N-Allyl-derivative of clonidine, a substance with specific bradycardic action at a cardiac site

Summary

The most prominant action of a new substance 2-[N-allyl-N-(2,6-dichlorophenyl)-amino]-2-imidazoline, St 567 is bradycardia. As shown by ECG recordings in anaesthetized rats and cats, the bradycardia (doses ≤0.5 mg/kg) is of the sinus type, changes in PQ- and QT-intervals were neglegible, there were no changes in the QRS-complex. The bradycardic action could be localized in the heart, as was observed in spinal rats and isolated guinea-pig atria, and is of high specificity — in the isolated atria the heart rate was decreased by much smaller concentrations (EC30=2.9 μg/ml) than contractility (EC30=155 μg/ml) and maximal driving frequency (EC30=40 μg/ml). Ratios between these 3 values were calculated and revealed a profile different from those of antiarrhythmics, so called “calcium antagonists”, and cholinergic drugs. In isolated guinea-pig atria the bradycardic effect of St 567 was not affected by phentolamine (1μg/ml) or atropine (0.05 μg/ml); the tachycardic action of isoprenaline (10⁻⁴–10⁻¹ μg/ml) was not affected by St567 (3 μg/ml) in a way that indicates competitive antagonism. Thereby an involvement of α-adrenoceptors, muscarinic receptors of β-adrenoceptors was excluded. With 30 mg/kg St 567 no gross changes in behaviour of rats were observed, allowing a differentation from other bradycardic drugs such as harmala alkaloids and veratramine. The hitherto unknown pharmacologic pattern of St567 is discussed, its possible therapeutic use in coronary heart disease is considered.