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Ventilation oscillates throughout a day in parallel with oscillations in metabolic rate. Histamine affects ventilation and the balance of the energy metabolism via H1 receptors in the brain. We tested the hypothesis that the ventilatory response to hypoxia varies between light and dark periods and that histamine H1 receptors are required for the circadian variation, using wild-type (WT) and histamine H1 receptor knockout (H1RKO) mice. Mice were exposed to hypoxic gas (7% [O.sub.2] + 3% [CO.sub.2] in [N.sub.2]) during light and dark periods. Ventilation initially increased and then declined. In WT mice, minute ventilation ([V.sub.E]) during hypoxia was higher in the dark period than in the light period, which was an upward shift along with the baseline ventilation. Hypoxia decreased the metabolic rate, whereas [O.sub.2] consumption ([VO.sub.2]) and [CO.sub.2] excretion were higher in the dark period than in the light period. However, in H1RKO mice, changes in VE during hypoxia between light and dark periods were minimal, because [V.sub.E] was increased relative to [VO.sub.2], particularly in the light period. In H1RKO mice, the H[CO.sub.3] concentration and base excess values were increased in arterial blood, and the level of ketone bodies was increased in the serum, indicating that metabolic acidosis occurred. Respiratory compensation takes part in the [V.sub.E] increase relative to [Vo.sub.2] during hypoxia. These results suggested that changes in [V.sub.E] during hypoxia vary between light and dark periods and that H1 receptors play a role in circadian variation in VE through control of the acid-base status and metabolism in mice. H1 receptor knockout mice; hypoxia; ventilation; metabolism; circadian variation

Constitutive activity has been mainly recorded for numerous overexpressed and/or mutated receptors. The histamine [H.sub.3] receptor ([H.sub.3]R) is a target of choice to study the physiological relevance of this process. In rodent brain, postsynaptic [H.sub.3]Rs show high constitutive activity, and presynaptic [H.sub.3] autoreceptors that show constitutive activity have a predominant role in inhibiting the activity of histamine neurons. [H.sub.3]R inverse agonists abrogate this constitutive brake and enhance histamine release in vivo. Some of these inverse agonists have entered clinical trials for the treatment of cognitive and food intake disorders. Studies performed in vitro and in vivo with proxyfan show that this [H.sub.3]R ligand is a 'protean agonist'--that is, a ligand with a spectrum of activity ranging from full agonism to full inverse agonism depending on the level of [H.sub.3]R constitutive activity. Consistent with its physiological and therapeutic relevance, the constitutive activity of [H.sub.3]R thus has a major function in the brain and regulates the activity of [H.sub.3]R-targeted drugs.

Activation of presynatic histamine [H.sub.3] receptors ([H.sub.3]R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of [[alpha].sub.2]-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, [H.sub.3]R-mediated antiexocytotic effects could result from a decreased [Ca.sup.2+] influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human [H.sub.3]R cDNA (SH-SY5Y-[H.sub.3]). We found that reducing [Ca.sup.2+] influx in response to membrane depolarization by inhibiting N-type [Ca.sup.2+] channels with [omega]-conotoxin ([omega]-CTX) greatly attenuated the exocytosis of [[sup.3]H]norepinephrine from both SH-SY5Y and SH-SY5Y-[H.sub.3] cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to [omega]-CTX, activation of [H.sub.3]R with the selective [H.sub.3]R-agonist imetit also reduced both the rise in intracellular [Ca.sup.2+] concentration ([Ca.sub.i]) and norepinephrine exocytosis in response to membrane depolarization. The selective [H.sub.3]R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking [H.sub.3]R, imetit affected neither the rise in [Ca.sub.i] nor [[sup.3]H]norepinephrine exocytosis, demonstrating that the presence of [H.sub.3]R is a prerequisite for a decrease in [Ca.sub.i] in response to imetit and that [H.sub.3]R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in [Ca.sub.i]. Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by [H.sub.3]R agonists may offer a novel therapeutic approach to this condition.

The histamine H2 receptor agonist exhibits multiple biological actions. For example, it plays an important role in the regulation of gastric acid secretion as well as gastrointestinal motility. This biogenic amine receptor is also involved in the regulation of secretion in the intestines and proliferation of the cells. The H2 receptor demonstrates the ability to activate multiple G proteins. However, its potential role in cell growth is still uncertain and therefore requires additional investigative studies.

