To investigate the possible involvement of histamine H₃ receptors in renal noradrenergic neurotransmission, effects of (R)alpha-methylhistamine (R-HA), a selective H₃-receptor agonist, and thioperamide (Thiop), a selective H₃-receptor antagonist, on renal nerve stimulation (RNS)-induced changes in renal function and norepinephrine (NE) overflow in anesthetized dogs were examined. RNS (0.5-2.0 Hz) produced significant decreases in urine flow and urinary sodium excretion and increases in NE overflow rate (NEOR), without affecting renal hemodynamics. When R-HA (1 µg · kg¹ · min¹) was infused intravenously, mean arterial pressure and heart rate were significantly decreased, and there was a tendency to reduce basal values of urine flow and urinary sodium excretion. During R-HA infusion, RNS-induced antidiuretic action and increases in NEOR were markedly attenuated. Thiop infusion (5 µg · kg¹ · min¹) did not affect basal hemodynamic and excretory parameters. Thiop infusion caused RNS-induced antidiuretic action and increases in NEOR similar to the basal condition. When R-HA was administered concomitantly with Thiop infusion, R-HA failed to attenuate the RNS-induced antidiuretic action and increases in NEOR. However, in the presence of pyrilamine (a selective H₁-receptor antagonist) or cimetidine (a selective H₂-receptor antagonist) infusion, R-HA attenuated the RNS-induced actions, similarly to the case without these antagonists. Thus functional histamine H₃ receptors, possibly located on renal noradrenergic nerve endings, may play the role of inhibitory modulators of renal noradrenergic neurotransmission.