The effects of proadrenomedullin N-terninaI 20 peptide (PAMP) on changes in renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs. The intrarenal arterial infusion of PAMP (10, 50, 100 ng/kg/min) did not influence basal levels of systemic and renal hemodynamics, or urine formation. RNS at a low frequency (0.5-2.0 Hz) caused significant decreases in urine flow and urinary excretion of sodium, and increases in NE secretion rate (NESR), without affecting renal hemodynamics. RNS at a high frequency (2.5-5.0 Hz), which diminishes renal hemodynamics, elicited more potent decreases in urine formation and increases in NESR. The low frequency RNS-induced reductions in urine formation and increases in NESR were almost completely abolished by the intrarenal arterial infusion of PAMP at 50 ng/kg/min, a dose that produced no alterations on basal renal hemodynamics and excretory responses. In contrast, high frequency RNS-induced renal vasoconstriction and reductions in urine formation, and increases in NESR were not affected by infusion of the peptide. We next examined the effect of PAMP on exogenously applied NE-induced renal actions, to determine if PAMP functions suppressively at postjunctional sites. The intrarenal arterial infusion of NE (100-150 ng/kg/min) produced a significant renal vasoconstriction and a reduction in urine formation, responses not affected by the administration of PAMP (50 ng/kg/min). From these findings, we suggest that PAMP functions as an inhibitory modulator of renal noradrenergic neurotransmission, via prejunctional mechanisms, and plays an important role in regulating renal functions.