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D Rampe, B Anderson, V Rapien-Pryor, T Li and RC Dage
Marion Merrell Dow Research Institute, Cincinnati, Ohio.
We compared the cardiovascular effects of two structurally distinct L- type Ca++ channel activators, the 1,4-dihydropyridine Bay K 8644 and the benzoylpyrrole FPL 64176. Both compounds prolonged action potential duration and enhanced contractility in guinea pig papillary muscle with these responses being greater in the presence of FPL 64176 compared to (S)-Bay K 8644. (S)-Bay K 8644 (300 nM) and FPL 64176 (300 nM) increased whole-cell Ca++ channel current amplitude in neonatal rat ventricular cells by 249 +/- 14 and 484 +/- 100%, respectively. (S)-Bay K 8644 had little effect on Ca++ channel activation but significantly enhanced the rate of Ca++ channel current inactivation. FPL 64176 significantly slowed Ca++ channel current activation and inactivation. Tail current decay at -50 mV was monoexponential in the presence of (S)- Bay K 8644 and had a time constant of 4.59 +/- 0.16 msec. FPL 64176 produced biexponential tail current decays at -50 mV with fast and slow time constants of 4.30 +/- 0.30 and 44.52 +/- 4.56 msec, respectively. Intravenous administration (1-100 micrograms/kg) of Bay K 8644 and FPL 64176 produced large increases in cardiac contractile force and diastolic blood pressure in anesthetized dogs. Pretreatment with nifedipine attenuated the blood pressure response to FPL 64176 but not the effects on cardiac contractility. This study demonstrates that the benzoylpyrrole FPL 64176 defines a new and potent class of Ca++ channel agonist molecule and that this compound has pharmacological activity that differs, at least in some respects, from the 1,4-dihydropyridine group of agonists.
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