Elsevier Science B.V.