Cardiovascular characterization of UL-FS 49, 1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-][2-(3,4-dimethoxyphenyl)ethyl] methylimino]propyl]-2H-3-benzazepin-2-on hydrochloride, a new "specific bradycardic agent"

Abstract

UL-FS 49, a chemical congener of AQ-A 39 with structural similarities to verapamil, decreased the rate of spontaneously beating guinea-pig atria at much lower concentrations (effective concentration 30%, EC30 = 0.030 microgram/ml) than it decreased the contractility (2.5 Hz; EC30 = 108 micrograms/ml) and maximal driving frequency (EC30 = 11 micrograms/ml) in electrically driven atria. In comparable experiments AQ-A 39 was much less effective, the EC30 for the negative chronotropic effect being 0.61 microgram/ml. In rabbit aortic strips in the presence of 43 mM K+ and 1.8 mM Ca2+, UL-FS 49 relaxed contraction by 30% at 15 micrograms/ml. In contrast to UL-FS 49, several "Ca2+-antagonists" elicited aortic relaxation at lower concentrations than bradycardia. In anaesthetized cats (n = 6) 0.3 mg/kg i.v., UL-FS 49 increased the cardiac cycle length by 56 +/- 3.5% (S.E.), there were slight or no changes in blood pressure and ECG intervals PQ and QRS. ST and the effective refractory period (ERP), as determined by R-triggered extrastimuli in the right ventricle, were prolonged by 28 +/- 3.1% and 24 +/- 2.5% respectively. At comparable increases in cycle length AQ-A 39 prolonged ST and ERP significantly more than UL-FS 49. In isolated guinea-pig atria UL-FS 49 antagonized the carbachol-induced bradycardia; a 10-fold shift of the dose-response curve (CA10) was achieved with 11.3 micrograms/ml and the CA10 for AQ-A 39 was 1.7 micrograms/ml. In conscious dogs UL-FS 49, 1 mg/kg i.v., decreased the heart rate without changes in blood pressure. This was observed in dogs with both genuine sinus rate and heart rate elevated by either atropine or hydralazine. The bradycardic effect was positively correlated with the control heart rate. In conclusion, sinus bradycardia was the most prominent action of UL-FS 49 in isolated preparations as well as in intact animals. In comparison to its congener AQ-A 39, UL-FS 49 was more potent in lowering heart rate but less effective in prolonging repolarization time and in anticholinergic activity. It thus represents a new specific bradycardic agent.