PHARMACOLOGICAL SEPARATION OF CARDIO-ACCELERATOR AND VAGAL INHIBITORY CAPACITIES OF SYMPATHETIC-NERVES

Prolonged attenuation of vagal action at the heart, proposed to be due to release of the sympathetic cotransmitter neuropeptide Y (NPY), follows stimulation of cardiac sympathetic nerves. It has been shown that pretreatment with reserpine depletes cardiac and neuronal stores of both noradrenaline and NPY, while combined pretreatment with reserpine and the ganglion blocking agent chlorisondamine reduces depletion of NPY, while still depleting noradrenaline. The effects of reserpine pretreatment and combined chlorisondamine and reserpine pretreatment on the inhibition of cardiac vagal action evoked by cardiac sympathetic nerve stimulation (16 Hz, 2 min) were compared in anaesthetised dogs. In dogs with no pretreatment (n = 6), sympathetic stimulation evoked an immediate cardio-acceleration, and a prolonged inhibition of cardiac vagal action, with a maximum percent inhibition (MPI) and time to half-recovery (T50) of 78 +/- 6% and 16 +/- 2 min respectively. In dogs pretreated with reserpine (n = 6, 1 mg/kg, 24 h), the immediate cardio-acceleration (ANOVA, P < 0.01), and the magnitude (MPI = 31.8%, ANOVA, P < 0.001) and duration (T50 = 6 +/- 1 min, ANOVA, P < 0.05) of inhibition of cardiac vagal action following sympathetic stimulation were significantly attenuated. In dogs with combined chlorisondamine (n = 5, 2 mg/kg, 48 and 24 h) and reserpine pretreatment, there was again significantly reduced cardio-acceleration (ANOVA, P < 0.01), but the inhibition of cardiac vagal action following sympathetic stimulation did not significantly differ from untreated animals (MPI = 79 +/- 8%, T50 = 21 +/- 6 min). Intravenous injections of NPY (25-50 mug/kg) evoked prolonged inhibition of cardiac vagal action in untreated and both groups of pretreated animals. These experiments indicate that the cardio-accelerator and vagal inhibitory capacities of sympathetic nerve stimulation can be separated, and are consistent with the sympathetic vagal inhibitory factor being NPY.