Some behavioral effects of histamine H1-, and H2-receptor agonists in rats.

2-Pyridylethylamine (2-PEA) and 4-methylhistamine (4-MeHI) when given intraventricularly at doses of 30 and 100 microgram had no discernible effect on spontaneous locomotor activity and did not visibly change gross behavior of rats. 4-MeHI(100 micrograms) injected to tranylcypromine-pretreated rats increased locomotor activity and induced head twitches. Locomotor activation was not antagonized by either cimetidine or metergoline but was prevented by alpha-methyl-p-tyrosine and haloperidol and reduced by phentolamine. 4-MeHI-, and histamine (HI)-induced head twitches were not antagonized by either cimetidine or metiamide but were completely abolished by metergoline and p-chlorophenylalanine. It is concluded that 4-MeHI--induced locomotor activation and both HI-, and 4-MeHI-induced head twitches are respectively catecholamine-, and serotonin-dependent phenomena. The behavioral effects of HI and HI H1-and H2-receptor agonists are discussed with regard to possible HI interactions with both catecholamine and serotonin systems in brain.     

Chemical differentiation of histamine H1- and H2-receptor agonists.

Histamine exists predominantly as the NT-H tautomer of the monocation (IIa) at a physiological pH of 7.4 and structure-activity studies indicate that this tautomer is likely to be the pharmacologically active species for both H1 and H2 receptors. Effective H2-receptor agonists appear to require a prototropic tautomeric system whereas H1-receptor agonists do not need to be tautomeric. This identifies a chemical difference in the receptor requirements which provides the basis for obtaining selective histamine H1-receptor agonists. Thus 2-(2-aminoethyl)thiazole and 2-(2-aminoethyl)pyridine are nontautomeric and are highly selective agonists for histamine H1 receptors (H1:H2 ca. 90:1 and 30:1, respectively). In conjunction with the selective H2-receptor agonist, 4-methylhistamine, they are of great value for studying the pharmacology of histamine receptors.     

Analeptic effect of centrally administered histamine H2-receptor agonist dimaprit but not impromidine in urethane-anesthetized rats

Intracerebroventricularly administered dimaprit decreased the depth of urethane anaesthesia. Ventilatory stimulation, positive corneal reflex and increased susceptibility to pain were observed. Furthermore, dimaprit decreased the lethal effect of large doses of urethane. The analeptic property of dimaprit was not shared by the potent H2-receptor agonist, impromidine, Histamine increased ventilatory tidal volume but no other stimulatory effects were observed. These findings suggest that the analeptic effects of dimaprit were not mediated by H2-receptors. Among the analeptic effects of dimaprit, only the protection against urethane toxicity was antagonized by metiamide. However, this phenomenon appeared to be due to the nonspecific interaction between the three bradypnoeic drugs metiamide, dimaprit and urethane. The histamine-induced increase in ventilatory tidal volume was not antagonized by diphenhydramine or metiamide, suggesting the existence of a novel histaminergic mechanism in the central nervous system.     

Structure-activity relationships of histamine H1-receptor agonists

Significant progress in the development of potent and selective histamine H1-receptor agonists has been achieved since 1990. Optimisation of the class of 2-phenylhistamines has furnished 2-[3-(trifluoromethyl)phenyl]histamine and its Nalpha-methyl derivative. The discovery of histaprodifen (2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) and the novel lead compound suprahistaprodifen (Nalpha-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) represents additional milestones in the H1-receptor agonist field.     

Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists

The positive inotropic effects of 2-pyridyl-ethylamine (PEA) and of 4-methylhistamine (4MeH) were studied in isolated guinea-pig ventricular strips electrically stimulated at a rate of 60 and 150/min. The increase in contractile tension induced by PEA (10(-7)-3 X 10(-4) M) in the presence of cimetidine (10(-5) M) was associated with a slight increase in time to peak tension and with a lengthening of the relaxation phase; the positive inotropic effect of PEA was significantly higher at a frequency of 60/min than at 150/min. Conversely, the inotropic response to 4MeH (10(-8)-3 X 10(-6) M) was not frequency dependent, and was associated with an evident decrease in relaxation time. Moreover, 4MeH consistently antagonized, in dose-dependent manner, the negative inotropic effects induced by the calcium antagonistic drug D600 and by lowering calcium concentration in the medium, and was able to restore the contractility abolished by treatment of preparations with a high K+ medium. On the other hand PEA, in the presence of cimetidine, scarcely antagonized the negative inotropic effects induced either by D600 or by low calcium solution, and was unable to restore the contractility of K+-depolarized preparations. The characteristics of the inotropic response of the H1-receptor agonist were very similar to those of the alpha-adrenoceptor agonist phenylephrine. This observation suggests that a common mechanism is probably involved in the inotropic effects mediated by H1 and by alpha receptors, and that this mechanism does not include a stimulation of the calcium transmembrane influx.     

