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Vasodilation. This is by far the most important vascular effect of histamine in human beings. Vasodilation involves both H1 and H2 receptors distributed throughout the resistance vessels in most vascular beds; however, quantitative differences are apparent in the degree of dilation that occurs in various beds. Activation of either the H1 or H2 receptor can elicit maximal vasodilation, but the responses differ. H1 receptors have a higher affinity for histamine and mediate an endothelium-NO-dependent dilation that is relatively rapid in onset and short-lived. By contrast, activation of H2 receptors (stimulating the cyclic AMP-PKA pathway in smooth muscle) causes dilation that develops more slowly and is more sustained. As a result, H1 antagonists effectively counter small dilator responses to low concentrations of histamine but only blunt the initial phase of larger responses to higher concentrations of the amine. There seems to be a variable distribution of H1 receptors on vascular smooth muscle as well, such that direct constrictor responses can be observed in vein, in skin and skeletal muscle, and in larger coronary arteries. Histamine causes hepatic venoconstriction in dogs (Chien and Krakoff, 1963).

Increased "Capillary" Permeability. This effect of histamine on small vessels results in outward passage of plasma protein and fluid into the extracellular spaces, an increase in the flow of lymph and its protein content, and edema formation. H1 receptors on endothelial cells are the major mediators of this response; the role of H2 receptors is uncertain.
Increased permeability results mainly from actions of histamine on postcapillary venules, where histamine causes the endothelial cells to contract and separate at their boundaries and thus to expose the basement membrane, which is freely permeable to plasma protein and fluid. The gaps between endothelial cells also may permit passage of circulating cells that are recruited to the tissues during the mast cell response. Recruitment of circulating leukocytes is promoted by H1-receptor-mediated up-regulation of leukocyte adhesion. This process involves histamine-induced expression of the adhesion molecule P-selectin on the endothelial cells (Gaboury et al., 1995).

Constriction of Larger Vessels. Histamine tends to constrict larger blood vessels, in some species more than in others. In rodents, the effect extends to the level of the arterioles and may overshadow dilation of the finer blood vessels. A net increase in total peripheral resistance and an elevation in blood pressure can be observed. As noted earlier, H1-receptor-mediated constriction may occur in some veins and in conduit coronary arteries (Toda, 1987).

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