The role of central histamine H1- and H2-receptors in hypothermia induced by histamine in the rat

Histamine administered intraventricularly or into the anterior hypothalamic preoptic region induced dose-dependent hypothermia in rats with chronic i.c.v. cannula. This hypothermia was almost totally abolished by both the histamine H1- and H2-receptor antagonists, mepyramine or chloropyramine and metiamide or cimetidine, respectively, give i.c.v. prior to histamine. In behavioural thermoregulation studies histamine considerably diminished the mean duration of dwelling of the rat under the heat lamp. This effect was abolished by histamine H1- but not by H2-receptor antagonists. It is concluded that histamine induces hypothermia by lowering the set point of the hypothalamic thermostat by means of H1-receptors. Histamine H2-receptor blockers antagonized the increase in tail skin temperature after histamine administration, suggesting that h2-receptors are involved in a heat loss mechanism.     

Nature of histamine receptors in the emetic chemoreceptor trigger zone.

1 The protective effects of the intracerebroventicular (i.c.v.) administration of the H1-receptor antagonist, mepyramine and the H2-receptor antagonists, burimamide and metiamide on centrally induced histamine-emesis were studied in unanaesthetized dogs. 2 The PD50 values of intraventricular mepyramine, burimamide and metiamide against the 100% emetic dose of histamine (3.0 mg i.c.v.) were found to be approximately 200 mug, 20 mug and 20 mug respectively. 3 Although burimamide (i.c.v. or i.v.) afforded protection against histamine-induced emesis, there was no protection against intravenous apomorphine-or oral copper sulphate-induced emesis. 4 The results suggest that both H1- and H2-histamine receptors in the emetic chemoreceptor trigger zone of the area postrema are concerned in histamine-induced emesis.     

Lipolytic responses induced by intracerebroventricular administration of histamine in the rat

Histamine (10-50 microgram) administered intraventricularly in conscious rats induced an increase in serum-free fatty acids. The maximum, significant increase appeared 30-60 min after administration. Histamine H1-receptor antagonists, mepyramine and chloropyramine, when injected 2 h prior to histamine, abolished considerably hyperlipaemic responses to histamine. H2-Receptor antagonists, metiamide and cimetidine, given i.c.v. only moderately diminished histamine-induced hyperlipaemia. Histamine injected i.c.v. also increased serum corticosterone levels considerably. This elevation was prevented significantly by the H1-receptor antagonist, mepyramine, but not by the H2-receptor blocker, cimetidine. It seems likely that histamine given i.c.v. induces lipolysis through the release of ACTH, one of the known lipid-mobilizing hormones. The central lipid-mobilizing mechanism after histamine depends more on activation of H1- than H2-receptors.     

Central hypertensive action of histamine in conscious normotensive cats.

In conscious normotensive cats intraventricular (i.c.v.) administration of histamine (2.0-50.0 mug) induced dose-related rises in blood pressure, with no increase in heart rate. The hypertensive response elicited by a sub-maximal dose of histamine (10.0 mu i.c.v.) was significantly antagonised by central pretreatment with the H1-receptor antagonist mepyramine maleate (200 mug i.c.v.) but not by the H2-receptor antagonist metiamide hydrochloride (1.0 mg i.c.v.). Behavioural responses were obtained in response to to histamine (10.0 and 50.0 mug i.c.v.), which were not antagonised by these antihistamine pretreatments.     

Central histaminergic stimulation of hyperlipemic response in rats under stress

In rats subjected to a mild stress of immobilization histamine, the H1-receptor agonist 2-pyridylethylamine (PEA), and the H2-receptor agonists 4-methyl histamine (4-MeHA) and impromidine administered intracerebroventricularly (i.c.v.) 1 h prior to stress, intensified the stress-induced increase in serum free fatty acid (FFA) levels. Impromidine was far more potent than histamine and its agonists in increasing hyperlipemia in stressed rats. The hyperlipemic response to histamine was abolished by i.c.v. pretreatment of rats with mepyramine, a H1-receptor antagonist, but was unchanged in rats pretreated with cimetidine or metiamide, H2-receptor antagonists. The increase in serum FFA levels induced in stressed rats by PEA was abolished by mepyramine but the hyperlipemic responses to 4-MeHA and impromidine were not antagonized by cimetidine. These results suggest that central H1-receptor mediate the histamine-stimulated hyperlipemic response in stressed rats.     

