Acute and chronic cardiac and regional haemodynamic effects of the novel bradycardic agent, S16257, in conscious rats.

1. We carried out experiments to assess the cardiac and regional haemodynamic effects of single or repeated injections of the novel bradycardic agent. S16257, (7,8-dimethoxy 3-[3-([(IS)-(4,5-dimethoxybenzocyclobutan-1- yl)methyl]methylamino)propyl] 1,3,4,5-tetrahydro-2H-benzapin 2-one), in conscious rats. 2. In the first experiment, male Long Evans rats were chronically instrumented 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 at a dose of 1 mg kg-1. 3. In animals instrumented for the measurement of cardiac haemodynamics (n = 9), following injection of vehicle, there were no immediate changes, and 7-8 h later there were slight reductions in heart rate and mean arterial blood pressure only. Injection of S16257 caused an immediate, transient, pressor effect but thereafter there were reductions in heart rate, mean arterial blood pressure, cardiac index and total peripheral conductance, together with increases in stroke index and peak aortic flow. 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/dtmax 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 linearly related. 4. In animals instrumented for the measurement of regional haemodynamics (n = 9). the bradycardic effect of i.v. S16257 was accompanied by reductions in renal, mesenteric and hindquarters blood flows and vascular conductances that were greater than the changes seen following injection of vehicle, but only for the first 1 h. Considering animals instrumented for the measurement of cardiac and regional haemodynamics together, the bradycardic effect of S16257 was greater the higher the resting heart rate.5. In the second experiment, animals chronically instrumented for the measurement of cardiac or regional haemodynamics (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 onset of effects were slower. The bradycardic effect of S16257 was less on the first, than on the subsequent, three days.6 Overall, these results indicate that the bradycardic action of S16257 is not associated with any signsof negative inotropic action. Only the initial depressor effect of i.v. S16257 is associated with reductions in renal, mesenteric and hindquarters flow and vascular conductance significantly greater than those seen after vehicle injection. With repeated s.c. injection of S16257, there are no signs of desensitization to its bradycardic actions, nor impairment of regional perfusion. If these results extrapolate 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.