The effect of histamine on coronary blood flow (CBF) was studied in anaesthetized grayhounds. CBF and systemic blood pressure were measured using electromagnetic flow transducers and catheters in the aorta during infusions of drugs into the left circumflex coronary artery. Histamine infusions (5, 10, and 20 microng/min) produced dose-related increases in CBF without changing heart rate or blood pressure. Metiamide (100 microng/min) given simultaneously produced a parallel displacement of the histamine dose-response curve to the right (P less than 0.05) with a dose ratio of 2. Mepyramine (100 microng/min) produced a larger parallel displacement of the dose-response curve (dose ratio = 4). Together, metiamide and mepyramine greatly reduced the histamine response (dose ratio = 16), showing that the metiamide blockade is augmented in the presence of mepyramine. Similarly, mepyramine blockade is augmented in the presence of metiamide. The increase in CBF produced by histamine infusion (20 microng/min) was similar to the peak flow response of reactive hyperemia following 8-second occlusions. However, mepyramine and metiamide together had no effect on the peak flow response, duration, or total repayment of flow debt in reactive hyperemia. These results show that histamine-induced coronary vasodilation is mediated by both H1 and H2 receptors. However, the vasodilation of reactive hyperemia after brief coronary artery occlusions does not appear to involve histamine.