Abstract
Cardiac effects of 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7), a novel multidrug resistance (MDR) inhibitor, in Langendorff-perfused rat heart have been investigated and compared to that of nifedipine. Nifedipine decreased concentration-dependently (IC50=8.89+/-1.09x10(-8) M) left ventricular pressure leaving unaltered coronary perfusion pressure, whereas DP7 did not affect both parameters. Nifedipine did not modify both QRS and QT intervals of electrocardiogram (ECG). Second-degree atrioventricular block or ventricular rhythm occurred in presence of nifedipine, however, in 4 out of 6 hearts. DP7, up to 30 microM, failed to alter ECG parameters. In conclusion, DP7, may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of cardiac effects.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacology*
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Arrhythmias, Cardiac / chemically induced
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Calcium Channel Blockers / adverse effects
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Calcium Channel Blockers / pharmacology*
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Dihydropyridines / adverse effects
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Dihydropyridines / pharmacology*
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Dose-Response Relationship, Drug
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Electrocardiography
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Heart / drug effects*
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Heart Conduction System / drug effects
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In Vitro Techniques
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Male
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Nifedipine / adverse effects
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Nifedipine / pharmacology*
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Perfusion
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Rats
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Rats, Sprague-Dawley
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Ventricular Function, Left / drug effects
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Ventricular Pressure / drug effects
Substances
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3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine
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ATP Binding Cassette Transporter, Subfamily B
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Antineoplastic Agents
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Calcium Channel Blockers
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Dihydropyridines
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Nifedipine