The interaction of ethanol with central histaminergic stimulation of the pituitary-adrenocortical and hyperlipemic activity

Ethanol introduced intragastrically (i.g.) in rats increased the pituitary-adrenocortical activity, measured indirectly through corticosterone concentration in blood serum. Since this increase reached only about 40% of the maximum hormone levels observed in that species after another stimuli, ethanol may be considered as a relatively weak stimulus. Ethanol induced also a significant decrease in serum free fatty acid (FFA) levels which was blocked totally by a prior intracerebroventricular (i.c.v.) administration of either H1- or H2-histamine receptor antagonists, mepyramine or metiamide and cimetidine. The ethanol-induced increase in serum corticosterone was insensitive to a central histamine H1- and H2-receptors blockade. Ethanol abolished the rise in serum FFA levels induced by an i.c.v. administration of histamine, pyridylethylamine (PEA)-a H1-receptor agonist, and dimaprit--a H2-receptor agonist. The histamine- and histamine-agonists induced increases of serum corticosterone were generally slightly intensified by a prior i.g. administration of ethanol.     

Naloxone antagonizes a central histaminergic stimulation of corticosterone secretion in rats

The interaction of central opioid receptors with histaminergic stimulation of the hypothalamo-pituitary-adrenocortical axis, evaluated indirectly through corticosterone secretion, was investigated in conscious unstressed rats. To avoid any possible direct action on the adrenal cortex, all drugs were given intracerebroventricularly (i.c.v.). Histamine, 2-pyridylethylamine (PEA), a histamine H1-receptor agonist, and 4-methyl-histamine (MeHA) and dimaprit, the H2-receptor agonists, considerably increased the serum corticosterone levels 1 h after administration. Naloxone, an opioid receptor antagonist, almost abolished the corticosterone response to PEA and considerably reduced the responses to MeHA, dimaprit and histamine. The maximum inhibitory effects of naloxone on corticosterone responses induced by histamine and histamine agonists were comparable with those of the H1- and H2-receptor antagonists, mepyramine and cimetidine. These results strongly suggest that a major part of the histaminergic stimulation of the hypothalamo-pituitary-adrenal axis is mediated by central opioid receptors.     

Regulatory influence of histamine receptor activation and inhibition on the synthesis and level of hypothalamic histamine

The blockade of histamine receptors by repeated i.p. administration of 10-20 mg/kg of chloropyramine and tripelennamine, the potent H1-receptor antagonists, or by the i.c.v. administration of 2 mg/kg of metiamide and cimetidine, the highly selective H2-receptor antagonists, led to significant enhancement in the hypothalamic HD2(L-histidine carboxylase; EC 4.1.1.22.) activity and the histamine content; whereas the activation of the histamine H1-receptor by 4 mg/kg i.e.v. doses of 2-pyridylethylamine, the specific histamine H1 agonist, resulted in significant diminution in both the synthesis and level of this amine. These compounds either do not influence the hypothalamic HD in vitro or cause opposite effects in relatively high concentrations. After repeated administration of either agonists or antagonists, no significant alteration have been observed in the hypothalamic HNMT (histamine-N-methyl-transferase; EC 2.1.1.8.) activity. There were, however, two exceptions: 2 mg/kg i.c.v. doses of 2-methylhistamine and 4-methylhistamine produced remarkable inhibitions in the hypothalamic HNMT activity. These effects do not seem to correspond to the agonistic character of the compounds, but mask the indirect actions and create difficulties in the discovery of regulatory events. The regulatory influence which suppresses or stimulates the basal activity of HD under the activation or the inhibition of the functional state of histamine receptor, is assumed to be mediated through the cyclic AMP system.     

Algogen-specific pain processing in mouse spinal cord: differential involvement of voltage-dependent Ca(2+) channels in synaptic transmission

