The newborn gut circulation is characterized by a very low resting vascular resistance, a circumstance which facilitates substantial gut perfusion during the transition from fetal to newborn life. Endothelium-derived nitric oxide(NO), a potent vasodilator, appears to be a key mediator in this process. The stimulus for NO production in newborn gut is not known. One candidate for this role is SP, a peptide whose vascular effect is mediated by generation of NO and which is present in abundance in the intestine. Three studies were carried out in postnatal swine to test this hypothesis: i) SP was measured by RIA in intestinal homogenates from 1-day, never fed (1dNF), 1-day, fed(1dF) and 14-day, fasted (14dF) subjects. Results (M±SD; pg SP/mg protein): 1dNF 126±35; 1dF 210±53; 14dF 51±10* (p<.01 vs 1d). Thus, the presence of SP within gut tissue is high at birth and declines thereafter. ii) N-acyl-l-trp-3,5bis(trifluoromethyl)benzyl ester (NATB), a highly selective antagonist to the NK-1 receptor to which SP binds to exert its vascular effect, was infused (5×10-9M) into the mesenteric artery perfusing a vascularly isolated, in vivo loop of small intestine in 3- or 14-day old, anesthetized swine. NATB had no effect on hemodynamics within 14-day old intestine, but significantly increased (by21±4%) vascular resistance in 3-day old gut loops. Thus, the hemodynamic effect of SP receptor blockade was age dependent.iii) The effect of NATB on flow-induced dilation (FID) was determined. FID is a NO-mediated process whereby the mechnostimulus of flow enhances vascular conductance, ie., keeps resistance low. FID plays an essential role in maintaining oxygen delivery. Gut loops were removed from 3-day old swine and perfused in vitro by means of a blood reservoir and pump. In controls, vascular resistance decreased 28±4% in response to a 50% increase in flow rate (pump-induced). This FID was virtually eliminated by pretreatment with NATB. Conclusion: SP is present in newborn gut and participates in setting vascular resistance in the newborn gut circulation. Speculation: The intestine proceeds from a relatively dormant fetal existence to an intensely active state after birth. This transition might be facilitated by increasing gut perfusion, and thus oxygen delivery at the time of birth, even before the initation of feeding, ie., the gut may be “prepared” for its postnatal function. SP, present in the gut as a neurotransmitter and endothelium-derived peptide, may participate in this function, which might be under developmental regulation.