Effects of Ca Antagonists on Force Interval Relationships in Guinea-pig Atrial Preparations

The effects of Ca antagonists, nifedipine (NF), verapamil, nicardipine (NC), bepridil on the steady state levels of the isometric force were studied at 0.1-2Hz. The pD_2 values for depresssion at 2 Hz were 6.7, 6.5, 6.4 and 6.1, and at 0.5 Hz were 6.8, 5.6, 5.6 and 5.4, respectively. The latter three drugs were thus selective at high frequencies. Mechanical restitution curves after converting to logistic function (n=4) reached a peak nearly at 15s and were fitted well to double exponential functions with time constants of 0.4s (τA) and 7s (τB). All drugs at the concentrations at which forces were reduced by 40-50% at 1 Hz enhanced the intercepts of slow components, whereas NC significantly reduced the intercepts of fast components and decreased τB. The change in mechanical restitution was interpreted as showing that contribution of Isi to the contraction of the accompanying beat was not large. A computer model was constructed to simulate these effects of drugs assuming that Ca^<2+> transported through slow channels and Na-Ca exchange mechanisms was sequestered into intracellular, uptake, release and store sites. The frequency dependent actions of Ca antagonists were explained in terms of the reduction of the maximum influx through these channels for NF, and the use-dependent retardation of the slow channel recovery for the other drugs.