The group at C2 of N-ethylnicotinamide determines the vasodilator potencies and mechanisms of action of nicorandil and its congeners in canine coronary arteries

Summary

The relaxant mechanisms of action of nicorandil and its congeners (SG-86, SG-103, SG-209 and SG-212) on large coronary arteries were investigated in isolated canine circumflex arteries contracted with 25 mmol/l KCl or 10⁻⁷ mol/l U46619, a thromboxane A₂ analogue. SG-212, SG-86, SG-209 and SG-103 were obtained by replacement of the nitroxy group of nicorandil by bromine, the hydroxy, acetoxy and nicotinoyloxy groups, respectively.

Nicorandil (10⁻⁶–10⁻³ mol/l), SG-212 (3 × 10⁻⁴ –10⁻² mol/l),SG-209 (10⁻⁴–10⁻² mol/l), SG-103 (3 × 10⁻⁴–10⁻² mol/l), and SG-86 (10⁻³–10⁻² mol/l) all produced a concentration-dependent relaxation in KCl- or U46619-contracted arteries. The order of relaxant potency was as follows: Nicorandil » SG-209 > SG-212 = SG-103 > SG-86. The relaxant effect of nicorandil was not affected by glibenclamide but antagonized by methylene blue. In the presence of glibenclamide, the concentration-relaxation curves for SG-209 underwent rightward parallel shifts. The relaxant effect of SG-209, however, was not affected by methylene blue. The concentration-relaxation curves for SG-212 underwent rightward parallel shifts only to a limited extent in the presence of glibenclamide, but they were not affected by methylene blue. The relaxant effect of SG-103 was affected by neither glibenclamide or methylene blue. The relaxant effect of SG-86 was not affected by glibenclamide. The relaxant effect of nicorandil accompanied an increase in cyclic-GMP levels but that of SG-209 did not. These results indicate that the group at C2 of the parent structure of nicorandil and its congeners, i.e., N-ethylnicotinamide determines not only the vasodilator potency but the vasodilator mechanism of action of the compound.