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Histamine increases the permeability of capillaries and venules but little is known of its precapillary actions on the control of tissue perfusion. Using gene ablation and pharmacological interventions, we tested whether histamine could increase muscle blood flow through stimulating nitric oxide (NO) release from microvascular endothelium. Vasomotor responses to topical histamine were investigated in second-order arterioles in the superfused cremaster muscle of anesthetized C57BL6 mice and null platelet endothelial cell adhesion molecule-1 (PECAM-[1.sup.-/-]) and null endothelial NO synthase ([eNOS.sup.-/-] ) mice aged 8-12 wk. Neither resting (17 [+ or -] [micro]m) nor maximum diameters (36 [+ or -] 2 [micro]m) were different between groups, nor was the constrictor response (~5 [+ or -] 1 [micro]m) to elevating superfusate oxygen from 0 to 21%. For arterioles of C57BL6 and PECAM-[1.sup.-/-] mice, cumulative addition of histamine to the superfusate produced vasodilation (1 nM-1 [micro]M; peak response, 9 [+ or -] I [micro]m) and then vasoconstriction (10-100 [micro]M; peak response, 12 [+ or -] 2 [micro]m). In [eNOS.sup.-/-] mice, histamine produced only vasoconstriction. In C57BL6 and PECAM-[1.sup.-/-] mice, vasodilation was abolished with [N.sup.[omega]]-nitro-L-arginine (30 [micro]M); in all mice, vasoconstriction was abolished with nifedipine (1 [micro]M). Vasomotor responses were eliminated with pyrilamine (1 [micro]M; [H.sub.1] receptor antagonist) yet remained intact with cimetidine (1 [micro]M; [H.sub.2] receptor antagonist). These findings illustrate that the biphasic vasomotor response of mouse cremaster arterioles to histamine is mediated through [H.sub.1] receptors on endothelium (NO-dependent vasodilation) as well as smooth muscle ([Ca.sup.2+] entry and constriction). Thus histamine can increase as well as decrease muscle blood flow, according to local concentration. However, when NO production is compromised, only vasoconstriction and flow reduction occur. microcirculation; blood flow control; endothelial nitric oxide synthase