Effects of substance P (SP) on gastric acid secretion and mucosal blood flow (MBF) were examined in anesthetized Wistar rats. Intravenous infusion of graded doses of SP (5 and 10 nmol/kg/min) had no effects on either the basal gastric acid secretion or on the MBF. When gastric acid secretion was increased by giving a supramaximal dose of bethanechol (10 micrograms/kg/min), a muscarinic parasympathetic stimulant, SP had no effect on the gastric acid secretion but did decrease the MBF. On the other hand, when gastric acid secretion was increased by left cervical vagus nerve stimulation (0.5 mA, 3 Hz, 0.5 msec duration), SP inhibited both acid secretion and MBF, in a dose-dependent manner. The inhibitory effects of SP on the vagally stimulated gastric responses were not affected by pretreatment with phentolamine (5 mg/kg i.m.), propranolol (10 mg/kg i.m.), mepyramine (20 mg/kg i.m.) or indomethacin (30 mg/kg i.v., followed by 4 mg/kg/hr). These findings suggest that SP acts directly on the gastric vascular system and decreases gastric MBF, and that this substance also acts on the parasympathetic neurons in the gastric wall and inhibits the vagally stimulated gastric acid secretion. The inhibitory effects of SP on the gastric acid secretion do not appear to be mediated by adrenergic or by histamine H-1 receptor-, prostaglandin-involved mechanisms.