The negative inotropic effect of nicorandil is independent of cyclic GMP changes: a comparison with pinacidil and cromakalim in canine atrial muscle.
1. The negative inotropic effects of nicorandil, a nitrate with K-channel opening properties, have been compared with those of pinacidil, cromakalim and nifedipine, in canine right atrial muscle. 2. Cromakalim, pinacidil and nicorandil all produced a negative inotropic effect. However, even at their maximally effective concentrations, the force of contraction remained at about 10% of control levels, whereas contraction was abolished by nifedipine. 3. The pD2 values for the negative inotropic effects of cromakalim, pinacidil and nicorandil were 5.93, 5.37, and 4.35, respectively. 4. The negative inotropic effects of cromakalim (3 x 10(-5)M), pinacidil (3 x 10(-5) M and 3 x 10(-4) M) and nicorandil (3 x 10(-5) M) were not accompanied by changes in cyclic AMP and cyclic GMP levels, whereas that of 3 x 10(-4) M nicorandil was accompanied by an increase in cyclic GMP but not cyclic AMP concentrations. 5. The negative inotropic effect produced by 3 x 10(-4) M nicorandil was greatly reduced by 10(-2) M tetraethylammonium, whereas the increase in cyclic GMP produced by this concentration of nicorandil was not significantly changed. Sodium nitroprusside (10(-3) M) produced a large increase in cyclic GMP concentrations but had no significant negative inotropic effect. 6. It is concluded that the negative inotropic effects of nicorandil like those of cromakalim and pinacidil do not result from an increase in cyclic GMP concentrations. Instead these effects may be due to their action as K-channel openers.
Yanagisawa
T
T
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Hashimoto
H
H
Taira
N
N
D000818:Animals; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D009543:Nifedipine / Q000494:pharmacology; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D001578:Benzopyrans; D006146:Guanidines; D008996:Monoamine Oxidase Inhibitors; D015221:Potassium Channels; D011758:Pyrroles; D013757:Tetraethylammonium Compounds; D014665:Vasodilator Agents; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D020110:Pinacidil; D000242:Cyclic AMP; D006152:Cyclic GMP; D009543:Nifedipine