The histaminergic system (histamine and its [H.sub.1]-receptor) of the central nervous system has been implicated in control of food intake. The reported studies were designed to examine the effects of food restriction and very low (1%) protein diets on central nervous system [H.sub.1]-receptors in male and female rats. In a series of experiments, groups of rats were freely fed a 25% protein diet, a 1% protein diet, or fed the 25% protein diet at 4 g/100 g body weight for 14-20 d. When freely fed 25% protein diets, females had higher whole-brain [H.sub.1]-receptor binding than males on d I (female 122.36 [+ or -] 4.53 and male 65.78 [+ or -] 3.82 pmol/g protein; P < 0.001). Changing diets affected central [H.sub.1]-receptor binding in both males and females (P < 0.003). When rats were fed both restricted levels of food and 1% protein diets, the receptor binding of males increased by d 5 whereas that of females decreased by d 5 (P < 0.001). When fed 1% protein diets, females had decreased [H.sub.1]-receptor binding (98.4 [+ or -] 2.38 pmol/g protein) and that in males increased to 119.81 [+ or -] 5.09 pmol/g protein. After 15 d, females had eaten significantly more food than males: females 166 [+ or -] 4.9 g, males 124 [+ or -] 1.9 g (P < 0.0007). Males had a significantly greater weight loss than females: males -28.8 [+ or -] 2.6 g, females -17.08 [+ or -] 0.97 g (P < 0.0007). When fed restricted diets, females had decreased [H.sub.1]-receptor binding (93.81 [+ or -] 5.58 pmol/g) whereas binding in males increased to 111.27 [+ or -] 8.55 pmol/g. Preliminary saturation binding studies indicated that restricted food intake lowered receptor density (females consuming 25% protein: 715 [+ or -] 30 pmol/g protein; female restricted: 467 [+ or -] 28 pmol/g protein, P < 0.05), while 1% protein increased receptor sensitivity, i.e., lowered [K.sub.D] (males consuming 25% protein: 15.3 [+ or -] 1.8 nmol; males fed low protein: 2.8 [+ or -] 0.27 nmol). This study suggests that dietary manipulation affects central [H.sub.1]-receptor binding in a gender-specific manner, thereby modulating central histaminergic activity during food or protein deficit. INDEXING KEY WORDS: * receptor * growth * histamine * rats * gender * diet

The effects of endothelium-derived relaxing factor (EDRF) on the response of lymphatic vascular smooth muscles to histaminergic (H) receptor activation and inhibition were analyzed in porcine tracheobronchial lymph vessel rings. The histamine-mediated release of EDRF into the lymphatic vessels is vital for the regulation of lymph flow in porcine tracheobronchial lymph vessels. Administration of dipenhydramine in tracheobronchial lymph vessels inhibited the H1-specific contractile activity of histamine. Furthermore, the release of EDRF in lymphatic vessels is mediated by H1 receptors.

From pharmacological studies using histamine antagonists and agonists, it has been demonstrated that histamine modulates many physiological functions of the hypothalamus, such as arousal state, locomotor activity, feeding, and drinking. Three kinds of receptors ([H.sub.1], [H.sub.2], and [H.sub.3]) mediate these actions. To define the contribution of the histamine [H.sub.1] receptors (H1R) to behavior, mutant mice lacking the H1R were generated by homologous recombination. In brains of homozygous mutant mice, no specific binding of [3H]pyrilamine was seen. [3H]Doxepin has two saturable binding sites with higher and lower affinities in brains of wild-type mice, but H1R-deficient mice showed only the weak labeling of [3H]doxepin that corresponds to lower-affinity binding sites. Mutant mice develop normally, but absence of H1R significantly increased the ratio of ambulation during the light period to the total ambulation for 24 hr in an accustomed environment. In addition, mutant mice significantly reduced exploratory behavior of ambulation and rearings in a new environment. These results indicate that through H1R, histamine is involved in circadian rhythm of locomotor activity and exploratory behavior as a neurotransmitter.

The 9HTEo- tracheal epithelium cell lines and the CFNPE9o- nasal epithelium cell lines of cystic fibrosis patients were analyzed to determine the cellular signaling mechanism that is triggered by histamine. Histamine-induced intracellular Ca2+ mobilization in airway epithelial cells is mediated by the presence of histamine receptors that are linked by pertussis toxin-insensitive G proteins to phospholipase C.

Isolated cell membranes from purified canine parietal and rat hepatoma cells with histamine H2 receptors were analyzed to determine the effects of histamine on adenylate cyclase (AC) and phospholipase C (PLC) signaling. PLC and AC were activated by histamine H2 receptors by utilizing two guanosine triphosphate (GTP)-dependent pathways. The histamine-induced activation of PLC by GTP-dependent pathway is sensitive to cholera toxin. However, histamine activation of PLC is not affected by AC and cyclic adenosine monophosphate generation.

