The positive inotropic, antiarrhythmic and Na⁺, K⁺-ATPase inhibitory effects of the isoquinoline derivative, BIIA

Summary

The effect of the isoquinoline derivative 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-5,1-a-isoquinoline-hydrochloride (BIIA) were studied in the cat in situ and guinea-pig isolated heart preparations:

• 1. Administration of BIIA (2 mg/kg i.v.) to anaesthetized cats results in a rapid rise in cardiac (dP/dt)_max, decrease in heart rate and increase in systolic and diastolic blood pressure. These effects reach their maximum within a minute and disappear within 20 min. With increasing dosage a depression in the S T-segment of the ECG is observed, being similar to that induced by cardiac glycosides. Toxic doses lead to ventricular flutter and fibrillation.

• 2. In the concentration range of 0.3–10 μmol/l, BIIA exerts a strong positive inotropic effect in isolated guinea-pig heart preparations which is not mediated via α- or β-adrenoceptors and a negative chronotropic effect in spontaneously beating right atria.

• 3. BIIA inhibits Na⁺, K⁺-ATPase preparations isolated from guinea-pig heart and kidney in the range of 5–100 μmol/l. Unlike that of cardiac glycosides, this inhibition is competitive with Na⁺. The concentration response curves for the positive inotropic and Na⁺, K⁺-ATPase inhibitory effects of BIIA are both one order of magnitude higher in concentration than the respective concentration response curves found for ouabain.

• 4. BIIA is more potent than quinidine in increasing the threshold for arrhythmia induced by alternating current in isolated guinea-pig atria and papillary muscles. However, at a concentration of 3 μmol/l, BIIA can itself be arrhythmogenic.

• 5. A delay of repolarisation of the cardiac action potential may account for the antiarrhythmic properties of this drug, whereas strong inhibition of Na⁺, K⁺-ATPase and a decrease in resting potential may account for its toxicity at high concentrations. As there is a decrease in the plateau phase of the action potential at positive inotropic concentrations of BIIA, the increase in the force of contraction cannot be explained by alterations in the transmembrane potential, but similar to cardiac glycosides may be attributed to an inhibition of the Na⁺, K⁺-ATPase of the cell membrane.