Selective cardiodepressant activity of fluodipine, a fluorenone-1,4-dihydropyridine derivative.
The effect of the dihydropyridine derivative, 1,4-dihydro-2,6-dimethyl-4-(fluorenon-4-yl)pyridine-3,5-dicarboxyl ic 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 profile at cardiac and at vascular sites. Compared to nifedipine, fluodipine showed a similar cardiodepressant activity, and a much lower inhibitory activity on vascular contraction. The highest tissue selectivity was observed in guinea pig preparations: fluodipine was about 2-3 times more effective than nifedipine on chronotropism and inotropism in isolated atria, and about 150 times less effective on aortic strip contraction. Accordingly, fluodipine (i) showed high-affinity binding to guinea pig ventricular L-type cardiac Ca2+ channels (Ki=2.57 nM), (ii) was about 80 times less effective than nifedipine to inhibit Ca2+ influx in vascular smooth muscle cells and (iii) induced a significant reduction 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), whereas nifedipine showed a significant hypotensive effect at very low doses (ID25=0.18 mg kg(-1), i.v.). The pacemaker current If of rabbit sino-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 Ca2+ channels.
Budriesi
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R
Department of Pharmaceutical Sciences, University of Bologna, Italy.
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Valenti
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Chiarini
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D000758:Anesthesia; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016275:Atrial Function; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004095:Dihydropyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009543:Nifedipine / Q000378:metabolism / Q000494:pharmacology; D010138:Pacemaker, Artificial; D018408:Patch-Clamp Techniques; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003998:Dicarboxylic Acids; D004095:Dihydropyridines; D014665:Vasodilator Agents; C116561:fluodipine; C038806:1,4-dihydropyridine; D009543:Nifedipine; D002118:Calcium