COMPARATIVE RELAXANT EFFECTS OF CROMAKALIM AND PINACIDIL ON THE TONICCONTRACTION OF CANINE CORONARY-ARTERY INDUCED BY PHORBOL 12,13-DIBUTYLATE

1. Phorbol esters, activators of protein kinase C (PKC), have been wid ely used to investigate the role of PKC in the regulation of smooth mu scle contraction. However, limited studies have so far been made of th e sensitivity of the contraction induced by phorbol esters to relaxant drugs. We therefore examined the relaxant effects of the KC channel o peners, cromakalim and pinacidil, on the tonic contraction of canine i solated coronary artery rings induced by phorbol 12,13-dibutylate (PDB u). 2. In rings contracted with 10(-7) mol/L PDBu, cromakalim and pina cidil, as well as nifedipine, produced a concentration-dependent relax ation. At their maximum effects, both cromakalim and nifedipine caused a partial relaxation, whereas pinacidil produced nearly a full relaxa tion. 3. The relaxant effects of cromakalim and pinacidil were effecti vely antagonized by the ATP-sensitive K+ channel blocker, glibenclamid e (10(-6) mol/L). 4. In the presence of nifedipine, high KC was ineffe ctive while PDBu (10(-7) mol/L) still induced a tonic contraction. Thi s PDBu-induced contraction was inhibited by concentrations of cromakal im and pinacidil higher than those needed in the absence of nifedipine . 5. In rings partially depolarized with 35 mmol/L KCI, the ability of cromakalim to inhibit PDBu-induced contractions in the presence of ni fedipine was completely abolished. Under the same conditions, the rela xant response to pinacidil, unlike cromakalim, was inhibited only part ially. 6. These results suggest that cromakalim inhibits PDBu-induced contractions through an opening of K+ channels. Pinacidil does so by a mechanism shared with cromakalim as well as by another that is indepe ndent of this K+ channel opening action. These multiple modes of actio n may confer on pinacidil a vasorelaxant activity greater than that of cromakalim.