Hi and H2 histamine receptors

Phentolamine is a potent competitive antagonist at both K and k2 receptors (Table 10-1). Phentolamine reduces peripheral resistance through blockade of K receptors and possibly k2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic k2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and Hi and H2 histamine receptors. Phentolamine s principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States. 

Impicciatore, M., 1978. Occurrence of Hi- and H2 -histamine receptors in the guinea-pig gall bladder in situ. Br. J. Pharmacol. 64, 219-222. 

Does carnosine receptor exist All effects of carnosine mentioned above are performed with no participation of specific receptor proteins. In some cases, however, specific receptors can be involved. In brain tissue carnosine is released together with glutamate in response to electric stimulation [11]. It can modulate the affinity of glutamate receptors to the neuromediator controlling concentration of fi ee zinc ions [69]. Modulation of Hi and H2 histamine receptors in heart (the former stimulate and the latter prevent mobilization of carnosine into histamine, thus regulating inflammation development) by carnosine is apparently carried out with participation of zinc ions [70]. Similar interrelations were found between carnosine and histamine receptors in blood vessel muscles responsible for the tone of blood vessels [15] this is closely related to hypotensive response appeared after intravenous administration of carnosine noted as early as in 1936 [71]. 

Wood-Baker R, Lau L, Howarth PH. Histamine and the nasal vasculature the influence of HI and H2-histamine receptor antagonism. Clin Otolaryngol 1996 21 348-352. 

Following release, histamine binds to either HI or H2 histamine receptors causing a variety of effects (listed in Table 9.8). In addition to allergens, several other substances cause histamine release, including radiodiagnostic dyes, some antibiotics, kinins (chemicals released by immune cells) and some venoms. Several synthetic histamine agonists are available for laboratory studies of histamine functions, but there are virtually no clinical indications for histamine receptor agonists. 

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

Histamine produces its pharmacological actions by three subtypes of receptors the postsynaptic Hi and H2 receptors and the presynaptic H3 receptor. The H3 receptor is mainly located in the central nervous system (CNS), where it acts as an inhibitory autoreceptor in the central histaminergic neuronal pathways [176]. A number of therapeutic applications have been proposed for selective H3 receptor antagonists, including several CNS disorders such as Alzheimer s disease. Attention Deficit Hyperactivity Disorder, Schizophrenia, or for enhancing memory or obesity control. 

Munakata, M. Akaike, N. (1994). Regulation of K+ conductance by histamine HI and H2 receptors in neurones dissociated from rat neostriatum. J. Physiol. 480, 233-45. 

Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OAR, Malolepszy J, et al Histamine regulates T-cell and antibody responses by differential expression of HI and H2 receptors. Nature 2001 413 420-425. 

Hf and H Receptors. Histamine exerts its actions by binding to receptors on cell membranes. Two types of histamine receptors, the Hi and H2 receptors, are known specific agonists and antagonists exist for each of these receptors. Black et al. (55) differentiated H and H2 receptors with the compounds, 2-methylhistamine and 4 methylhistamine. 2-Methylhistamine is active on tissues with H receptors 4-methylhistamine is active on tissues with H2 receptors. Classical antihistaminic drugs were developed in the 1930 s these compounds block H but not H2 receptors. Among the clinically used H -blockers are derivatives of ethanolamine, ethylenediamine, alkylamine, piperazine and phenothiazine (32). These agents are valuable in the treatment of... 

Histamine Hi receptor antagonists which enter the brain (diphenhydramine, promethazine and others) have sedative actions and polysomnographic recordings have shown that they suppress REM sleep and modestly increase SWS. A rebound in REM sleep sometimes occurs on discontinuation. Stimulation of central Hi and H2 receptors markedly potentiates signals produced by excitatory amino acids and it has been suggested that histamine acts as a waking amine (Schwartz et al., 1986). The effects of centrally acting antihistamines on sleep may be due to inhibition of these effects. 

Currently, three subtypes of histamine receptors are proposed Hi and H2 receptors are found in peripheral tissues and the central nervous system (CNS), and H3 receptors are found in the CNS. The second messenger pathway that mediates Hi-receptor stimulation is... 

The biological effects of histamine (Table 15.1) are mediated via three receptor subtypes, HI, H2 and H3 that are linked to G protein but activate different cell-signalling systems. The histamine HI receptor is associated with the phospholipase C-catalysed formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). The H2-receptor is coupled to adenylyl cyclase, increasing the production of cAMP. The cellular messenger system involved in H3-receptor activation has not been fully defined, but it may couple to N-type Ca2+-channels. The genes encoding for HI and H2 receptors have been cloned. A mutation of the human H2 receptor has been linked to schizophrenia. 

Most of the important effects of histamine in allergic diseases, including bronchoconstriction and contraction of the gut, are mediated through HI receptors. Other effects, including the cardiovascular responses, involve both HI and H2 receptors. In man the predominant cardiovascular effect is vasodilatation and a lowering of blood pressure. This response is also responsible for the cutaneous flushing commonly observed with histamine release. The... 

Although histamine is distributed in the gallbladder, its functional effects have been identified only following activation of Hi and H2 receptors which mediate muscle contraction and relaxation, respectively (Impicciatore 1978) The H3 receptor agonist (R)a-... 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

Histamine H3 receptor stimulation is not involved in the direct effects of histamine in the permeability response in in vivo rats, (Pile and Smaje., 1992) In this last study, Hi and H2 receptors seem to have a dominant role. However, the H3-receptor antagonist thioperamide prevents the effects induced by histamine and by the Hi-agonist 2-thiazolylethylamine, thus suggesting non-specific interactions of these histamine receptor ligands... 

Guc, M.O., Ilhan, M., Kayaalp, S O., 1988. Epithelium-dependent relaxation of guinea-pig tracheal smooth muscle by histamine evidence for non-Hi- and non-H2-histamine receptors. Arch. int. Pharmacodyn. 296, 57-65. 

Owen, D.A.A., Poy, E., Woodward, D.F., Daniel, D., 1980 Evaluation of the role of histamine Hi- and H2-receptors in cutaneous inflammation in the guinea-pig produced by histamine and mast cell degranulation. Br. J. Pharmacol. 69, 615-623. 

Subsequent systematic variations of the histamine side chain lead to some chiral branched derivatives which were observed to be strikingly active at and selective for the H3 receptor. In contrast to Hi and H2 receptors, respectively, the H3 receptor shows a considerably more pronounced stereoselectivity for agonistic binding, because the introduction of a single methyl group in the a-position of the histamine side chain... 

All four receptor types have been cloned and belong to the large superfamily of receptors having seven membrane-spanning regions and intracellular association with G proteins. The structures of the Hi and H2 receptors differ significantly and appear to be more closely related to muscarinic and 5-HTi receptors, respectively, than to each other. The H4 receptor has about 40% homology with the H3 receptor but does not seem to be closely related to any other histamine receptor. 

Histamine receptors are related to skin barrier function.44 Three different types of histamine receptors, HI, H2, and H3 have been reported. First, topical application of histamine HI and H2 receptor antagonists accelerated the barrier repair. Histamine itself, H2 receptor agonist, and histamine releaser delayed the barrier repair. Histamine H3 receptor antagonist and agonist did not affect the barrier recovery rate. Topical application of the HI and H2 receptor antagonists prevented the epidermal hyperplasia induced by barrier disruption under low humidity. The mechanism of the relationship between the histamine receptors and the barrier repair process has not been elucidated yet. 

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