Inhibitory action of SR33557 on L-type calcium current in single ventricular myocytes of rat.
1. The effect of SR33557 on L-type Ca2+ currents in rat ventricular myocytes was investigated by use of the whole-cell patch-clamp technique. 2. SR33557 inhibited Ca2+ current (ICa) in a concentration-dependent manner without change in the current-voltage relationship. 3. The inhibitory effect of SR33557 on ICa was dependent on the holding potential (Vh). The IC50 values were estimated to be 2.2 x 10(-8) M at Vh = -50 mV and 9.0 x 10(-6) M at Vh = -80 mV. SR33557 (10(-7) M) shifted the steady state inactivation curve of ICa toward more negative potentials. Thus, the affinity of the drug for inactivated channels was considerably higher than for resting channels. 4. Blockade of ICa by SR33557 was both tonic and use-dependent. 5. The time constant of onset of block was 36.4 s at -50 mV and 41.9 +/- 11.1 s at -40 mV. 6. The time course of unblock was voltage-dependent. The time constant declined from 400.7 +/- 68.1 is at -50 mV to 5.2 +/- 1.2 s at -80 mV. 7. The rate of block of ICa was related to the number of openings per unit time and to the amount of time spent depolarized. The affinity of drug for open channels was considered to be similar to that for inactivated channels. 8. These results suggest that SR33557 inhibits L-type Ca2+ current through binding to both open and inactivated channels in rat ventricular myocytes.
Yasui
K
K
Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston 77555-0641.
Palade
P
P
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D004594:Electrophysiology; D006352:Heart Ventricles / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007212:Indolizines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007212:Indolizines; D010627:Phenethylamines; C059901:fantofarone