Comparison of two substances with a possible alpha-adrenoceptor blocking and calcium channel blocking activity in rabbits in vivo under the paced and non-paced heart conditions. II. The hemodynamic effects.

Abstract

The effects of i. v. administration of substances VUFB 17951 (0.046 and 0.46 mg/kg) and VUFB 17959 (0.045 and 0.45 mg/kg) on hemodynamics of rabbits in vivo have been determined under the paced and non-paced heart conditions. The substances (N-arakyl derivatives of 2-aminomethyl-1, 4 benzodioxane) used in our study possessed calcium-channel and alpha-adrenoceptor blocking activity in the isolated preparations. The administration of VUFB 17951 (in the non-paced heart) induced a dose-dependent decrease in blood pressure (max. 62.2%), a mild slowing-down of the heart rate (max. 83.6%), a progressive and marked decrease in the values of the minute (max. 40.6%) and stroke (max. 41.4%) blood flow in the abdominal aorta. The administration of the lower dose of VUFB 17959 induced a mild increase in the blood pressure (max. 115.6%), after the higher dose a mild decrease in blood pressure was found (max. 83.1%). VUFB 17959 induced a mild slowing down of the cardiac frequency (max. 88.2%) and a progressive and marked decrease in minute (max. 45.3%) and stroke (max. 43.2%) blood flow in the abdominal aorta. In most intervals (during 120 min observation) no significant differences in the followed parameters were found between the conditions of the paced and non-paced hearts. The effects of VUFB 17951 were mostly more marked compared with those of VUFB 17959. From the point of view of a further study of the substances under examination the fact that premature death of animals occurred seems to be substantial. The premature death (followed up to the 240th min after the administration of substances) occurred in about 2/3 of animals and was accompanied with signs of an acute cardiac and hemodynamic failure. The observed hemodynamical changes may be manifestations of a presence of calcium-channel antagonistic effects of substances, possibly in combination with their alpha-adrenergic blocking activity. However, they do not exclude other possible mechanisms of their action or toxicity. On the basis of the results obtained in our study a need follows to investigate the effects of substances during a long period after their administration. A consideration should be paid to other routes of administration as well as a necessity of further detailed study concerning the pharmacodynamics and pharmacokinetics of substances.