The action of histamine, histamine H1-and H2-receptor agonists on noradrenaline level in rat brain.

Intraventricularly administered histamine (HI) (20--1000 micrograms) decreased noradrenaline (NA) .level in rat hypothalamus. 4-Methyl-HI (4-MeHI), but not 2-pyridylethylamine (2-PEA), reproduced the action of HI. Neither HI, nor 4-MeHI induced depression of hypothalamic NA content was antagonized by HI H2-receptor antagonists, cimetidine or metiamide. Chloropyramine reversed the NA-depleting action of HI.     

Pharmacological analysis of the tachycardia produced by histamine and specific H1-and H2-receptor agonists in anesthetized dogs.

A study was designed to investigate the mechanism(s) of the tachycardia produced by histamine and specific H₁- and H₂-receptor agonists in anesthetized dogs. I.v. administration of histamine, 2-methylhistamine, and 4-methylhistamine caused a fall in blood pressure and an increase in heart rate. Prior administration of mepyramine, a histamine H₁-receptor antagonist, significantly antagonized the depressor and positive chronotropic effects of histamine and completely abolished the cardiovascular actions of 2-methylhistamine, whereas responses to 4-methylhistamine were not affected. Subsequent administration of metiamide, a specific H₂-receptor antagonist, completely abolished the remaining cardiovascular effects of histamine and the hypotension and tachycardia observed after 4-methylhistamine were also antagonized.In another series of experiments, bilateral vagotomy significantly attenuated the tachycardia and subsequent removal of cardiac sympathetic nerve supply completely abolished it without affecting the depressor effects of these agents. Pharmacological blockade of muscarinic receptors with atropine in another group of animals also significantly attenuated the positive chronotropic effect which was completely prevented by further treatment with propranolol. The hypotension produced by histamine agonists was not affected by atropine and propranolol. These results demonstrate that in pentobarbital-anesthetized dogs, the tachycardia produced by histamine and specific H₁- and H₂-receptor agonists are due to reciprocal alterations in cardiac autonomic activity as a result of the fall in the arterial pressure. Activation of cardiac histamine receptors does not seem to account for the positive chronotropic effects of these compounds in intact dogs.     

Pharmacological characterization of histamine receptors in the mouse seminal vesicle: sensitivity to H1- and H2-receptor agonists and antagonists

Neither histamine nor the more specific H1- or H2-receptor agonists (0.2-220 micrometers) produced a contraction of the mouse seminal vesicle. However, all these agonists decreased resting tone and caused a dose-related inhibition of the electrically evoked twitch responses in these concentrations. The slopes of the percentage response versus log molar concentration curves for all agonists did not differ significantly from that of histamine. The rank order and relative potency of the compounds tested were: histamine (100%) greater than dimaprit (65%) greater than 4-methylhistamine (36%) greater than 2-methylhistamine (4.5%) greater than 2-(2-thiazolyl) ethylamine (1.7%). Inhibition of the twitch response by histamine was antagonized by cimetidine (3.5-140 micrometers) but not by mepyramine (0.1-1.0 micrometer). The slopes of Schild plots for cimetidine against histamine and dimaprit did not differ from unity, and the calculated pA2 values of cimetidine were 5.70 and 5.55, respectively. Histamine (2.2 and 6.5 micrometers) inhibited the contraction elicited by a submaximal concentration of exogenous noradrenaline (1 micrometer); this inhibition could also be selectively antagonized by cimetidine. These results demonstrate that histamine and selective H1- and H2-receptor agonists have an inhibitory action on the mouse seminal vesicle, and that this action is mediated via a post-junctional H2-receptor. The calculated pA2 values of cimetidine against histamine and dimaprit also suggest that the receptor in the mouse seminal vesicle of the conventional H1-type. The results further indicate that an H1-receptor is absent in the mouse seminal vesicle.     

Influence of histamine H1- and H2-receptor blockers on sympathetic vasodilator and vasoconstrictor responses in canine paw.

