ACUTE AND CHRONIC CARDIAC AND REGIONAL HEMODYNAMIC-EFFECTS OF THE NOVEL BRADYCARDIAC AGENT, S16257, IN CONSCIOUS RATS

1 We carried out experiments to assess the cardiac and regional haemod ynamic effects of single or repeated injections of the novel bradycard ic agent, S16257, (7,8-dimethoxy oxybenzocyclobutan-1-yl)methyl]methyl amino}propyl} 1,3,4,5-tetrahydro-2H-benzapin Zone), in conscious rats. 2 In the first experiment, male Long Evans rats were chronically inst rumented for the measurement of cardiac or regional haemodynamics (n = 9 in each group), and, on separate experimental days, were randomized to receive i.v. bolus injections of vehicle (5% dextrose) or S16257 a t a dose of 1 mg kg(-1). 3 In animals instrumented for the measurement of cardiac haemodynamics (n = 9), following injection of vehicle, the re were no immediate changes, and 7-8 h later there were slight reduct ions in heart rate and mean arterial blood pressure only. Injection of S16257 caused an immediate, transient, presser effect but thereafter there were reductions in heart rate, mean arterial blood pressure, car diac index and total peripheral conductance, together with increases i n stroke index and peak aortic how. The integrated decreases in heart rate, mean arterial blood pressure, cardiac index and total peripheral conductance and increases in stroke index, peak aortic flow, dF/dt(ma x) and central venous pressure following S16257 were all significantly greater than the changes after vehicle injection. After injection of S16257, the fall in heart rate and fall in cardiac index were not line arly related. 4 In animals instrumented for the measurement of regiona l haemodynamics (n = 9). the bradycardic effect of i.v. S16257 was acc ompanied by reductions in renal, mesenteric and hindquarters blood flo ws and vascular conductances that were greater than the changes seen f ollowing injection of vehicle, but only for the first 1 h. Considering animals instrumented for the measurement of cardiac and regional haem odynamics together, the bradycardic effect of S16257 was greater the h igher the resting heart rate. 5 In the second experiment, animals chro nically instrumented for the measurement of cardiac or regional haemod ynamics (n = 9 in each group) were given s.c. injections of S16257 (1 mg kg(-1)) on four consecutive days. The general patterns of change in cardiac and regional haemodynamics following s.c. injection of S16257 were as described above for i.v. injection, although the rates of ons et of effects were slower. The bradycardic effect of S16257 was less o n the first, than on the subsequent, three days. 6 Overall, these resu lts indicate that the bradycardic action of S16257 is not associated w ith any signs of negative inotropic action. Only the initial depressor effect of i.v. S16257 is associated with reductions in renal, mesente ric and hindquarters flow and vascular conductance significantly great er than those seen after vehicle injection. With repeated s.c, injecti on of S16257, there are no signs of desensitization to its bradycardic actions, nor impairment of regional perfusion. If these results extra polate to the clinical setting, it seems likely that S16257 will have beneficial bradycardic effects, with no concurrent undesirable actions on other aspects of cardiovascular function.