The Relation Between Vascular Relaxant and Cardiac Electrophysiological Effects of Pinacidil

Abstract

Pinacidil may represent an example of a new class of vasodilators that act by increasing membrane permeability to potassium ions. In the present study, the cardiac electrophysiological and venorelaxant effects of a series of pinacidil analogs in canine tissues in vitro were examined. Piacidil (3 x 10(-5) M) markedly reduced action potential duration in Purkinje fibers (82 +/- 3% decrease) and ventricular muscle (54 +/- 2% decrease) without significantly affecting maximal upstroke velocity of the action potential or conduction time. The EC50 for the reduction in Purkinje fiber action potential duration was 2.6 +/- 0.5 microM. Pinacidil also decreased barium-induced automaticity in Purkinje fibers; the concentration that decreased the rate of firing by 50% was identical to the EC50 for decreasing action potential duration. In some preparations, high concentrations of pinacidil (greater than or equal to 3 x 10(-5) M) were associated with the appearance of spontaneous action potentials that were closely coupled to the preceding driven action potential. The EC50 for pinacidil in relaxing phenylephrine-contracted cephalic veins was 0.43 +/- 0.09 microM, and in isolated cat papillary muscle, pinacidil had a direct negative inotropic effect with an EC50 of 4.1 +/- 0.7 microM. Thus, pinacidil was 6 and 10 times more potent in relaxing phenylephrine-contracted veins than in shortening action potential or decreasing cardiac contractility. There was an excellent correlation (r = 0.933, p = 0.002) between decreases in action potential duration and venorelaxation for all pinacidil analogs, as well as for BRL 34915 and nicorandil, two purported potassium channel openers. Significant correlations were also obtained between negative inotropic effects and reductions in action potential duration for the pinacidil series. Pinacidil (10(-5) M) also inhibited the venoconstrictor responses to the selective alpha 2 agonist, B-HT 920, to a greater extent than the alpha 1 agonist, methoxamine. Since a good correlation exists in vitro among all the compounds studied in reducing action potential duration, relaxing vascular tissue, and decreasing cardiac contractility, it is concluded that pinacidil as well as nicorandil and BRL 34915 affect vascular and cardiac tissues by similar mechanisms, possibly by increases in potassium ion permeability, although other mechanisms may also play a role.