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Conducted vasodilation along arterioles manifests the spread of hyperpolarization through gap junction channels along endothelium. Whereas histamine increases the permeability of capillary and venular endothelium, its effect on the integrity of arteriolar endothelium is unknown. We tested whether histamine could inhibit conducted vasodilation. In second-order arterioles (2A) supplying the cremaster muscle of C57BL6, PECAM-1-/-, and eNOS-/- mice (8-12 wk), neither resting (16+/-2 microm) nor maximal (38+/-2 microm) diameters were different. Acetylcholine (ACh) microiontophoresis (1 microA, 500 ms pulse) triggered vasodilation that was conducted >1400 microm along arterioles. Neither local (14+/-2 microm) nor conducted vasodilation (10+/-2 microm) was different among mice. Histamine (5 microM) had no effect on resting diameter or local vasodilation to ACh yet inhibited conduction by >50% in C57BL6 and PECAM-1-/- mice (P<0.05); this effect was abolished after blockade of NO synthase or of soluble guanylate cyclase. Washout of histamine restored conduction, though recovery was longer (P<0.05) in PECAM-1-/- mice vs. C57BL6 mice. Remarkably, conducted vasodilation in eNOS-/- mice was insensitive to histamine. These findings indicate that histamine inhibits cell-to-cell coupling through an NO-dependent mechanism and suggests a dynamic interaction among intercellular adhesion molecules and gap junction channels along arteriolar endothelium.

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-/-) and null endothelial NO synthase (eNOS-/-) mice aged 8-12 wk. Neither resting (17 +/- 1 microm) nor maximum diameters (36 +/- 2 microm) were different between groups, nor was the constrictor response (approximately 5 +/- 1 microm) to elevating superfusate oxygen from 0 to 21%. For arterioles of C57BL6 and PECAM-1-/- mice, cumulative addition of histamine to the superfusate produced vasodilation (1 nM-1 microM; peak response, 9 +/- 1 microm) and then vasoconstriction (10-100 microM; peak response, 12 +/- 2 microm). In eNOS-/- mice, histamine produced only vasoconstriction. In C57BL6 and PECAM-1-/- mice, vasodilation was abolished with Nomega-nitro-l-arginine (30 microM); in all mice, vasoconstriction was abolished with nifedipine (1 microM). Vasomotor responses were eliminated with pyrilamine (1 microM; H1 receptor antagonist) yet remained intact with cimetidine (1 microM; H2 receptor antagonist). These findings illustrate that the biphasic vasomotor response of mouse cremaster arterioles to histamine is mediated through H1 receptors on endothelium (NO-dependent vasodilation) as well as smooth muscle (Ca2+ 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.

Cell-to-cell communication is a key element of microvascular blood flow control, including rapidly carrying signals through the vascular endothelium in response to local stimuli. This cell-to-cell communication is negatively impacted during inflammation through the disruption of junctional integrity. Such disruption is associated with promoting the onset of cardiovascular diseases as a result of altered microvascular blood flow regulation. Therefore, understanding the mechanisms how inflammation drives microvascular dysfunction and compounds that mitigate such inflammation and dysfunction are of great interest for development. As such we aimed to investigate extracts of mushrooms as potential novel compounds. Using intravital microscopy, the medicinal mushroom, Inonotus obliquus was observed, to attenuate histamine-induced inflammation conducted vasodilation in second-order arterioles in the gluteus maximus muscle of C57BL/6 mice. Mast cell activation by C48/80 similarly disrupted endothelial junctions and conducted vasodilation but only histamine was blocked by the histamine antagonist, pyrilamine not C48/80 suggesting the importance of mast cell activation. Data presented here supports that histamine induced inflammation is a major disruptor of junctional integrity, and highlights the important anti-inflammatory properties of Inonotus obliquus focusing future assessment of mast cells as putative target for Inonotus obliquus. [ABSTRACT FROM AUTHOR]