Histamine receptor subtypes mediating hyperpolarization in the isolated, perfused rat mesenteric pre-arteriolar bed

Histamine is a general dilator of rat blood vessels. We investigated the relative contribution of receptor subtypes to the rat mesenteric dilator responses initiated by histamine and related agonists. Histamine initiated dose, and endothelium-dependent, dilation of constricted mesenteric beds with an ED 50 of 0.4±0.1 nmol. The ED 50 was increased 10-fold by 0.1 μM chlorpheniramine (a histamine H 1-receptor selective antagonist). Histamine H 2 receptor blockade with tiotidine (0.1 μM) slightly decreased, while thioperamide (1 μM), a selective histamine H 3 receptor antagonist, did not block histamine-induced dilation. Mesenteric bed dilation initiated by histamine H 2 receptor selective agonists, amthamine and dimaprit, were antagonized markedly by tiotidine. However, the dilation initiated by the putative histamine H 3 receptor selective agonists, R(−)- or S(+)- α-methylhistamine and imetit were not affected by thioperamide (1 μM). Histamine H 2- and H 3-receptor mediated dilator effects were endothelium-independent and were blocked by either excess (80 mM) extracellular K +, or 1 mM tetrabutylammonium (a non-selective K + channel blocker), as well as by 1 μM dequalinium, a non-peptide blocker of the small conductance Ca 2+-activated (SK Ca) K + channels. We conclude that (i) histamine H 1 receptor subtype predominantly mediates endothelium-dependent dilator effect of histamine, and (ii) vascular hyperpolarization through opening of K + channels (SK Ca) mediate the dilator responses to histamine H 2 receptor (amthamine and dimaprit) and the putative histamine H 3 receptor ( R(−)- α-methylhistamine and imetit) agonists.