title: Enhancement of the vasorelaxant potency of nicorandil by metabolic inhibition and adenosine in the pig coronary artery.
abstract: OBJECTIVE
  Nicorandil is used clinically to treat angina and acts in part by opening ATP-sensitive K+ channels whose opening is also enhanced by metabolic compromise. We have therefore investigated whether treatments that mimic conditions in ischaemia can increase the potency of nicorandil to dilate coronary arteries.
  
  
  METHODS
  Ring segments from pig small coronary arteries were mounted on a myograph, contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 6844, and relaxations to cumulative doses of nicorandil were measured.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Davie
authors.forename: N B
authors.initials: NB
authors.lastname: Standen
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D015221:Potassium Channels / Q000187:drug effects*; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007476:Ionophores; D015221:Potassium Channels; D014665:Vasodilator Agents; D015762:2-Chloroadenosine; D009536:Niacinamide; D020108:Nicorandil; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D005947:Glucose; D005905:Glyburide