EFFECTS OF CALCIUM-CHANNEL ANTAGONISTS ON CA2+ TRANSIENTS IN RAT AND CANINE CARDIOMYOCYTES

First-generation Ca2+ channel antagonists depress myocardial contracti lity but many of the newer Ca2+ channel blockers have a high degree of ''vascular selectivity''. This study compares the effects of the Ca2 antagonists felodipine, amlodipine, mibefradil, verapamil and nifedip ine, and the Ca2+ channel agonist, (S)(-)-Bay K-8644 on Ca2+ transient amplitudes in fura-2/AM-loaded rat and canine ventricular cardiomyocy tes. At 10(-11) and 10(-10) M, felodipine increased [Ca2+](i) transien t amplitudes by 10-25% in field-stimulated fura-2-loaded cells from bo th species while at 10(-6) M it depressed [Ca2+](i) transients by 80%. Mibefradil increased [Ca2+](i) transient amplitudes by 16%, at 10(-11 ) and 10(-10) M and decreased the transients by 25% at 10(-6) M. The c alcium channel agonist. (S)(-)-Bay K-8644 increased [Ca2+](i) transien t amplitudes at 10(-10)-10(-6) M (maximally 37% at 10(-7) M) but depre ssed [Ca2+](i) transients by 10% at 10(-5) M. Nifedipine was inhibitor y at all concentrations tested (10(-11)-10(-6) M) in canine myocytes, but in rat cells, 10(-10) M nifedipine increased [Ca2+](i) transient a mplitudes by 37%. All concentrations of verapamil and amlodipine (10(- 11)-10(-6) M) depressed [Ca2+](i) transients in both rat and canine my ocytes. We conclude that: (1) felodipine and mibefradil may be positiv e rather than negative inotropes at low concentrations, which are ther apeutically relevant: and (2) low concentrations of nifedipine may hav e a positive inotropic effect in the rat but not the dog heart. (C) 19 97 Academic Press Limited.