COMPARATIVE RELAXANT EFFECTS OF CROMAKALIM AND PINACIDIL ON THE TONIC CONTRACTION OF CANINE CORONARY ARTERY INDUCED BY PHORBOL 12,13‐DIBUTYLATE

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Abstract
1. Phorbol esters, activators of protein kinase C (PKC), have been widely used to investigate the role of PKC in the regulation of smooth muscle contraction. However, limited studies have so far been made of the sensitivity of the contraction induced by phorbol esters to relaxant drugs. We therefore examined the relaxant effects of the K+ channel openers, cromakalim and pinacidil, on the tonic contraction of canine isolated coronary artery rings induced by phorbol 12,13‐dibutylate (PDBu). 2. In rings contracted with 10−7mol/L PDBu, cromakalim and pinacidil, as well as nifedipine, produced a concentration‐dependent relaxation. At their maximum effects, both cromakalim and nifedipine caused a partial relaxation, whereas pinacidil produced nearly a full relaxation. 3. The relaxant effects of cromakalim and pinacidil were effectively antagonized by the ATP‐sensitive K+ channel blocker, glibenclamide (10−6mol/L). 4. In the presence of nifedipine, high K+ was ineffective while PDBu (10−7mol/L) still induced a tonic contraction. This PDBu‐induced contraction was inhibited by concentrations of cromakalim and pinacidil higher than those needed in the absence of nifedipine. 5. In rings partially depolarized with 35mmol/L KCl, the ability of cromakalim to inhibit PDBu‐induced contractions in the presence of nifedipine was completely abolished. Under the same conditions, the relaxant response to pinacidil, unlike cromakalim, was inhibited only partially. 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 independent of this K+ channel opening action. These multiple modes of action may confer on pinacidil a vasorelaxant activity greater than that of cromakalim.