Hi-receptor activity

The human histamine Hi-receptor is a 487 amino acid protein that is widely distributed within the body. Histamine potently stimulates smooth muscle contraction via Hi-receptors in blood vessels, airways and in the gastrointestinal tract. In vascular endothelial cells, Hi-receptor activation increases vascular permeability and the synthesis and release of prostacyclin, plateletactivating factor, Von Willebrand factor and nitric oxide thus causing inflammation and the characteristic wheal response observed in the skin. Circulating histamine in the bloodstream (from, e.g. exposure to antigens or allergens) can, via the Hi-receptor, release sufficient nitric oxide from endothelial cells to cause a profound vasodilatation and drop in blood pressure (septic and anaphylactic shock). Activation of... 

Reiner, P. B. Kamondi, A. (1994). Mechanisms of antihistamine-induced sedation in the human brain HI receptor activation reduces background leakage potassium current. Neuroscience 59, 579-88. 

Hey, J.A., del Prado, M., Egan, R.W., Kreutner, W., Chapman, R.W., 1992b. (R)-a-methylhistamine augments neural, cholinergic bronchospasm in guinea pigs by histamine Hi-receptor activation. Eur. J. Pharmacol. 211, 421-426. 

Oishi, R., Adachi, N., Saeki, K., 1993. N -methylhistamine inhibits intestinal transit in mice by central histamine Hi receptor activation. Eur. J. Pharmacol. 237, 155-159. 

Malmberg-Aiello P, Lamberti C, Ipponi A, Btirtolini A, Schunack W (1998) Evidence for hypernociception induction following histamine HI receptor activation in rodents. Life Sci... 

FIGURE 9.20 Design of multiple ligancl activity, (a) Dual histamine HI receptor and leukotriene receptor antagonist incorporating known antihistaminic properties of cyproheptadine and LTD4. (b) Joint ACE/NEP inhibitor formed from incorporating similarities in substrate structures for both enzymes. From [57],... 

Hi-receptors in the adrenal medulla stimulates the release of the two catecholamines noradrenaline and adrenaline as well as enkephalins. In the heart, histamine produces negative inotropic effects via Hr receptor stimulation, but these are normally masked by the positive effects of H2-receptor stimulation on heart rate and force of contraction. Histamine Hi-receptors are widely distributed in human brain and highest densities are found in neocortex, hippocampus, nucleus accumbens, thalamus and posterior hypothalamus where they predominantly excite neuronal activity. Histamine Hrreceptor stimulation can also activate peripheral sensory nerve endings leading to itching and a surrounding vasodilatation ( flare ) due to an axonal reflex and the consequent release of peptide neurotransmitters from collateral nerve endings. 

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. 

From time to time it has been suggested that histamine has some role in a number of behaviours and motor activity while the established and marked sedative effect of Hi receptor antagonists, mentioned at the start of this section, has consistently been considered to indicate a role for histamine in arousal and the sleep-waking cycle (see Chapter 22). 

One of these compounds, venlafaxine (licensed in the UK in 1996), is regarded as an inhibitor of both 5-HT and noradrenaline reuptake but this is based on its actions in vitro. At low doses in vivo, it is a more potent inhibitor of 5-HT (Ki 39 nM) than noradrenaline reuptake (K 210 nM). Moreover, its active metabolite, O-demethylven-lafaxine, is a weaker inhibitor of NA reuptake, and has a longer half-life, than its parent compound. However, at high doses, venlafaxine inhibits reuptake of both these monoamines but has negligible activity at muscarinic, Hi-receptors or ai-adrenoceptors and... 

Although histamine has mixed excitatory and inhibitory effects on central neurons, those antihistamines (Hi-receptor antagonists) that enter the brain produce sedation this indicates that the predominant overall effect of histamine is excitatory. The preferred explanation for this rests on evidence that histaminergic neurons in the posterior hypothalamus are active in waking and silent in deep SWS and REM sleep. 

The H2 receptor is the second class of HA receptors. This is another G-protein-coupled receptor but, unlike the Hi receptor, the H2 receptor is coupled to adenylyl cyclase via the GTP-binding Gs protein (Hill et ah, 1997). Encoded by an intronless gene and located on human chromosome 5, the H2 receptor is made up of c. 358 amino acids (Gantz et ah, 1991 Traiffort et ah, 1995). Activation of the H2 receptor causes an accumulation of cAMP and activation of protein kinase A that eventually leads to the activation of cyclic-AMP-response element (CRE)-binding protein (CREB) (Hill et ah, 1997). In neurons, the H2 receptor mediates its excitatory effects by blocking the Ca2+-dependent K+ channel (Haas Konnerth, 1983). 

Administration of HA and its effect on sleep-wakefulness Local application of HA (5, 30 and 60 pg) in the TMN region of cats increased the latency to sleep, increased arousal, and reduced NREM sleep in a site-specific, dose-dependent manner. The highest dose produced the maximal effect, which lasted for 6 h. The HA-induced arousal was completely blocked when the cats were pretreated intraperitoneally with the Hi receptor antagonist mepyramine (Lin et at, 1986, 1988). In rats, intraventricular administration of HA blocked the increase in delta and theta activity (0-6 Hz) in the EEG induced by repeated low-frequency stimulation of the midbrain reticular formation. This effect was blocked if specific thalamic nuclei were lesioned (Tasaka et at, 1993) or by simultaneous administration of an Hi receptor antagonist, but not by an H2 receptor antagonist (Tasaka et at, 1989). Application of HA... 

Inoue, I., Yanai, K., Kitamura, D. etal. Impaired locomotor activity and exploratory behavior in mice lacking histamine Hi receptors. Proc. Natl Acad. Sci. U.S.A. 93 13316-13320,1996. 

Kim, S.F., Huang, A.S., Snowman, A.M., Teuscher, C. and Snyder, S.H. (2007) From the coven Antipsychotic drug-induced weight gain mediated by histamine HI receptor-linked activation of hypothalamic AMP-kinase. Proceedings of the National Academy of Sciences of the United States of America, 104 (9), 3456-3459. 

The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine (p. 82) and serotonin (p. 116) is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, a-adrenocep-tors, and certain 5-HT and hista-mine(Hi) receptors are blocked. Interference with the dopamine system is relatively minor. 

The vasodilatory effect of Hi-receptor stimulation is mainly due to an endothelial release of nitric oxide, which is able to activate the soluble guany-late cyclase in vascular smooth muscle cells. This effect is mainly responsible for the erythema seen after injection (insect sting) of histamine. Furthermore, it is responsible, together with the increased capillary permeability, for the cardiovascular symptoms seen in anaphylactic or allergic shock. 

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