R. Budriesi et al., SELECTIVE CARDIODEPRESSANT ACTIVITY OF FLUODIPINE, A FLUORENONE-1,4-DIHYDROPYRIDINE DERIVATIVE, European journal of pharmacology, 359(2-3), 1998, pp. 161-170
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.