1 Vasodilator responses to histamine, bradykinin and sympathetic nerve stimulation were elicited in the perfused paw of dogs treated with bretylium (15-20 mg/kg) and atropine. The H2-receptor blocking agent, burimamide, when administered in the dose of 5 mg/kg intravenously and 4 mg intra-arterially did not depress significantly these vasodilator responses. The subsequent administration of tripelennamine in the dose of 2.5-5 mg/kg intravenously and 4 mg intra-arterially produced a significant blockade of the response to histamine and reduced the sustained vasodilator response to nerve stimulation. 2 In guanethidine-treated dogs, tripelennamine administered in the same dose following burimamide produced a blockade of the response to histamine comparable to that in the bretylium experiments, but decreased only the sustained vasodilator response to stimulation at 1 Hz. When the order of administration of the antihistamines was reversed in another group of guanethidine-treated dogs, tripelennamine had only a slight blocking effect on the response to histamine and did not affect the responses to nerve stimulation. Burimamide exerted a significant blocking effect on the response to histamine, but not to nerve stimulation. Another H2-receptor blocking agent, metiamide, when given after tripelennamine, also had a marked blocking effect on the response to histamine and almost abolished the vasodilator response to 4-methylhistamine, an H2-agonist. Nevertheless, even in the presence of this profound histamine blockade, the sustained vasodilator response to nerve stimulation remained unchanged. 3 In another group of experiments vasoconstrictor responses to exogenous noradrenaline and sympathetic stimulation were initially depressed by burimamide and later returned to control values. Tripelennamine increased these responses by its uptake blocking action. 4 It is concluded that the sustained vasodilator response is not antagonized by a specific antihistaminic action. The decrease in the sustained vasodilator response produced by antihistamines is produced attributable to potentiation of a residual adrenergic vasoconstricotr effect not completely blocked by bretylium.     

Electrophysiological actions of histamine and H1-, H2-receptor antagonists in cardiac tissue

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results: Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments. Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD90) in atria. Histamine effects in atrial myocardium are completely reversed by the H1-antagonist dimetindene. Stimulation of atrial H1-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content. Histamine reduces AH-interval, increases V max of NH-cells and may induce AV-node arrhythmias (at concentrations greater than or equal to 3 mumol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV-nodal conduction via H2-receptors. Unspecific membrane actions of cimetidine are not observed up to 100 mumol/l. Dimetindene increases action potential duration (APD) in left atria and decreases Vmax at concentrations greater than or equal to 10 mumol/l. However, H1-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA2-values 8.39-9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.     

Temporal responses of cutaneous blood flow and plasma catecholamine concentrations to histamine H1- or H2-receptor stimulation in man

Summary We have studied the effect of histamine and H₁- or H₂-receptor antagonists on cutaneous blood flow and catecholamine release in man.Histamine was infused alone or in combination with mepyramine, an H₁-antagonist or cimetidine, an H₂-antagonist for 2 h. Cutaneous blood flow was measured continously with a laser Doppler flowmeter, and noradrenaline and adrenaline concentrations were determined in blood samples drawn every 15 min.The infusion of histamine caused an immediate and sustained vasodilatation. The Concomitant infusion of mepyramine prevented the immediate vasodilatation, but had no effect on the sustained response. The Concomitant infusion of cimetidine was without effect on the immediate vasodilatation, but abolished the sustained response. Infusion of the antagonists alone had no effect on cutaneous blood flow.Histamine caused a rapid and sustained increase in plasma noradrenaline, while the increase during concomitant H₁-receptor blockade was delayed but achieved the level observed during the histamine infusion. The response to histamine during H₂-receptor blockade was small and transient. The rise in plasma adrenaline was not significant.These findings suggest that histamine causes an immediate cutaneous vasodilatation through H₁-receptors and a more sustained response through H₂-receptors. The vasodilatation is accompanied by an increase in plasma catecholamine concentrations. Despite the continuous infusion of histamine, blood flow decreased during the last hour of histamine infusion, while the plasma noradrenaline concentration was still elevated.     

Selective impairment of atrioventricular conduction by 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, two histamine H1-receptor agonists.

To further characterize the receptor mediating histamine-induced impairment of atrioventricular conduction, the effects of two selective histamine H1-receptor agonists, 2-(2-pyridyl)-ethylamine (PEA) and 2-(2-thiazolyl)-ethylamine (ThEA), were investigated using the isolated guinea pig heart. These effects were compared with those of histamine and other selective agonists. PEA and ThEA produced a weak stimulation of cardiac rate and contractility; however, they produced a marked prolongation of atrioventricular conduction. The orders of relative potencies observed substantiate the hypothesis that H2-receptors mediate the positive inotropic and chronotropic effects and H1-receptors mediate the negative dromotropic effect of histamine.     

Heterogeneity of histamine H2-receptor mediated responses in the rabbit aorta

Distribution and properties of histamine H2-receptor mediated responses in segments of rabbit aorta was studied with histamine and H2-receptor stimulating drugs, dimaprit and impromidine. All agonists produced concentration-dependent tonus decreased in precontracted vascular strips, which were antagonised by selective H2-receptor antagonists, cimetidine and oxmetidine. Activities of the agonists were segment-dependent, and increased caudally along the aorta. A nonspecific smooth muscle relaxant, papaverine had homogeneous activity along the vessel, suggesting receptor specific nature of the observed heterogeneity.     

