Investigations into the bradycardic action of indoramin

Indoramin is a selective alpha 1-antagonist which reduces blood pressure without reflex tachycardia and can cause a bradycardia. The direct bradycardic effect of indoramin was investigated in various isolated cardiac preparations as well as in the intact cat. In isolated guinea-pig atria indoramin reduced spontaneous atrial rate in concentrations similar to those that reduced maximal driving frequency but smaller than those reducing contractility (EC30 = 0.9, 1.3 and 5.2 micrograms/ml, respectively). In the isolated perfused electrically driven (2.5 Hz) guinea-pig heart, indoramin 1 microgram/ml mainly increased ST interval with no effect on QRS interval, higher concentrations (3 micrograms/ml) also increased the QRS interval. In anaesthetized cats indoramin 6 mg/kg i.v. reduced blood pressure and heart rate (increased cycle length), increased the ST interval and effective refractory period (measured by electrical stimuli from the right ventricle) but had little or no effect on the QRS interval and the diastolic stimulation threshold. With the 10 mg/kg dose the latter two parameters were increased. Analogous experiments with the antiarrhythmic drug mexiletine (class I) showed little changes in cycle length, effective refractory period and the ST interval, however, there was a marked increase in diastolic threshold. DL-sotalol, which as well as having a beta-adrenoceptor blocking action, also prolongs action potential duration (class III antiarrhythmic activity), had the same cardiac profile as indoramin. For both indoramin and sotalol a significant positive correlation was shown between increase in cycle length and increase in effective refractory period. It is suggested that indoramin exerts class III antiarrhythmic activity and that this property is responsible for the bradycardic action of the drug which is seen in doses that already markedly reduce blood pressure. In higher doses or concentrations indoramin also exerts class I antiarrhythmic activity which, however, does not contribute to the bradycardic effect.