1. The effects of intrathecal (i.t.) administration of N-, P/Q- or L-type voltage-dependent Ca(2+)-channel blockers were tested in two pain models involving bradykinin (BK)- and alpha,beta-methylene ATP (alpha,beta meATP)-induced activation of primary afferent neurons in mice. 2. The nociceptive response (amount of time spent licking and biting the hindpaw) induced by intraplantar injection of BK (500 pmol mouse(-1)) was significantly attenuated by both omega-conotoxin GVIA (N-type blocker) and calciseptine (L-type) but not by omega-agatoxin IVA (P/Q-type). 3. The nociceptive response induced in a similar way by alpha,beta meATP (100 nmol) was significantly inhibited by both the above N- and P/Q-type Ca(2+)-channel blockers but not by the L-type blocker. 4. The nociceptive responses elicited by BK and alpha,beta meATP were dose-dependently inhibited by a tachykinin-NK1-receptor antagonist (L-703,606) and an N-methyl-D-aspartate (NMDA)-receptor antagonist (D-AP5), respectively. 5. Intrathecal administration of substance P (SP) (1.8 nmol) or NMDA (350 pmol) elicited algesic responses, such as licking, biting and scratching of the hindquarters. The SP-induced algesic behaviour was significantly inhibited by the L-type blocker but not by the N-type. The NMDA-induced response was not affected by either the N- or the P/Q-type blocker. 6. These findings suggest that BK and ATP most likely excite different types of sensory neurons in the periphery and that within the spinal cord the former stimulates peptidergic transmission regulated by presynaptic N- and postsynaptic L-type Ca(2+) channels, while the latter stimulates glutamatergic transmission regulated by presynaptic N- and P/Q-type channels.     

Involvement of central histamine receptors in corticosterone secretion induced by intraventricular administration of morphine

The effect of intracerebroventricular (i.c.v.) administration of morphine on corticosterone secretion was studied in conscious, unstressed rats. A dose-dependent increase in serum corticosterone levels was observed 1 h after morphine injection. The corticosterone response to morphine was antagonized in a dose-dependent manner, and at larger dose almost abolished, by i.c.v. pretreatment of rats with naloxone, an opioid receptor antagonist. Intraventricular pretreatment of rats with mepyramine and cimetidine, the histamine H1- and H2-receptor antagonists, significantly diminished the corticosterone response to morphine. These results suggest that central opioid receptors are involved in the stimulating effect of morphine on the hypothalamo-pituitary-adrenocortical axis. Central histamine H1- and H2-receptors seem to be substantially involved in the stimulatory effect of morphine on corticosterone secretion in conscious, unstressed rats.     

Inducible histamine protects mice from hepatitis through H2-receptor stimulation

Histamine is well known for its roles in allergic diseases and anaphylaxis through H(1)-receptor stimulation. The H(1)-receptor stimulation by histamine results in an increase in vascular permeability, vasodilatation, and stimulation of nerve terminals in primary sensory neurons, thereby accelerating the inflammatory responses. On the other hand, histamine has been demonstrated to be involved in the regulation of innate and acquired immune responses through H(2)-receptors. In a previous study with human peripheral blood mononuclear cells, we observed that histamine exerts various regulatory effects on monocyte/macrophage function. In this review, we discuss how inducible histamine protects mice from lethal hepatitis, induced by heat-killed P.acnes (1 mg, i.v.) followed by challenge with a low dose of lipopolysaccharide (1 microg), by reducing the excessive cytokine response in the liver. In addition, from in vivo studies with histidine decarboxylase knockout and H(1)-, H(2)-receptor knockout mice, the protective effect of histamine against fulminant hepatitis is shown to be elicited through H(2)-receptor stimulation.     

Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists

In the present study we searched for neutral antagonists for the human histamine H(1)-receptor (H(1)R) by screening newly synthesized ligands that are structurally related to H(1)R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-kappaB driven reporter-gene assay that allows for the detection of both agonistic and inverse agonistic responses. Starting from the endogenous agonist for the H(1)R, histamine, we synthesized and tested various analogues and ultimately identified several compounds with partial inverse agonistic properties and two neutral H(1)-receptor antagonists, namely 2-[2-(4,4-diphenylbutyl)-1H-imidazol-4-yl]ethylamine (histabudifen, 18d) (pK(i) = 5.8, alpha = 0.02) and 2-[2-(5,5-diphenylpentyl)-1H-imidazol-4-yl]ethylamine (histapendifen, 18e) (pK(i) = 5.9, alpha = -0.09).     

Vascular reactions to histamine and compound 48/80 in human skin: suppression by a histamine H2-receptor blocking agent.

1 The ability of a specific competitive histamine H2-receptor antagonist, cimetidine, to inhibit vascular responses to histamine in human skin provides new evidence that skin blood vessels possess histamine H2 receptors. 2 Simultaneous systemic administration of cimetidine and chlorpheniramine (an H1-receptor antagonist) was more effective than either drug alone in inhibition of the erythematous reaction both to exogenous histamine, and endogenous histamine secreted by skin mast cells in response to compound 48/80. 3 These results suggest that combined therapy of histamine-mediated skin diseases included urticaria and dermatitis using a combination of H1- and H2-histamine receptor antagonists may be more effective than either class of drug alone.     

