PHARMACOLOGICAL SEPARATION OF CARDIO-ACCELERATOR AND VAGAL INHIBITORYCAPACITIES OF SYMPATHETIC-NERVES

Prolonged attenuation of vagal action at the heart, proposed to be due to release of the sympathetic cotransmitter neuropeptide Y (NPY), fol lows stimulation of cardiac sympathetic nerves. It has been shown that pretreatment with reserpine depletes cardiac and neuronal stores of b oth noradrenaline and NPY, while combined pretreatment with reserpine and the ganglion blocking agent chlorisondamine reduces depletion of N PY, while still depleting noradrenaline. The effects of reserpine pret reatment and combined chlorisondamine and reserpine pretreatment on th e inhibition of cardiac vagal action evoked by cardiac sympathetic ner ve stimulation (16 Hz, 2 min) were compared in anaesthetised dogs. In dogs with no pretreatment (n = 6), sympathetic stimulation evoked an i mmediate cardio-acceleration, and a prolonged inhibition of cardiac va gal action, with a maximum percent inhibition (MPI) and time to half-r ecovery (T50) of 78 +/- 6% and 16 +/- 2 min respectively. In dogs pret reated with reserpine (n = 6, 1 mg/kg, 24 h), the immediate cardio-acc eleration (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 inhibiti on of cardiac vagal action following sympathetic stimulation were sign ificantly attenuated. In dogs with combined chlorisondamine (n = 5, 2 mg/kg, 48 and 24 h) and reserpine pretreatment, there was again signif icantly reduced cardio-acceleration (ANOVA, P < 0.01), but the inhibit ion 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 prolo nged inhibition of cardiac vagal action in untreated and both groups o f pretreated animals. These experiments indicate that the cardio-accel erator and vagal inhibitory capacities of sympathetic nerve stimulatio n can be separated, and are consistent with the sympathetic vagal inhi bitory factor being NPY.