Über den Mechanismus der positiv inotropen Wirkung von Theophyllin am Warmblüterherzen

Summary

Isometric tension was measured in isolated electrically driven left guinea-pig atria (frequency 3 Hz) before and 5 min after addition of theophylline (T).

In normal Tyrode solution (1.8 mM Ca⁺⁺), T produced a concentration-dependent positive inotropic effect, threshold and peak concentrations being 10⁻⁵ and 5×10⁻⁴ g/ml, respectively. Higher, i.e. toxic concentrations caused contractures and a decrease in contractile force (Figs. 1 and 3).

The positive inotropic effect of T began immediately after addition of the drug and was maximal after about 2 min (Fig. 2). It was exclusively due to an increase in the rate of tension development; the time to peak tension and the duration of contraction remained unchanged (Tab. 2; Fig. 4). Toxic concentrations, however, resulted in a decrease in the rate of tension development and an increase in time to peak tension and duration of contraction (Tab. 2, Fig. 4).

The action of T was dependent on the [Ca]_e (Figs. 5 and 6). An increment in myocardial contractility was seen only at normal and reduced (0.45; 0.9 mM) [Ca]_e. Quantitatively, there was no difference in the absolute effect of T (measured asΔg/g dry weight) at 0.45; 0.9 and 1.8 mM Ca⁺⁺, but when plotted relatively (as % increase in force) the action of T was greater at 0.45 and 0.9 mM than at 1.8 mM Ca⁺⁺. At 3.6 and 7.2 mM Ca⁺⁺, low concentrations of T had no effect, but high concentrations diminished contractile force and caused contractures. In Ca⁺⁺ free solution neither contractions nor potassium contractures were obtained within 15 min after addition of 5 · 10⁻⁴ g/ml T (Fig. 7).

Reducing the [K]_e from 5.4 to 4.05 mM did not increase the positive inotropic effect of T. Likewise, the action of T was not diminished at an increased [K]_e of 8.1 mM (Fig. 10).

Reduction of the [Na]_e from 149.2 to 74.6 mM (Fig. 8) had no influence on the contractile response to T, provided that the [Ca]_e/[Na]_e ² ratio was kept constant.

It could be excluded that the positive inotropic effect of T was mediated by a release of endogenous catecholamines, as it was found not to be reduced in reserpinized atria (Tab. 4).

In conclusion, the experiments provide further evidence that the positive inotropic effect of T in therapeutic concentrations qualitatively ressembles that of adrenaline, which increases Ca⁺⁺ influx during the excitation process. Differences in the actions of both drugs, however, are observed with toxic concentrations, especially in that T causes contractures, which do not occur with adrenaline even in supramaximal doses.