R-(-)-.ALPHA.-Methylhistamine, a Histamine H3 Receptor Agonist, Induces Endothelium-Dependent Vasodilation in Rat Mesenteric Resistance Arteries

Abstract

The histamine H 3 receptor, a novel histamine receptor subtype, has been identified in rat brain cortical slices and shown to inhibit histamine release 1,2) in the brain and several peripheral tissues.3,4) Inhibitory presynaptic histamine H 3 receptors have also been found on non-histaminergic nerves including cholinergic, 5) adrenergic 6,7) and non-adrenergic noncholinergic nerves. 8) Characterization of histamine H 3 receptor-mediated responses has been greatly facilitated by the development of selective histamine H 3 receptor agonists such as R-(Ϫ)-a methylhistamine (a-methylhistamine), 2,9,10) and antagonists such as thioperamide 2,9) and clobenpropit. 11,12) Various physiological responses to a-methylhistamine, a potent and selective histamine H 3 receptor agonist, have been shown to be reduced by the histamine H 3 receptor antagonists thioperamide and clobenpropit, but not by histamine H 1 or H 2 receptor antagonists. 3,[5][6][7]13) It also has been reported that intravenous administration of a-methylhistamine causes a decrease in systemic blood pressure in the rat and that responses are blocked by histamine H 1 receptor antagonists, but not by histamine H 2 or H 3 receptor antagonists.14) However, the mechanisms of histamine H 3 receptor-mediated vascular relaxant effects induced by a-methylhistamine remain unclear.It is widely accepted that the endothelium at the luminal surface of blood vessels is an important regulator of vascular tone via release of various endothelium-derived endogenous substances, such as relaxing factors (EDRFs) and contracting factors (EDCFs). [15][16][17][18] EDRFs and EDCFs include nitric oxide (NO), prostaglandin I 2 (PGI 2 ), endothelium-derived hyperpolarizing factors (EDHFs) and endothelin, prostaglandin F 2a , thromboxane A 2 , respectively. Evidence has accumulated that NO, PGI 2 and/or EDHFs play a prominent role in the tone control of the endothelium contact arteries. [19][20][21][22][23] Therefore, the purpose of the present study was to investigate the vascular responses mediated by histamine H 3 receptors using a-methylhistamine and the underlying mechanisms in the mesenteric vascular bed of the rat. MATERIALS AND METHODS AnimalsMale Wistar rats weighing 220-350 g were used in the present study. The animals were given food and water ad libitum. They were housed in the Animal Research Center of Okayama University at a controlled ambient temperature of 22Ϯ2°C with 50Ϯ10% relative humidity and with a 12-h light/12-h dark cycle (lights on at 8:00 a.m.). This study was carried out in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research Center, Japanese Government Animal Protection and Management Law (No. 105), and Japanese Government Notification on Feeding and Safekeeping of Animals (No. 6). Every effort was made to minimize the number of animals used and their suffering. Perfusion of Mesenteric Vascular BedsThe animals were anesthetized with pentobarbital-Na (50 mg/kg, intraperitoneally) and mesenteric vascular beds were i...

Pharmacological evidence that histamine H3 receptors inhibit the vasodepressor responses by selective stimulation of the rat perivascular sensory CGRPergic outflow

“…2B). Although we have no clear-cut explanation for this finding, it is tempting to speculate that 31 mg/kg/min immepip could also be interacting with endothelial H 3 receptors producing vasodilatation (Sun et al, 2010); this, in turn, would counteract the sensory-inhibition by immepip. It is noteworthy, within this context, that 31 mg/kg/min immepip is an i. v. continuous infusion (not an i.v.…”

“…This study, however, focussed only on cardiac, rather than perivascular, sensory CGRPergic fibres. More recently, two studies in the isolated rat mesenteric artery have reported that histamine H 3 receptors mediate: (i) endotheliumdependent vasodilatation via the release of nitric oxide, prostaglandin I 2 and/or endothelium-derived hyperpolarizing factors (Sun et al, 2010); and (ii) inhibition of both vascular sympathetic and CGRPergic neurogenic tones in the absence of endothelium (Sun et al, 2011). Consistent with the latter in vitro findings, our study further shows that activation of histamine H 3 receptors results in inhibition of the sensory CGRPergic outflow in the systemic vasculature of pithed rats, and provides additional pharmacological evidence for excluding the role of histamine H 1 , H 2 and H 4 receptors.…”

Gallic acid improves endothelium‐dependent vasodilatory response to histamine in the mesenteric vascular bed of diabetic rats

“…The vasodilatory response to histamine is predominantly mediated by histamine H 1 receptors located in the endothelium . In addition, some studies have suggested that histamine H 3 receptors are involved in endothelium‐dependent vasodilatory responses . However, the effects of diabetes (as a major risk factor to the cardiovascular system) on histamine‐induced vasodilation is not well understood.…”

Histamine‐induced vasodilatation in the human forearm vasculature

“…Finally, it is possible that histamine receptors, other than those studied here, may be involved in mediating the clinical effects described. Recent animal studies show that H 3 ‐receptors may be important in mediating endothelium dependent vasodilatation . Also, activation of H 1 ‐ and H 4 ‐receptors, together with inhibition of H 3 ‐receptors, are involved in eliciting histamine‐induced itch .…”