COMPARISON OF THE INVITRO AND INVIVO CARDIOVASCULAR EFFECTS OF 2 STRUCTURALLY DISTINCT CA(-K-8644 AND FPL-64176(+) CHANNEL ACTIVATORS, BAY)

We compared the cardiovascular effects of two structurally distinct L- type Ca++ channel activators, the 1,4-dihydropyridine Bay K 8644 and t he benzoylpyrrole FPL 64176. Both compounds prolonged action potential duration and enhanced contractility in guinea pig papillary muscle wi th 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) inc reased whole-cell Ca++ channel current amplitude in neonatal rat ventr icular cells by 249 +/- 14 and 484 +/- 100%, respectively. (S)-Bay K 8 644 had little effect on Ca++ channel activation but significantly enh anced the rate of Ca++ channel current inactivation. FPL 64176 signifi cantly slowed Ca++ channel current activation and inactivation. Tail c urrent 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 produc ed 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. Intr avenous administration (1-100 mug/kg) of Bay K 8644 and FPL 64176 prod uced 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 cardi ac 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 l east in some respects, from the 1,4-dihydropyridine group of agonists.