SELECTIVE CARDIODEPRESSANT ACTIVITY OF FLUODIPINE, A FLUORENONE-1,4-DIHYDROPYRIDINE DERIVATIVE

The effect of the dihydropyridine derivative, methyl-4-(fluorenon-4-yl )pyridine-3,5-dicarboxylic acid diallyl ester (fluodipine) was studied in vitro in different rabbit, rat and guinea pig preparations and in vivo in the rabbit in order to characterize its pharmacological profil e at cardiac and at vascular sites. Compared to nifedipine, fluodipine showed a similar cardiodepressant activity, and a much lower inhibito ry activity on vascular contraction. The highest tissue selectivity wa s observed in guinea pig preparations: fluodipine was about 2-3 times more effective than nifedipine on chronotropism and inotropism in isol ated atria, and about 150 times less effective on aortic strip contrac tion. Accordingly, fluodipine (i) showed high-affinity binding to guin ea pig ventricular L-type cardiac Ca2+ channels (K-i = 2.57 nM), (ii) was about 80 times less effective than nifedipine to inhibit Ca2+ infl ux in vascular smooth muscle cells and (iii) induced a significant red uction of heart rate in the anesthetized rabbit (ID25 = 8.5 mg kg(-1), i.v.) without affecting the blood pressure up to 20 mg kg(-1), wherea s nifedipine showed a significant hypotensive effect at very low doses (ID25 = 0.18 mg kg(-1), i.v.). The pacemaker current I, of rabbit sin o-atrial node myocytes was not affected by fluodipine. These findings demonstrate that fluodipine exerts selective cardiodepressant activity , likely due to a higher affinity for cardiac than for vascular Ca-2channels. (C) 1998 Elsevier Science B.V. All rights reserved.