Antisecretory effects of two new histamine H2-receptor antagonists

N-(3-[3-(1-Piperidinylmethyl)phenoxy]propyl)acetoxyaceta mide hydrochloride (Hoe 760) and N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)glycolamine hydrochloride (Hoe 062) are highly specific H2-receptor antagonists. The compounds are equipotent after intragastrical or intravenous administration. The antagonists inhibited gastric acid secretion in the rat induced by all stimuli tested, carbachol, desglugastrin and histamine. In the Heidenhain pouch dog whose gastric acid secretion was stimulated by food or histamine the two receptor blockers proved to be 4-6 times more potent inhibitors than cimetidine.     

Diuretic and saliuretic effects of 1,3-dipropyl-8-cyclopentylxanthine, a selective A1-adenosine receptor antagonist.

We have previously shown that 8-phenyltheophylline (8-PT), a non-selective antagonist at adenosine A1- and A2-receptors, has a diuretic effect. In this study, the diuretic and adenosine antagonist effects of the A1-receptor selective compound 1,3-dipropyl-8-cyclopentylxanthine (CPX) have been examined in the conscious rat. CPX (0.1 and 0.3 mg kg-1 i.v.) significantly attenuated bradycardic but not hypotensive responses evoked by adenosine. In contrast, 8-PT (3 mg kg-1 i.v.) significantly antagonized both adenosine-induced bradycardia and hypotension. CPX (0.1 and 0.3 mg kg-1 i.v.) evoked a dose-related diuretic and saliuretic response in the conscious rat. These results indicate that the diuretic effects of adenosine antagonists are associated with blockade of the A1-receptor sub-type.     

Alteration by histamine-receptor blockers of the potentiation of angiotensin I in the pulmonary vascular bed

The interaction of histamine receptor blockers and angiotensin I was studied in the isolated perfused pulmonary circulation of the rat lung. Rat colon and rabbit aorta were used as test organs, and they were continuously superfused with the effluent of lung. The response of rabbit aorta to the directly applied angiotensin II was found to be potentiated in the presence of histamine H2-receptor blockers but not H1-receptor blockers. No change was observed in rat colon in the presence of either H2- or H1-receptor blockers. Angiotensin I given through the lung caused an increased myotropic response in both assay when H2-receptor blocker was added to the perfusion medium. Histamine H1-receptor blockers did not change the potentiated response of the test organs to the angiotensin I-injected lung effluent. The possible mechanisms of the interaction of angiotensin I and histamine H2-receptor blockers are discussed.     

Histamine H3-receptors modulate nonadrenergic noncholinergic neural bronchoconstriction in guinea-pig in vivo

We have investigated whether the histamine H3-receptors influence nonadrenergic noncholinergic (NANC) bronchoconstriction in guinea-pig in vivo. Atropine, propranolol, mepyramine and cimetidine were administered to block the effects of beta-adrenoceptor-, acetylcholine, H1- and H2-receptor-mediated responses, respectively. Vagal stimulation evoked a NANC bronchoconstrictor response. The selective H3-agonist, alpha-methylhistamine (alpha-MeHA, 1-10 mg/kg i.v.) did not alter basal respiratory insufflation pressure, but reduced the NANC bronchoconstrictor response to vagal stimulation in dose-dependent manner (with a maximal inhibition of 46.0 +/- 10.3%; mean +/- S.E. at 10 mg/kg) (P less than 0.02). Histamine itself also had a significant inhibitory effect on NANC responses with H1- and H2-blockade. The alpha-adrenoceptor antagonist phentolamine had no effect on the inhibitory response produced by alpha-MeHA, but the H3-receptor antagonist thioperamide blocked the inhibitory effect of alpha-MeHA. alpha-MeHA had no inhibitory effect on bronchoconstriction induced by exogenous substance P (5-25 micrograms/kg i.v.). We conclude that H3-receptors inhibit the release of transmitter from NANC nerves and that H3-receptors might play a role in regulation of neurogenic inflammatory responses in the airways.     

Stimulatory and inhibitory histamine receptors in canine cystic duct.

