INVESTIGATIONS INTO THE BRADYCARDIC EFFECTS 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) IN ISOLATED GUINEA-PIG ATRIA

  • 1 January 1986
    • journal article
    • research article
    • Vol. 8  (4) , 791-797
Abstract
The new bradycardic agent 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) was investigated in isolated guinea pig atria. In spontaneously beating preparations UL-FS 49, (0.03 and 0.1 .mu.g/ml) reduced the rate of contraction and decreased the maximal effect of isoprenaline added thereafter. The cumulative concentration-response curve of isoprenaline was antagonized, but not in a competitive manner, excluding an interaction at the .beta.-adrenoceptor. The rate of spontaneous electrical activity in sinoatrial node preparations was increased by superfusion with isoprenaline (0.1 .mu.g/ml). Addition of UL-FS 49 (0.1 .mu.g/ml) as well as propranolol (0.3 .mu.g/ml) reduced rate to control values. In electrically driven (1 Hz) left atrial UL-FS 49 (1 .mu.g/ml) did not reduce contractile force and did not antagonize the positive inotropic effect of isoprenaline added cumulatively thereafter. When contractile force was first elevated by isoprenaline (0.1 .mu.g/ml), addition of UL-FS 49 (0.1 .mu.g/ml) did not affect contractility, whereas propranolol (0.3 .mu.g/ml) abolished the positive inotropic effect of isoprenaline. The experiments, therefore, demonstrate the specificity of UL-FS 49 to decrease heart rate but not contractility during .beta.-adrenoceptor stimulation. In contrast to propranolol (0.3 .mu.g/ml) UL-FS 49 (0.1 .mu.g/ml) also reduced sinoatrial rate elevated by histamine (1 .mu.g/ml) or theophylline (300 .mu.g/ml), thus indicating a possible use as an antitachycardic drug at tachycardias of various origins. In sinus node preparations depolarized by high external K+ concentrations (10.8 mM), the bradycardic effect of UL-FS 49 (0.1 .mu.g/ml) was diminished. Under these conditions the sinus node depressant effects of nifedipine and diltiazem were enhanced. This makes it unlikely that the negative chronotropic effects of UL-FS 49 and of "Ca2+-antagonists" are due to the same mechanism of action; UL-FS 49 rather resembles strongly the "specific bradycardic agents" alinidine and falipamil, which previously gave analogous results in depolarized preparations.