Analysis of the effects of (−) and (+) isomers of the 1,4-dihydropyridine calcium channel agonist BAY k 8644 on postrest potentiation in the canine ventricular muscle

Contraction of canine ventricular trabeculae were recorded at a stimulation frequency of 0.5 Hz and after rest periods of 2 and 8 min to analyze the effect of the Ca channel agonist BAY k 8644, on sarcoplasmic reticular function. Short periods of rest interposed between steady trains of stimuli caused a potentiation of the postrest beat. This is believed to be due to the mobilization of activator Ca from the sarcoplasmic reticulum (SR). Racemic BAY k 8644 and its Ca channel agonist enantiomer, (−) BAY k 8644, both produced an increase in contraction in response to a steady train of stimuli but converted rest potentiation into rest depression. This has been interpreted as increased loss of Ca from the SR during diastole. Addition of Ca channel antagonists, (+) BAY k 8644, nitrendipine, or nifedipine, to reverse the agonistic effect of (−) and racemic BAY k 8644 on the Ca channel did not convert the rest depression into rest potentiation. In the presence of any of the Ca channel antagonist alone, rest potentiation was not reversed but enhanced. The rank order of rest potentiation after these drugs was nifedipine > nitrendipine > (+) BAY k 8644. It is concluded that (−) BAY k 8644 enhances the ongoing loss of Ca from the SR during diastole in a manner similar to that of racemic BAY k 8644. However, its depressant effect on the postrest tension cannot be attributed to an increase in Ca current because (+) BAY k 8644 and other Ca channel antagonists did not reverse rest depression due to (−) or racemic BAY k 8644 even though they normalized steady-state tension. The difference between the effects of the three Ca channel antagonists on the postrest contraction suggests that they may have variable effects on the release of Ca from the SR in addition to causing inhibition of transsarcolemmal Ca influx. This difference may be related to different degrees of intracellular penetration of these compounds.