EXTRACELLULAR SITE OF ACTION OF PHENYLALKYLAMINES ON L-TYPE CALCIUM CURRENT IN RAT VENTRICULAR MYOCYTES

The effects of the phenylalkylamines verapamil, gallopamil, and devapa mil on L-type calcium currents (I-Ca) were studied in ventricular myoc ytes from rat hearts using the whole-cell patch-clamp technique. In pa rticular, the question was addressed, whether the pharmacological bind ing sites for these drugs were located at the inner and/or at the oute r surface of the cell membrane. Therefore, tertiary verapamil, gallopa mil, and devapamil and their corresponding quaternary derivatives were applied either from the outside or the inside of the cell membrane. E xtracellular application of verapamil, gallopamil and devapamil (each at 3 mu M) reduced I-Ca to 16.1 +/- 8.6%, 11 +/- 8.9%, and 9.3 +/- 6% of control, respectively. Intracellular application of the same substa nces, via the patch pipette filled with 30 mu M of either verapamil, g allopamil, or devapamil, failed to depress I-Ca. The quaternary deriva tives of the phenylalkylamines (30 mu M) were ineffective both when ap plied extracellularly or intracellularly. It is suggested that phenyla lkylamines block I-Ca in ventricular myocytes by acting on a binding s ite of the calcium channel molecule located at the outer surface of th e cell membrane.