The role of histamine H1- and H2-receptors in the generation of thromboxane A2 in perfused guinea-pig lungs.

1. When isolated perfused lungs from normal and ovalbumin sensitized guinea-pigs were challenged with histamine and 2-methylhistamine (agonists for H1-receptor), a release of thromboxane A2-like substance was observed. The effect of histamine on production of thromboxane A2 (TXA2) in sensitized lungs, was more pronounced than in normal lungs (P less than 0.01). 2. Specific activation of histamine H2-receptors in normal lungs with large doses (100 micrograms) of dimaprit and 4-methylhistamine, does not produce thromboxane-like or prostaglandin-like substances. 3. Perfusion of the lungs with pyrilamine (10 micrograms/ml) inhibited the release of arachidonate metabolites induced by histamine H1-receptor stimulation, whereas cimetidine (5 micrograms/ml) was ineffective. 4. It is concluded that only the stimulation of histamine H1-receptors appears to be responsible for generation of thromboxane A2 and other prostaglandin-like substances in normal guinea-pig lungs. In sensitized lungs, an increased ability of histamine to release TXA2 could be due to a possible interconversion of H2 into H1-receptors.     

Histamine H1-receptors in the guinea-pig urinary bladder

Histamine H1-receptors were identified in the guinea-pig urinary bladder. Histamine (10(-8)-10(-3) M) produced a dose-dependent contraction which was not altered by either scopolamine or tetrodotoxin. Specific [3H]mepyramine binding to the urinary bladder was saturable and there was a single population of high affinity binding sites with an equilibrium dissociation constant (KD) of 0.77 nM and maximum binding capacity (Bmax) of 68.5 fmol/mg protein. Histamine-induced contraction and [3H]mepyramine binding were inhibited by triploridine, promethazine, d-chlorpheniramine and mepyramine but not by cimetidine. There was a good correlation between mechanical activity and [3H]mepyramine binding as shown by the inhibition affinity constant (Ki) of H1-antagonists. These results provide evidence that the histamine H1-receptor in the guinea-pig urinary bladder is involved in the histamine-induced contraction.     

Evidence against the temperature-dependent interconversion of histamine H1- and H2-receptors in the guinea-pig ileum.

1 The possible temperature-dependent interconversion of histamine H1- and H2-receptors in the guinea-pig ileum suggested from previous studies was re-investigated by use of new and selective H2-receptor agonists and antagonists. 2 Chlorpheniramine, and H1-blocker, caused a rightward shift of the cumulative histamine dose-response curve at both 37 degrees C and 12 degrees C. Conversely cimetidine and tiotidine, two H2-receptor blockers, were ineffective at both temperatures. Metiamide behaved as a non competitive antagonist at 12 degrees C but only in very high concentrations. 3 Dimaprit and impromidine, two selective H2-receptor agonists, were inactive at both 37 degrees C and 12 degrees C when given alone, whereas at both temperatures they elicited the already described relaxation of the contractions induced by histamine. 4 Similar results were obtained on the guinea-pig whole ileum and on the longitudinal muscle strip: this indicates a lack of interference of the circular smooth muscle. 5 Our results allow us to conclude that no temperature-dependent interconversion of histamine H1- and H2-receptors occurs in the guinea-pig ileum.     

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.     

Histamine H1- and H2-receptors in the gastrointestinal circulation

Summary Evidence for the presence of specific histamine H₁- and H₂-receptors in the gastrointestinal circulation was obtained using histamine, 2-methylhistamine (a specific H₁-agonist), 4-methylhistamine (a specific H₂-agonist), and selective H₁- and H₂-receptor antagonists in the anesthetized dog. Histamine and 2-methylhistamine increased conductance in the vascular beds of the superior mesenteric artery, the left gastric artery and the common hepatic artery, whereas 4-methylhistamine mainly enhanced conductance in the vascular beds of the left gastric artery and the common hepatic artery. All three agents depressed systemic arterial blood pressure. The vasodilatory effect of histamine and 2-methylhistamine on the superior mesenteric artery bed occurred earlier and was of shorter duration than their effect on the two other vessels. The H₁-receptor antagonists mepyramine and clemastine blocked the response of the superior mesenteric artery bed to histamine, but had a lesser inhibitory effect on the histamine response of the common hepatic artery and the left gastric artery. The addition of the H₂-receptor antagonist cimetidine to mepyramine blockade augmented the inhibiting effect of mepyramine on the common hepatic artery. Cimetidine bolus injections prevented enhancement of vascular conductance by 4-methylhistamine, but did not influence conductance enhancement by histamine or 2-methylhistamine. These data demonstrate there are separable histamine H₁- and H₂-receptors in the gastrointestinal circulation which are distinguished by anatomic location, temporal relationships of receptor response, and response to specific histamine H₁- and H₂-agonists and antagonists.     

