HETEROGENEITY OF HISTAMINE Hi‐RECEPTORS: SPECIES VARIATIONS IN [<sup>3</sup>H]MEPYRAMINE BINDING OF BRAIN MEMBRANES

Chang, Raymond S.L.; Tran, Vinh T.; Snyder, Solomon H.

doi:10.1111/j.1471-4159.1979.tb02276.x

Cited by 213 publications

(80 citation statements)

References 19 publications

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“…Marked differences between the activity of the enantiomers have also been observed in rabbit aorta (O'Neill & Patil, 1975 (Hill et al, 1978;Tran et al, 1978;Chang et al, 1979;Quach et al, 1980). It is of interest that there are no marked species differences in stereoselectivity ratios, even though the ability of chlorpheniramine to displace the labelled ligand varies (Chang et al, 1979). Dimethindene is a potent H, antihistamine, with activity similar to or greater than that of (+)-chlorpheniramine in a number of tests of histamine receptor function (Barrett et al, 1961) and in receptor binding studies (Tran et al, 1978;Kubo et al, 1987). Its stereoselectivity with respect to H1 sites is less well documented, but (-)-dimethindene is between 20 and 100 times more potent than the (+)-isomer in blocking the response to histamine receptor activation in various guineapig tissue preparations (Borchard et al, 1985).…”

Section: Discussionmentioning

confidence: 96%

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Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Nicholson

Pascoe

Turner

et al. 1991

British J Pharmacology

118

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1 The effects of 10mg (+)-and (-)-chlorpheniramine and 5mg (+)-and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5mg triprolidine hydrochloride as an active control and two placebos. 2 Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+ )-chlorpheniramine. 3 Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4 In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine Hl-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

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Section: Discussionmentioning

confidence: 96%

“…However, the affinities of the isomers for the Hl-receptor indicate a high degree of stereoselectivity (Chang et al, 1979;Borchard et al, 1985), and so studies with the enantiomers may help to resolve whether sedation is related specifically to the steric configuration and is due to Hl-receptor antagonism alone.…”

Section: Introductionmentioning

confidence: 99%

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Nicholson

Pascoe

Turner

et al. 1991

British J Pharmacology

118

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“…Our results support the notion that histamine H 1 receptors have distinct anatomic location and show striking differences in their density and regional distribution among different species. 11,29,30 Saturation binding revealed that in rat brain, B max was significantly higher in the tissue representing the rest of the brain. In contrast to B max , the K d value was similar in the two brain regions, suggesting that the receptors have similar affinity.…”

Section: Discussionmentioning

confidence: 99%

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

Lozeva¹

2001

Hepatology

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The binding properties and the regional densities of histamine H 1 receptors were studied in brain of rats with portacaval anastomosis (PCA) and in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE). Receptor binding studies and quantitative receptor autoradiography were performed, employing [ 3 H]mepyramine. Histamine H 1 receptors in rat brain displayed a higher density and a lower affinity compared with control human frontal cortex. Specific [ 3 H]mepyramine binding was heterogeneously distributed throughout the brain in both species. In human brain, binding was highest in the parietal and temporal cortices and lowest in caudate-putamen. In rat brain, binding was highest in the suprachiasmatic nucleus, dentate gyrus of the hippocampus, ventromedial hypothalamus, and nucleus accumbens. Hepatic encephalopathy (HE) is a potential long-term complication of chronic liver disease. Despite extensive research and a succession of different hypotheses, the exact mechanisms underlying the development of the clinical symptoms of HE are not well understood. 1,2 Consequently, progress in the treatment of HE in cirrhotic patients has been limited. Among the least exploited consequences of HE are the marked changes in the brain histaminergic system, which have been previously documented both in patients with HE 3 and in rats with portacaval anastomosis (PCA), a well-established animal model of the disease. [4][5][6][7][8] There is substantial evidence that histamine acts as a neurotransmitter in mammalian brain. 9 Histaminergic neurons are located exclusively in the tuberomammillary nucleus of the posterior hypothalamus and send their varicose fibers to almost every region of the brain. 10 This widespread distribution of histaminergic neurons suggests that the brain histaminergic system is involved in the regulation of a wide range of neurobiologic functions. Histaminergic signaling is mediated by 3 types of receptors, histamine H 1 , H 2 , and H 3 receptors, distinguished by their pharmacologic properties, specific anatomic location, and by the intracellular responses they mediate. 11,12 Interest has focused on the histamine H 1 receptors, because histamine, through the activation of the postsynaptic histamine H 1 receptors, is involved in the regulation of the neuroendocrine system, 13,14 locomotor activity, 15-17 circadian rhythmicity, 18,19 and the sleep-wake cycle, 20 as well as in various behaviors, including feeding and drinking (for a review, see Schwartz, 9 Yamatodani et al., 21 and Sakata 22 ).We have previously shown that altered histaminergic neurotransmission is an important part of the neurophysiologic background responsible for the behavioral changes after PCA surgery in the rat, leading us to propose that it may contribute to the pathogenesis of HE in human subjects. [6][7][8] Relating the functions controlled by histamine to the clinical presentation of HE, it appears a priori that histamine could participate in the pathogenesis of the sleep disturbances, decreased spontaneous vo...