Histamine [H.sub.2] receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the [H.sub.2] antagonists cimetidine and ranitidine. This effect appears to be [H.sub.2] receptor-mediated as no change in receptor density was observed after [H.sub.1] or [H.sub.3] antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no [H.sub.2] antagonistic effects. By using transfected CHO cells expressing different densities of wild-type [H.sub.2] receptors or an uncoupled [H.sub.2][Leu.sup.124]Ala receptor, the histamine [H.sub.2] receptor was found to display considerable agonist-independent [H.sub.2] receptor activity. Cimetidine and ranitidine, which both induce [H.sub.2] receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent [H.sub.2] receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce [H.sub.2] receptor upregulation after long-term exposure. The displayed inverse agonism of [H.sub.2] antagonists appears to be a mechanistic basis for the observed [H.sub.2] antagonist-induced [H.sub.2] receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the [H.sub.2] antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.

A study of the effects of selective H3-receptor agonists such as R-alpha-methyl histamine (alpha-MH) and Imetit on bombesin (BN)-or cholecystokinin (CCK)-induced satiety reveals that BN induces satiety by promoting histaminergic activity at unknown locations and that the BN effects on food intake are lowered by H3-receptor agoinsts by preventing histamine secretion. Satiety inhibition by H3-receptor agonists is dose-dependent and selective to BN and is absent when the activation is by CCK. The inhibitory effects of the agonists are prevented by H3-receptor antagonists.

A study of the regulation of spontaneous and retinoic-induced differentiation of normal and leukemic human monocytes and macrophages by histamine H2 receptors and histamine decarboxylase reveals that histamines control the various autocrine, paracrine and intracrine mechanisms that regulate immune and inflammatory phagocytic responses in peripheral blood and tissues. The all-trans-retinoic acid (RA)-induced differentiation of normal human monocytes and of THP-1 leukemic monocytes into macrophages results in PMA-induced inhibition of H2O2 formation and attenuated cAMP production by histamine, mediated by RA-induced H2 R gene expression.

The reported studies were designed to examine relationships between central nervous system histamine, histaminergic receptors ([H.sub.1]) and food intake in rats. The hypothesis being tested was as follows: 'One component of the neuroregulation of food intake involves histaminergic activity in the hypothalamus as influenced by variation of histamine levels and/or [H.sub.1] receptor concentrations.' We performed combinations of dietary, surgical and pharmacological treatments on male or female rats. We fed groups of male or female rats diets containing either 4 g casein/100 g diet (low protein diet) or 25 g casein/100 g diet (normal protein). Rats with surgical ablation of the paraventricular nucleus did not decrease food intake when fed the low protein diet, whereas adrenalectomized rats did. Increasing central histamine levels decreased food intake, whereas decreasing central histamine increased food intake. Rats injected with histaminergic ([H.sub.1]) antagonists lost the ability to detect low protein diet in short-term experiments and had improved efficiency of weight gain. Rats that were fed the low protein diet or pair-fed the normal protein diet had greater [H.sub.1] receptor concentrations in whole brain preparations when compared with rats fed the normal protein diet. No differences were noted due to gender. Thus, manipulation of histamine levels affected food intake as hypothesized, i.e., increasing central histamine decreased food in rats fed the normal protein diet, whereas decreasing central histamine or blockade of [H.sub.1] receptors increased food intake in rats fed the low protein diet.

Studies on rat gastric H+-K+-ATPase alpha subunit reveal that H2 receptor activation leads to histamine stimulation of H+-K+-ATPase alpha subunit activity. Famotidine, which enhances gastric pH and serum gastrin, reduces the H2 receptor action. It also reduces the level of H+-K+-ATPase mRNA.

Antral gastritis is an inflammatory disease involving the portion of the stomach near its junction with the esophagus. It is becoming increasingly clear that the bacterium Helicobacter pylori plays an important role in the development of this disease. Hence, many treatment strategies have incorporated administration of one or several antibiotic medications. Although multiple-drug regimens have yielded high eradication rates, results have been much poorer with single-agent treatments. This may be due to the emergence of antibiotic resistance, antagonistic effects of gastric acid on the therapeutic actions of the drug, or less than optimal concentrations of the antibiotic at the gastric mucosa (the lining of the stomach) where the bacterial infection is present. To evaluate the effects of decreasing gastric acidity on mucosal antibiotic activity, an experiment was carried out in guinea pigs (an animal model of gastrointestinal function that has been shown to be very similar to human). Animals were pretreated with the histamine H2 receptor blocker cimetidine, which caused a reduction in gastric acid secretion; the guinea pigs were then treated with the antibiotic clindamycin. Blood samples as well as tissue sections were taken from the gastric antrum several times after drug treatment, and analyzed for antibiotic levels. Blood levels of clindamycin were similar to those that occur in the absence of cimetidine; however, following pretreatment with cimetidine, mucosal antibiotic concentrations were increased by as much as 10-fold (compared with normal levels of gastric acidity). Agents that reduce acidity may serve as useful adjuncts to antibiotic therapy for gastritis, particularly when single-antibiotic treatment is used. (Consumer Summary produced by Reliance Medical Information, Inc.)