1 The effects of histamine receptor stimulation were assessed on the resistance of the canine cystic duct in vivo and on the contractility of circular muscle preparations of canine cystic duct in vitro. 2 In anaesthetized dogs, the H1-receptor agonist, 2-pyridylethylamine (0.05 to 15 mumol, i.a.), elicited dose-dependent increases in cystic duct resistance, whereas the H2-receptor agonist, 4-methylhistamine (0.05 to 15 mumol, i.a.) decreased cystic duct resistance. These responses were antagonized by the H1-receptor antagonist, diphenhydramine, and the H2-receptor antagonist, cimetidine, respectively. 3 Histamine (0.1 to 3000 nmol, i.a.) also increased cystic duct resistance in vivo. In the presence of diphenhydramine, the stimulatory effect of histamine was antagonized and slight decreases in cystic duct resistance became apparent. Cimetidine or prazosin also antagonized the stimulatory effects of histamine. 4 Histamine (1 to 100 microM) or 2-pyridylethylamine (1 to 100 microM) contracted, whereas 4-methylhistamine (1 to 100 microM) relaxed, circular muscle preparations of cystic duct. These excitatory and inhibitory responses were antagonized by diphenhydramine and cimetidine, respectively. 5 These results indicate that the canine cystic duct possesses excitatory H1- and inhibitory H2-receptors. The predominant effect of histamine is an H1-receptor-mediated increase in cystic duct resistance. Histamine, which may be released in association with cholecystitis, may exert significant effects on the regulation of bile flow in and out of the gallbladder and may contribute to gallbladder stasis during biliary disease.     

Involvement of histamine H1- and H2-receptors in induced asthmas in dogs.

Participation of histamine H1- and H2-receptors in both asthmas, i.e. experimentally induced bronchoconstriction and bronchosecretion, with ascaris suum and histamine in anesthetized dogs was investigated. Dogs given 0.2% histamine solution or ascaris antigen (3 mg protein) by inhalation showed increases in respiratory resistance (Rrs) and respiratory rate to 2.5-5.0 fold. Airway secretion volume was also significantly increased 3-4 fold. The increase in Rrs by histamine inhalation was effectively inhibited or abolished by a histamine H1-receptor antagonist, chlorpheniramine (0.3-1 mg/kg i.v.), but not by a H2-receptor antagonist, cimetidine (1-3 mg/kg i.v.). The increase in Rrs by antigen inhalation was reduced by relatively high doses of chlorpheniramine (1-3 mg/kg i.v.), and not by cimetidine. In contrast, hypersecretion of tracheobronchial fluid in both asthmas was significantly prevented by either chlorpheniramine or cimetidine. Combinations of both antagonists abolished the hypersecretion. Atropine (2 mg/kg i.v.) significantly inhibited the occurrence of responses in both asthmas. The results suggest that histamine is involved in the allergic asthma produced by ascaris suum and that histamine directly evokes airway constriction through H1-receptors and hypersecretion of tracheobronchial fluid through H1- and H2-receptors, and, in part, indirectly activates the cholinergic pathway.     

Histamine H(3)-receptor antagonists inhibit gastroprotection by (R)-alpha-methylhistamine in the rat

(R)-alpha-methylhistamine, a selective agonist of histamine H(3) receptors, is capable of protecting the gastric mucosa against differently acting damaging agents. The objective of the present study was to determine whether H(3) receptors mediate its protective action in the rat. Gastric mucosal lesions were induced intragastrically (i.g.) by 0.6 N HCl, 1 ml rat(-1). (R)-alpha-methylhistamine, 100 mg kg(-1) i.g., substantially reduced the severity of macroscopically and histologically assessed damage caused by concentrated acid. Prior treatment with highly selective H(3)-receptor antagonists, ciproxifan (0.3, 1 and 3 mg kg(-1) i.g.) and clobenpropit (3, 10 and 30 mg kg(-1) i.g.), dose-dependently inhibited the protection exerted by (R)-alpha-methylhistamine up to a complete reversal. When given alone at high doses, both antagonists tended to worsen the HCl-induced histologic damage. During basal conditions, (R)-alpha-methylhistamine, 100 mg kg(-1) i. g., caused a significant increase in titratable acidity of the gastric juice. Prior treatment with ciproxifan (3 mg kg(-1) i.g.) and clobenpropit (30 mg kg(-1) i.g.) did not alter the secretory response to (R)-alpha-methylhistamine. Clobenpropit alone, but not ciproxifan, increased the volume of gastric juice, and both compounds alone had no effect on titratable acid. Present findings support evidence that H(3) receptors are actively involved in the maintenance of gastric mucosal integrity, with no apparent role in the regulation of basal gastric acid secretion.