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Experiments were carried out to get information about the shifting mode of the frequency-force relationship curve (FFRC) of several well-established agents in guinea pig ventricular myocardium to estimate the ionic mechanism of inotropic action. The increase in [Ca2+]o or decrease in [Na+]o shifted the FFRC to the left and upwards, but no shift was observed when [Ca2+]o/[Na+]o2 ratio was kept constant. Drugs increasing [Na+]i (veratridine, asebotoxin) caused a parallel leftward shift of FFRC in the middle range of contraction frequency. Tetrodotoxin depressed the force of contraction (Fc) at higher frequencies, reflecting the fast Na influx inhibition. Nifedipine depressed, while BAY K 8644 augmented, the Fc at all frequency ranges, reflecting the Ca influx modulation. Ouabain and [c-AMP]i-elevating agents (isobutyl methylxanthine, histamine) strengthened the Fc at all frequencies. The ionic mechanism of these two groups of cardiotonic agents depending primarily on either Na or Ca influx could be estimated from a distinct time difference of the peak in the "rested-state" contraction curves of guinea pig papillary muscle. The shifting pattern of FFRC will contribute to the estimation of the mechanism of inotropic agents.

Estimation of the ionic mechanism of inotropic agents from the shifting pattern of frequency-force relationship in guinea pig ventricular myocardium.