K+ channel opening mediates the vasorelaxant effects of nicorandil in the intact vascular system.
Nicorandil and cromakalim relaxed rat aortic rings denuded of endothelium and precontracted with a low concentration of KCl (25 mM). Glibenclamide (1 microM) strongly antagonized only the effects of cromakalim while those of nicorandil were inhibited by methylene blue, an inhibitor of the soluble form of guanylate cyclase. High concentrations of nicorandil also produced vasorelaxation in aortic preparations contracted with 55 mM KCl, whereas cromakalim did not. In pentobarbital-anesthetized rats a 20-min i.v. infusion of cromakalim (5 micrograms/kg/min) or nicorandil (100 micrograms/kg/min) similarly decreased the mean carotid artery blood pressure. These effects, as well as the antihypertensive activity of nicorandil (5.0 mg/kg p.o.) and cromakalim (0.25 mg/kg p.o.) in spontaneously hypertensive rats were markedly inhibited by glibenclamide (20 mg/kg i.v.). Finally, glibenclamide (4 mg/kg i.v.) displaced to the right the control dose-coronary vasodilatory response curve to nicorandil injected into the left circumflex coronary artery of pentobarbital-anesthetized dogs. In conclusion, these results indicate that in a rat conductive vessel (aorta) nicorandil acts exclusively like nitrates, that is, it stimulates guanylate cyclase, and in resistance vessels (in the intact rat or dog coronary vascular bed) it opens K+ channels, as does cromakalim. Thus, nicorandil can be expected to have a broader spectrum of antianginal activity than drugs with a single mechanism of action. Additionally, as mentioned in the discussion section, substantial evidence exists that K+ channel opening can also afford marked cardioprotection against ischemia.
Cavero
I
I
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Pratz
J
J
Mondot
S
S
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil