The evidence for histamine H3 receptor-mediated endothelium-dependent relaxation in isolated rat aorta

The presence of histamine H3 receptors was evaluated on the rat aorta endothelium. In the presence of pyrilamine (1 nM, 7 nM, 10 nM) or thioperamide (1 nM, 10 nM, 30 nM) the concentration–response curve for histamine-induced (0.1 nM − 0.01 mM) endothelium-dependent rat aorta relaxation was shifted to the right without significant change of the Emax indicating competitive antagonism by pyrilamine (pA2 = 9.33 ± 0.34, slope = 1.09 ± 0.36) or thioperamide (pA2 =9.31 ± 0.16, slope=0.94 ± 0.10). Cimetidine (1 μM) did not influence histamine-induced endothelium-dependent rat aorta relaxation. In the presence of thioperamide (1 nM, 10 nM, 30 nM) the concentration–response curve for (R)α-MeHA-induced (0.1 nM − 0.01 mM) endothelium-dependent relaxation was shifted to the right without significant change of Emax indicated competitive antagonism by thioperamide (pA2 = 9.21 ± 0.4, slope = 1.03 ± 0.35). Pyrilamine (100 nM) or cimetidine (1 μM) did not influence (R)α-MeHA-induced endothelium-dependent rat aorta relaxation. These results suggest the presence of a heterogenous population of histamine receptors, H1 and H3, on rat aorta endothelium.


Introduction
Two types of histamine receptors, H1 and H2, participate in vascular responses to histamine.
The novel histamine H receptors were identified as inhibitory presynaptic autoreceptors on histamine-containing nerve terminals in the rat brain cortex but have since been shown to inhibit the release of various neurotransmitters both in the central and peripheral nervous systems. 2 Recent articles provide strong evidence for the presence of histamine H receptors at the different sites, including the rabbit middle cerebral artery endo-3,4 5 6 thelium,' guinea-pig aorta, mesenteric artery, rabbit saphenous artery, 7 guinea-pig myo- 8 9 cardium, guinea-pig ileum, guinea-pig lung and 10 11 I2 bronchiole, guinea-pig intestine, porcine small intestine, rabbit gastric glands, 14 human 15 adenoidal mast cells, human and rhesus monkey brain. 6 .The purpose of the present study was to determine whether histamine H receptors are localized on rat aorta endothelium and to assess their possible role in endothelium-dependent responses.  Student's t-test, p values less than 0.05 were considered to be significant. 2) did not influence histamine-induced endothelium-dependent rat aorta relaxation (Fig. 1).  approximately 50% of the papaverine-induced The histamine H 3 receptors were found within maximum relaxation (0.1 mM). Removal of the the central nervous system of the rat and the endothelium abolished the relaxation to (R)(xhuman where they appear to be involved in the MeHA. feedback control of both histamine synthesis and Pyrilamine (100nM) or cimetidine (1 IM) did release at the level of histaminergic nerve not influence (R)(x-MeHA-induced endotheliumendings. 9'2 Furthermore, stimulation of histadependent rat aorta relaxation (Fig. 3).

mine H receptors has been shown to inhibit
When thioperamide (10 nM, 30 nM, 100 nM) adrenergic and cholinergic neurotransmission in was present, the concentration-response curve the peripheral autonomic neeeous system. 6'12 for (R)a-MeHA-induced relaxation was shifted to There is some controversy about whether histathe right without a significant change of the Emax. mine H3 receptors are present on the syrq.pa-Schild plot analysis indicated that antagonism by thetic nerve fibres inneeeating blood vessels. 6 In this compound was competitive. The slope for two isolated vessels, the rabbit middle cerebral the regression curve was 1.03 + 0.35, with a pA2 artery 3'4 and guinea-pig aorta, 5 a potent and value of 9.21 + 0.40 (Fig. 4).
selective histamine H agonist, (R)t-MeHA produced relaxation probably via stimulation of postsynaptic histamine H receptors. These find-

Discussion
ings suggest that depending on the species and the experimental model, several mechanisms Histamine is present in essentially all tissues and (activation of pre-and postsynaptic histamine H it can stimulate all three classes of histamine receptors or histamine H receptor-independent receptors. It is found in significant concentrations mechanisms) contribute to the overall effect of in the blood and also in the vessel walls. 17 Intra-(R)t-MeH on cardiovascular function. 22 Experivascular administration of histamine elicits a conments with the Langendorff perfusion of the centration-dependent fall in blood pressure in guinea-pig heart have shown that the histamine most species. Many studies have indicated the H agonist N-x-methylhistamine (N-ot-MeH) proinvolvement of H and H2 receptors in this duces an increase in coronary flow and a depressor response. decrease in coronary vascular resistance which  agonistic effects) and cimetidine. 23 The role of the endothelium in the relaxation of precontracted blood vessel preparations has been demonstrated for different physiologically important substances. The study presented here showed that the presence of endothelium is also essential for the relaxing effect of histamine and (R) cx-MeHA on the isolated rat aorta. The physiological role of the endothelium in histamineinduced relaxation could be of physiological importance. Sensitivity to histamine could also be higher in blood vessels with a more important role in the regulation of peripheral resistance.
The results with both histamine and pyrilamine suggest the presence of histamine H receptors on rat aorta endothelium which is in agreement 24 26 with results of the other authors.