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“…However, the binding of [3H]-doxepin is complex and not all the data are consistent with the receptor heterogeneity explanation, as the authors note. Caution is also necessary in interpreting Hill coefficients < 1 obtained from inhibition of [3H]-mepyramine binding, since even moderate concentrations of the 3H-ligand appear to label secondary, non H,-receptor sites in both guinea-pig and rat tissues (Hill & Young, 1980;Hadfield et al, 1983 (Chang et al, 1979;Figge et al, 1979;Palacios et al, 1979;Coupet & Szuchs-Myers, 1981; Tran et al, 1981;Kanba & Richelson, 1983). A similar disagreement exists in rat brain, 1.4 x 109M`to 5.0X 10'0M-' (Tran et al, 1978(Tran et al, , 1981 i) The Macmillan Press Ltd 1985 Richelson, 1980;, but in this species there is a further difficulty in that there is no reported affinity constant for doxepin derived from inhibition of a functional response mediated by Hi-receptors in an intact tissue preparation.…”

Section: Introductionmentioning

confidence: 99%

The binding of doxepin to histamine H₁‐preceptors in guinea‐pig and rat brain

Aceves

Mariscal

Morrison

et al. 1985

British J Pharmacology

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The affinity constant for doxepin obtained from inhibition of histamine‐induced contraction of guinea‐pig intestinal smooth muscle at 30°C was 2.6 ± 0.18 ± 1010m−1. The slope of a Schild plot was not significantly different from unity. The affinity constant of doxepin did not vary markedly with temperature. At 37°C it was 3.75 ± 0.02 ± 10m−1 and at 25°C 2.1 × 10m−1. Doxepin was a competitive inhibitor of [3H]‐mepyramine binding to guinea‐pig cerebellar homogenates. The affinity constant derived for doxepin at 30°C was 1.12 ± 0.45 ± 10m−1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]‐mepyramine binding in guinea‐pig cerebellum, cerebral cortex and hippocampus did not differ significantly from unity. The mean affinity of mepyramine for histamine H1‐receptors in rat brain homogenates at 30°C was 3.5 × 108m−1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]‐mepyramine binding to homogenates of rat cerebral cortex or rat whole brain were near unity. These studies provide no evidence that doxepin binds preferentially to a sub‐class of histamine H1‐receptors in rat brain.

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HETEROGENEITY OF HISTAMINE Hi‐RECEPTORS: SPECIES VARIATIONS IN [³H]MEPYRAMINE BINDING OF BRAIN MEMBRANES

Cited by 213 publications

References 19 publications

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

The binding of doxepin to histamine H₁‐preceptors in guinea‐pig and rat brain

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HETEROGENEITY OF HISTAMINE Hi‐RECEPTORS: SPECIES VARIATIONS IN [3H]MEPYRAMINE BINDING OF BRAIN MEMBRANES

Cited by 213 publications

References 19 publications

Sedation and histamine H1‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Sedation and histamine H1‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Increased density of brain histamine H1 receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy

The binding of doxepin to histamine H1‐preceptors in guinea‐pig and rat brain

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HETEROGENEITY OF HISTAMINE Hi‐RECEPTORS: SPECIES VARIATIONS IN [³H]MEPYRAMINE BINDING OF BRAIN MEMBRANES

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

The binding of doxepin to histamine H₁‐preceptors in guinea‐pig and rat brain