6533b873fe1ef96bd12d4ba9

RESEARCH PRODUCT

�ber den Mechanismus der positiv inotropen Wirkung von Theophyllin am Warmbl�terherzen

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In order to further elucidate the mechanism of the positive inotropiceffect of theophylline (T) in mammalian cardiac muscle, the influence of T on contractile force, extracellular space,45Ca uptake,45Ca release, and total myocardial calcium concentration was investigated in isolated, electrically driven (frequency 170 beats/min) or quiescent left guinea-pig atria. The investigations were performed in Tyrode solution containing 0.45 mM CaCl2. T concentration was 5×10−4 g/ml. Under these conditions, T exerted maximal positive inotropic but no toxic effects, that is, it did not cause contractures or arrythmias within 60 min (Fig. 1). The experiments provide evidence that T increases the rate of45Ca uptake and release without affecting the total amount of exchangeable cellular Ca or the myocardial Ca concentration. In this respect, as well as in others, its action ressembles that of adrenaline. It is assumed that the increased rate of45Ca uptake is due to an enhancement of membrane permeability to Ca, which must occur during the action potential since it was seen only in contracting and not in resting atria. With this assumption, it can be concluded that the positive inotropic effect of T, like that of adrenaline, in exclusively therapeutic and not toxic concentrations is mainly due to an increase in Ca influx from the extracellular space during the excitation process. As the fraction of exchangeable cellular Ca remained unchanged under the influence of T, an additional release ofintracellular Ca is unlikely to be an important factor in the therapeutic action of the drug in atrial preparations of mammalian cardiac muscle.