Histamine H1 and H2 receptors are present in the canine renal circulation. We have examined the effects of H1 and H2 receptor antagonists on autoregulation of renal blood flow in the dog. Renal arterial pressure was reduced in a step-wise fashion to 80 mm Hg by means of an adjustable aortic clamp positioned above the left renal artery. Infusion of H2 antagonists, cimetidine or ranidine, into the left renal artery at 10-5 mol/min had no effect on autoregulation of renal blood flow or on the reactive hyperemia that occurred when the aortic constriction was released. By contrast, intrarenal infusion of 10-5 mol/min chlorpheniramine, an H1 receptor antagonist, reversibly attenuated reactive hypermia and the ability of the kidney to autoregulate renal blood flow. Similar results were obtained with other, chemically dissimilar H1 antagonists (terfenadine, diphenhydramine, and pyrilamine). The effects of chlorpheniramine on autoregulation of glomerular filtration rate also were evaluated. Before chlorpheniramine was infused (at 10-5 mol/min), the reduction of renal arterial pressure to 90 mm Hg had no effect on the glomerular filtration rate, whereas, during infusion of the H1 antagonist, the glomerular filtration rate fell significantly when renal arterial pressure was reduced to 90 mm Hg. Infusion of histamine (1 μg/kg per min) with increasing amounts of cimetidine, chlorpheniramine, diphenhydramine, or pyrilamine resulted in virtually identical dose-dependent decreases in histamine-induced renal vasodilation. However, even with 10-5 mol/min cimetidine or 10-5 mol/min chlorpheniramine, diphenhydramine, or pyrilamine, a significant histamine-induced renal vasodilation was observed. Thus, the amount of H1 antagonist required to inhibit histamine activation of H1 receptors is the same as needed to block autoregulation. Finally, renal vascular reactivity as estimated by acetylcholine-induced vasodilation was not substantially affected by chlorpheniramine or by pyrilamine. These observations provide evidence in support of a role for histamine as a chemical mediator of renal autoregulation.