In myocardial ischemia, adrenergic nerves release excessive amounts of norepinephrine (NE), causing dysfunction and arrhythmias. With anoxia and the concomitant ATP depletion, vesicular storage of NE is impaired, resulting in accumulation of free NE in the axoplasm of sympathetic nerves. Intraneuronal acidosis activates the [Na.sup.+]/[H.sup.+] exchanger (NHE), leading to increased [Na.sup.+] entry in the nerve terminals. These conditions favor availability of the NE transporter to the axoplasmic side of the membrane, causing massive carrier-mediated efflux of free NE. Neuronal NHE activation is pivotal in this process; NHE inhibitors attenuate carrier-mediated NE release. We previously reported that activation of histamine [H.sub.3] receptors ([H.sub.3]R) on cardiac sympathetic nerves also reduces carrier-mediated NE release and alleviates arrhythmias. Thus, [H.sub.3]R activation may be negatively coupled to NHE. We tested this hypothesis in individual human SKNMC neuroblastoma cells stably transfected with [H.sub.3]R cDNA, loaded with the intracellular pH (p[H.sub.i]) indicator BCECF. These cells possess amiloride-sensitive NHE. NHE activity was measured as the rate of [Na.sup.+]-dependent p[H.sub.i] recovery in response to an acute acid pulse ([NH.sub.4]CI). We found that the selective [H.sub.3]R-agonist imetit markedly diminished NHE activity, and so did the amiloride derivative EIPA. The selective [H.sub.3]R antagonist thioperamide abolished the imetit-induced NHE attenuation. Thus, our results provide a link between [H.sub.3]R and NHE, which may limit the excessive release of NE during protracted myocardial ischemia. Our previous and present findings uncover a novel mechanism of cardioprotection: NHE inhibition in cardiac adrenergic neurons as a means to prevent ischemic arrhythmias associated with carrier-mediated NE release.

Adaptation of circadian rhythms to the environmental light-dark cycle is necessary for the survival of organisms. This synchronization or entrainment is only caused by light (photic input) during the dark period, according to the internal biological clock of an organism. During the light period, internal factors (non-photic input), rather than light, are able to entrain circadian rhythms. In this article, the data that implicate the neurotransmitter system for histamine in circadian entrainment are reviewed. Furthermore, we speculate that histamine receptors are the final gate at which both photic and non-photic entrainment mechanisms converge before sending a resetting signal to the intracellular biological clock.

N-alpha-methyl-histamine, which is produced in the gastric mucosa by Helicobacter pylori, is a potent [H.sub.2] receptor agonist as well as a [H.sub.3] receptor agonist It is over 80 years since [...]

Histamine [H.sub.1] receptors mediate the anorectic action of the pancreatic hormone amylin. Am J Physiol Regulatory Integrative Comp Physiol 281: R1442-R1448, 2001.--We investigated the role of histamine [H.sub.1] receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 [micro]g/kg), the amylin agonist salmon calcitonin (sCT; 10 [micro]g/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 [micro]g/kg). The experiments were performed with mice lacking functional [H.sub.1] receptors ([H.sub.1]Rko) and wild-type (WT) controls. The mice were also injected with the [H.sub.3] antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic [H.sub.3] receptors. The feeding-suppressive effect of thioperamide was abolished in [H.sub.1]Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived [H.sub.1]Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 [+ or -] 0.05 g vs. WT-amylin (5 [micro]g/kg) 0.30 [+ or -] 0.06 g (P < 0.01); [H.sub.1]Rko-NaCl 0.45 [+ or -] 0.05 g vs. [H.sub.1]Rko-amylin 0.40 [+ or -] 0.04 g; WT-NaCl 0.40 [+ or -] 0.09 g vs. WT-sCT (10 [micro]g/kg) 0.14 [+ or -] 0.10 g (P < 0.05); [H.sub.1]Rko-NaCl 0.44 [+ or -] 0.08 g vs. [H.sub.1]Rko-sCT 0.50 [+ or -] 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed [H.sub.1]Rko mice, whereas CCK equally reduced feeding in WT and [H.sub.1]Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine [H.sub.1] receptors. The same applies to leptin but not to CCK. [H.sub.1]Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight. food intake; histamine [H.sub.1] receptor knockout mice; thioperamide; salmon calcitonin; leptin; cholecystokinin