Histamine H2-receptors in the brain and sleep produced by clonidine

Sleep was induced in chicks aged 4-7 days by intravenous injection of clonidine hydrochloride 0.04 mumol/kg. Sleep was not prevented or altered by a preceding intramuscular injection of blockers of histamine H2-receptors which were used in doses (as mumol/kg) of up to 800 (metiamide) and 2400 (cimetidine). Clonidine, therefore, does not cause sleep by stimulating H2-receptors in the brain. The highest dose of cimetidine used had a hypnotic action of its own.     

Cardiovascular effects of histamine mediated by H1- and H2-receptors

Histamine was found to suppress the myocardial contractile function, to decrease systemic arterial blood pressure and to exert a positive chronotropic effect in unanesthetized dogs. A preliminary blockade of H1-receptors prevented the hypotensive effect of histamine, blockade of H2-receptors prevented the development of the positive chronotropic effect.     

Histamine H1- and H2-receptors in the gastric vasculature of the rabbit

The histamine receptors in the rabbit blood perfused gastric vasculature were analysed pharmacologically. Histamine elicited a monophasic increase in perfusion pressure which was antagonized by mepyramine and enhanced by metiamide. The maximum observed response was enhanced by metiamide to that produce by a specific H₁-receptor agonist. It is concluded that the gastric vasculature responds to histamine with an H₁-receptor mediated vasoconstriction and an H₂-receptor mediated dilation. In this preparation the H₁-effect predominates in response to injection of histamine.     

Histamine H3-receptors inhibit cholinergic neurotransmission in guinea-pig airways.

The histamine H3-agonist (R)-alpha-methylhistamine (alpha-MeHA) caused a dose-dependent inhibition of vagally-mediated contraction of a guinea-pig tracheal tube preparation but did not alter tracheal contraction induced by exogenously-applied acetylcholine. Blockade of H1- and H2-histamine receptors, and alpha- and beta-adrenoceptors failed to prevent the inhibitory effect of alpha-MeHA, whereas the specific H3-antagonist thioperamide prevented the effect of alpha-MeHA on tracheal contraction. In the presence of H1- and H2-receptor antagonists, histamine also inhibited vagally-mediated tracheal contraction. The inhibitory effect of alpha-MeHA was greater with preganglionic (vagus nerve) stimulation than with postganglionic stimulation by electrical field stimulation, suggesting that H3-receptors are localized both to cholinergic ganglia and to post-ganglionic nerve-endings. Our results suggest that H3-receptors exist on the vagus nerve which modulate cholinergic neurotransmission in the airways.     

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 H1- and H2-receptors in the mesenteric vascular bed of the pig

In order to study whether both histamine H₁- and H₂-receptors are present in the pig mesenteric vascular bed, natural histamine, 2-(2-pyridyl) ethylamine and 4-methylhistamine, as well as mepyramine and metiamide, were infused directly into the superior mesenteric artery. The results indicate that histamine H₁- and H₂-receptors, both inducing vasodilation, are present in the mesenteric circulation of the pig. Jejunal motility proved to be influenced by H₁-receptor stimulation only.     

Cholinergic-mediated gastric mast cell degranulation with subsequent histamine H1-and H2-receptor activation in stress ulceration in rats.

The effects of atropine, mepyramine, metiamide or NaHCO3 on gastric ulceration, gastric secretion and gastric mast cell degranulation were studied in stressed pylorus-occluded rats. The influence of dexamethasone pretreatment on stress ulcers in animals without pylorus occlusion (intact rats) was also examined. Stress produced a high glandular lesion incidence and ulcer index, and markedly lowered gastric secretion and glandular wall mast cell counts. Injected 0.5 h before stress, atropine, mepyramine or metiamide strongly antagonised ulceration. Atropine or metiamide, but not mepyramine, reduced gastric secretion. Only atropine prevented stress-induced mast cell changes. NaHCO3, given intragastrically before stress, did not prevent ulceration or mast cell degranulation despite complete neutralisation of gastric acid. Dexamethasone-induced gastric mucosal mast cell depletion could reduce stress ulceration. The findings show that stress degranulates stomach mast cells via a cholinergic pathway; released histamine from this source is largely responsbile for gastric ulceration through H1- and H2-receptor effects. Histamine H2-receptor-mediated gastric acid may play only a small contributory role in stress ulcers in rats. The antiulcer mechanisms of histamine H1- and H2-receptor blockade are discussed.     

