1. The effect of R-alpha-methylhistamine, a histamine H1 receptor agonist, was studied on cardiovascular hemodynamics in bilateral vagotomized, anesthetized guinea pigs. 2. R-alpha-methylhistamine (100 micrograms/kg, IV) a dose that selectively activates histamine H3 receptors, produced hypotension and bradycardia. Total peripheral resistance (TPR) and rate pressure product (RPP) were also decreased at this dose. 3. Pretreatment with the ganglionic blocker hexamethonium (20 mg/kg, IV) blocked the blood pressure (BP), heart rate (HR), TPR, and RPP effects of R-alpha-methylhistamine (100 micrograms/kg, IV). Hexamethonium did not block the hypotensive and TPR lowering actions of the muscarinic agonist methacholine (1 and 3 micrograms/kg, IV). 4. Pretreatment with the alpha 1-adrenoceptor antagonist prazosin (0.5 mg/kg IV), blocked R-alpha-methylhistamine's (100 micrograms/kg, IV) effects on BP, TPR, and RPP. Prazosin did not antagonize the bradycardia effect of R-alpha-methylhistamine. 5. Pretreatment with the beta-adrenoceptor antagonist atenolol (1 mg/kg, IV) did not alter the BP, TPR, or RPP actions of R-alpha-methylhistamine. The HR effects of R-alpha-methylhistamine were blocked by atenolol. 6. The hemodynamic effects of R-alpha-methylhistamine were compared to the hemodynamic profile of the calcium channel blocker, verapamil (0.5 mg/kg, IV). Verapamil had little effect on TRP and had a greater cardiac depressant effect as evidenced by a significant reduction in HR and cardiac output (CO). 7. In summary, these results show that activation of prejunctional H3 receptors with R-alpha-methylhistamine decreases basal, BP, HR, TPR, and RPP in anesthetized guinea pigs. The fall in BP is mediated by a decrease in TPR. Furthermore, the inhibitory effects of R-alpha-methylhistamine on sympathetic control of the vasculature appears to impart a greater physiologic effect on the H3-histamine mediated hypotension than its inhibitory effects on sympathetic agents to the heart.