Comparison of the effects of pinacidil and its metabolite, pinacidil‐N‐oxide, in isolated smooth and cardiac muscle

Abstract

AbstractThe effects of pinacidil and its major metabolite, pinacidil‐N‐oxide, were compared in isolated smooth and cardiac muscle preparations. Wide variation occurred in the sensitivity of different smooth muscle preparations to the relaxant effect of pinacidil. Relaxant sensitivity of pinacidil was greatest in the one vascular preparation examined, the rat aorta, where the ED50 for pinacidil was approximately 0.5 μM. Pinacidil was equally potent in relaxing serotonin‐ or norepinephrine‐contracted aortic preparations. Although pinacidil was also a smooth muscle relaxant in the guinea pig trachea, guinea pig ileum, rat vas deferens, and rat stomach funds, the ED50 ranged from 1‐‐25 μM in these smooth muscle preparations. In the trachea, pinacidil was most effective in relaxing histamine‐induced contractions as compared to contractions induced by carbamylcholine. Thus, bronchodilatory effects of pinacidil might be most apparent when bronchoconstriction is produced by allergic responses that result from histamine release. Pinacidil was least effective in quiescent rat uterine smooth muscle, where approximately 80% of the maximum contractile response to oxytocin was maintained in the presence of 10−4 M pinacidil. Although a direct cardiostimulatory effect of hydralazine has been postulated, no direct stimulatory effect on guinea pig cardiac rate or force occurred with pinacidil. Furthermore, an inhibitory effect on rate and force of atrial responses occurred only in higher doses of pinacidil. The major metabolite of pinacidil, pinacidil‐N‐oxide, also relaxed the rat aorta, although it was approximately eight‐ to tenfold less potent than pinacidil. These data are consistent with the contention that pinacidil‐N‐oxide would contribute to the antihypertensive activity seen after pinacidil only when plasma levels were approximately tenfold greater than the parent compound. Furthermore, because of the relative insensitivity of other smooth and cardiac.