RAPID ATTENUATION (FADE) OF THE CHRONOTROPIC RESPONSE DURING VAGAL-STIMULATION IN THE CANINE NEWBORN - EVIDENCE FOR A PROMINENT NEUROPEPTIDE-Y EFFECT

We studied the time-dependent changes in the response of heart rate (sinus cycle length) to 30-second trains of vagal stimulation (8 Hz), repeated every 2 minutes, in canine neonates aged 7.1 +/- 2.5 (mean +/- SD) days. The first vagal train prolonged the sinus cycle length by 58 +/- 35%, but the response was attenuated during subsequent trains (98 +/- 5% inhibition of the vagal response after only 6.4 +/- 1.7 trains). After 40 minutes, complete restoration of the chronotropic response could be demonstrated. Receptor desensitization could be excluded as the reason for the attenuation by demonstrating preserved responses to exogenous acetylcholine. Neuropeptide Y, a sympathetic cotransmitter that has been shown to attenuate parasympathetic responses (thought to be the result of inhibition of the release of acetylcholine from parasympathetic nerve terminals), was administered (50-mu-g/kg) to eight newborns. Exogenous neuropeptide Y resulted in a complete inhibition of the chronotropic response to vagal stimulation, with restoration of the chronotropic response occurring after 60 minutes. Thus, exogenous neuropeptide Y mimicked the effect of repetitive vagosympathetic trunk stimulation; this finding suggested that neuropeptide Y release from sympathetic nerves during repetitive vagosympathetic trunk stimulation may have resulted in the observed attenuation of the vagal chronotropic response. To test this hypothesis, seven other newborns underwent chemical sympathectomy (50 mg/kg i.p. 6-hydroxydopamine for 3 days, tyramine verified), and in these newborns, stable chronotropic responses to repetitive vagosympathetic trunk stimulation were observed (inhibition of vagal response was 0 +/- 18% after 10 stimulus trains). These data suggest that in the newborn neuropeptide Y is a potent inhibitor of cardiac vagal responses and that relatively low levels of sympathetic activity may, through a nonadrenergic mechanism, attenuate or even eliminate the ability of the parasympathetic nervous system to modulate neonatal cardiac function.