PD 122860: a novel dihydropyridine with sodium channel stimulating and calcium channel blocking properties

SJ Haleen, RP Steffen, I Sircar, TC Major, MD Taylor, TA Pugsley and RE Weishaar

Department of Pharmacology, Chemistry, and Biochemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan.

The cardiac and vascular activities of ethyl 5-cyano-1,4-dihydro-6- methyl-2-[(4-pyridinyl-sulfonyl)methyl]-4-[2- (trifluoromethyl)phenyl]- 3-pyridine carboxylase (PD 122860), a novel dihydropyridine, were investigated in vitro using rat heart and rabbit aorta, and compared with reference inotropic and vasodilator agents. In the rat heart, PD 122860 increased left ventricular contractility, decreased coronary resistance and altered the shape of the electrocardiogram T-wave. All three effects were observed at comparable concentrations of PD 122860. The inotropic response to PD 122860 was reversed by the Na+ channel blocker tetrodotoxin and blunted by the Na+-Ca++ exchange inhibitor dichlorobenzamil. The effects of tetrodotoxin and dichlorobenzamil on the inotropic response to the reference Na+ channel stimulant veratridine were comparable to PD 122860, whereas tetrodotoxin and dichlorobenzamil had no inhibitory effect on the inotropic responses to the adenylate cyclase stimulator forskolin or the Ca++ channel stimulant BAY K 8644. PD 122860 selectively relaxed potassium- contracted aortic rings and inhibited [3H]nitrendipine binding to rat brain membranes, suggesting that the vasodilator activity of PD 122860 is due to Ca++ channel blockade. In contrast to BAY K 8644, PD 122860 did not contract partially depolarized aortic rings, suggesting an absence of Ca++ channel stimulant activity. PD 122860 is a racemic mixture and both the vasorelaxant and [3H]nitrendipine binding inhibitory activities selectively reside in the (+)-enantiomer [(+)-PD 122860]. In contrast, the inotropic response resides with both enantiomers of PD 122860. It is therefore concluded that PD 122860 represents a unique dihydropyridine derivative which possesses both Na+ channel stimulating and Ca++ channel blocking activities.

Volume 250, Issue 1, pp. 22-30, 07/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics