Hemodynamic responses to histamine were investigated in the anesthetized rabbit. Intravenous injections of histamine induced dose-dependent decreases in systemic arterial pressure that were blocked by the H₁-receptor antagonist pyrilamine but not the H₂ antagonist cimetidine. Injections of histamine and the H₁ agonist 6-[2-(4-imidazolyl)ethylamine]-N-(4-trifuormethylphenyl)-heptanecardoxamide dimaleate (HTMT) into the hindlimb perfusion circuit increased hindlimb perfusion pressure, whereas the H₂ agonist dimaprit decreased perfusion pressure and the H₃-receptor agonist R-()--methylhistamine did not alter perfusion pressure. Pyrilamine reduced hindlimb vasoconstrictor responses to histamine and HTMT but did not alter vasodilator responses to dimaprit. Cimetidine reduced the response to dimaprit but did not alter vasoconstrictor responses to histamine or HTMT. The H₃-receptor antagonist thioperamide was without effect on responses to the histamine agonists. These data suggest the presence of H₁ and H₂ receptors and that histamine for the most part acts by stimulating H₁ receptors to produce vasoconstriction in the hindlimb vascular bed of the rabbit. Responses to histamine, HTMT, and norepinephrine were significantly enhanced by a nitric oxide synthase inhibitor at a time when vasodilator responses to dimaprit were unaltered and responses to acetylcholine were significantly reduced. Responses to histamine and the H₁ and H₂ agonists were not affected by the cyclooxygenase inhibitor meclofenamate or by ATP-sensitive K⁺ channel, -adrenergic, or angiotensin AT₁ receptor antagonists. The present data suggest that H₁ receptors mediate both systemic vasodepressor and hindlimb vasoconstrictor responses to histamine.