Potential species differences in cardiovascular responses to histamine H3 receptor activation were studied in the conscious guinea pig, rabbit, normotensive rat and the spontaneously hypertensive rat. R-alpha-Methylhistamine (100 micrograms/kg i.v.) decreased blood pressure in both the guinea pig and the rabbit. In the guinea pig, R-alpha-methylhistamine decreased heart rate, whereas in the rabbit it produced a tachycardia. In the normotensive rat and spontaneously hypertensive rat, R-alpha-methylhistamine (100 micrograms/kg i.v.) had no effect on blood pressure and heart rate. The cardiovascular action of R-alpha-methylhistamine in the guinea pig and rabbit was blocked by pretreatment with thioperamide (1.0 mg/kg i.v.) but not by chlorpheniramine (0.3 mg/kg i.v.) or cimetidine (3.0 mg/kg i.v.), respectively. These results indicate species differences in cardiovascular responses to histamine H3 receptor activation.