Differentiation of the roles of histamine H1- and H2-receptors in the mediation of the effects of histamine in the isolated working heart of the guinea-pig.

1 Differentiation of the roles of histamine H1- and H2-receptors in the mediation of the effects of histamine on the isolated working heart of the guinea-pig was achieved through the use of histamine and selective histamine receptor agonists and antagonists. 2 Histamine over the dose range 10(-9) mol to 10(-6) mol produced dose-related increases in sinus rate, left intraventricular pressure (LVP)max, LVdP/dtmax, coronary flow, aortic flow, total cardiac output and external pressure-volume work. 3 Dimaprit, a selective histamine H2-receptor agonist, produced very similar responses to histamine. 4 2-Pyridylethylamine, a selective histamine H1-receptor agonist, had little effect on cardiac function unless large doses were administered. Such doses produced increases in all measured parameters. 5 Cimetidine, a selective histamine H2-receptor antagonist, antagonized the effects of histamine and dimaprit and some but not all effects of 2-pyridylethylamine. In the presence of cimetidine a decrease in all parameters with the exception of sinus rate was observed with both histamine and 2-pyridylethylamine. 6 The selective histamine H1-receptor antagonist, mepyramine, had little effect on responses to all three agonists. However, the depressant effects observed with histamine and 2-pyridylethylamine in the presence of cimetidine were antagonized by mepyramine. 7 The results indicate the important role of the histamine H2-receptor in the mediation of the gross cardiac effects of histamine and also indicate that histamine H1-receptors can mediate cardiac depression.     

Histamine H1-and H2-receptors in coronary arteries of pigs.

Histamine exerts its action in smooth muscle via in two types of receptors. In coronary arteries of pigs both types of receptors are also involved in responses to histamine. Histamine initiates by an interaction with H1-receptors a contraction and with H2-receptors a relaxation. The histamine-induced contraction is reduced by the competitively antagonistic action of mepyramine. Metiamide potentiates dose-dependently the histamine-caused contraction in the absence and presence of mepyramine. The proportion of H2-receptors in relation to H1-receptors is calculated.     

Involvement of tyrosine phosphorylation in the positive inotropic effect produced by H(1)-receptors with histamine in guinea-pig left atrium

We investigated the effect of stimulation of H(1)-receptors with histamine on protein tyrosine phosphorylation levels in guinea-pig left atrium and evaluated the influences of tyrosine kinase inhibitors on the positive inotropic effect mediated by H(1)-receptors in this tissue. Histamine induced an increase in tyrosine phosphorylation in four main clusters of proteins with apparent molecular weights of 25, 35, 65 and 150 kDa. Tyrosine phosphorylation of these proteins attained a peak around 2 - 3 min following histamine stimulation and then declined to or below basal levels. Histamine-induced protein tyrosine phosphorylation was antagonized by the H(1)-receptor antagonists mepyramine (1 microM) and chlorpheniramine (1 microM), but not by the H(2)-receptor antagonist cimetidine (10 microM). The positive inotropic effect of histamine was depressed in a concentration-dependent manner by the tyrosine kinase inhibitors tyrphostin A25 (50 to 100 microM) and genistein (10 to 50 microM) but not by the inactive genistein analogue daidzein (50 microM). The positive inotropic effect of isoprenaline was unchanged by tyrphostin A25 and genistein. At a concentration of 1 microM histamine produced a dual-component positive inotropic response composed of an initial increasing phase and a second and late developing, greater positive inotropic phase. Treatment with tyrphostin A25 (100 microM) and genistein (50 microM), but not daidzein (50 microM), significantly attenuated the two components of the inotropic response, although genistein suppressed the initial component more markedly than the late component. We conclude that increased protein tyrosine phosphorylation may play an important role in initiating at least some part of the positive inotropic effect of H(1)-receptor stimulation in guinea-pig left atrium.     

The influence of H1-, H2- and H3-receptors on the spontaneous and ConA induced histamine release from human adenoidal mast cells.

The effects of the H3-agonist R-alpha-methylhistamine (R-alpha-MeHA) and the H3-antagonist thioperamide on the spontaneous and concanavalin A (ConA) induced histamine release from human mast cells were tested and compared with the effect of some H1- and H2-receptor active substances. R-alpha-MeHA (10(-9)-10(-7) M) exerted no effect on histamine release whereas thioperamide increased the spontaneous release at 10(-6)-10(-4) M but inhibited the ConA induced release in a narrow concentration range (10(-6)-10(-5) M). This enhancement might be taken as an indication of the existence of H3-receptor dependent autoregulation although presently other mechanism cannot be excluded.