Nonsedating histamine H1-receptor antagonists

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosages of the nonsedating histamine H1-receptor antagonists terfenadine, astemizole, loratadine, and acrivastine are reviewed. Terfenadine and astemizole are chemically unrelated to histamine H1-receptor antagonists such as diphenhydramine and chlorpheniramine. Loratadine is structurally related to the antihistamine azatadine, and acrivastine is a side-chain-reduced metabolite of the antihistamine triprolidine. Like other histamine H1-receptor antagonists, they competitively block histamine receptor sites rather than inhibiting histamine release. All four drugs have relatively long half-lives and are rapidly absorbed after oral administration. Terfenadine, astemizole, and loratadine are metabolized extensively in the liver; terfenadine and astemizole are both 97% protein bound. Terfenadine 60 mg twice daily has been shown to be as effective as conventional antihistamines for the treatment of seasonal allergic rhinitis. In clinical trials, astemizole 10 mg daily was comparable to or better than chlorpheniramine for treatment of chronic rhinitis. Both terfenadine and astemizole were effective for treatment of chronic urticaria. For treatment of seasonal allergic rhinitis, loratadine combined with pseudoephedrine may be preferable to triprolidine-pseudoephedrine and acrivastine-pseudoephedrine combinations that require more frequent dosing. Acrivastine must be administered more frequently than the other nonsedating antihistamines. None of these four agents impairs psychomotor activity. Infrequently reported adverse effects include dry mouth, skin reactions, and weight gain. The absence of substantial sedative effects and the less-frequent dosing schedules make these agents good alternatives to the classic antihistamines for treatment of seasonal and chronic rhinitis and chronic urticaria.     

Central effects of histamine H2-receptor agonists and antagonists on nociception in the rat

The effects of intracerebroventricular injection of histamine H2-receptor agonists (4-methylhistamine, 4-MeH; dimaprit, DIM), H2-antagonists (cimetidine, CIM; ranitidine, RAN; famotidine, FAM) and of the DIM chemical analogue SK&F 91487 on hot-plate latency in rats were examined. Both DIM (0.4-0.8 mumol/rat) and 4-MeH (0.4-0.8 mumol/rat) significantly enhanced the pain threshold, whereas SF&F 91487 (0.8 mumol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H2-antagonists CIM (0.8 mumol/rat) and RAN (0.6 mumol/rat) also enhanced the pain threshold, while FAM (0.03 mumol/rat) did not modify pain latency. When injected before 4-MeH, FAM reduced the antinociceptive effect of 4-MeH. These findings suggest that the antinociceptive activity of CIM and RAN is not related to specific blockade of H2-receptors and that the activation of HA-H2-receptors is inhibitory to nociception.     

Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in Balb C mice

The role of histamine H(1), H(2), H(3) and H(4) receptors in acute itch induced by histamine was investigated in female BalbC mice. Scratching was induced by intradermal injections of pruritogen into the back of the neck and "itch" assessed by quantifying the scratching evoked. Histamine (0.03-80 micromol), histamine-trifluoromethyl-toluidine (HTMT, H(1) agonist, 0.002-2 micromol), clobenpropit (H(4) agonist, H(3) antagonist, 0.002-0.6 micromol) and to a lesser extent imetit (H(3)/H(4) agonist, 0.03-3 micromol) all induced dose-dependent scratching. Dimaprit (H(2) agonist, 0.04-40 micromol) did not cause scratching. Mepyramine (H(1) antagonist, 20 mg kg(-1), i.p.) reduced scratching evoked by histamine and HTMT, but not that caused by H(3) or H(4) agonists. Thioperamide (H(3)/H(4) antagonist, 20 mg kg(-1), i.p.) reduced scratching induced by histamine, H(3) and H(4) agonists, but not that caused by HTMT. The non-sedating H(1) antagonist, terfenadine, also significantly reduced the scratching induced by the H(1) agonist, HTMT. Cimetidine (H(2) antagonist, 20 mg kg(-1), i.p.) did not affect histamine-induced scratching. These results indicate that activation of histamine H(4) receptors causes itch in mice, in addition to the previously recognised role for H(1) receptors in evoking itch. Histamine H(4) receptor antagonists therefore merit investigation as antipruritic agents.     

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.     

The antianaphylactic action of histamine H2-receptor agonists in the guinea-pig isolated heart.

The effects of histamine and of H1- and H2-receptor agonists on the response to specific antigen were studied in isolated hearts taken from actively sensitized guinea-pigs. Histamine and H2-receptor agonists (dimaprit, impromidine) dose-dependently decrease the positive chronotropic and inotropic effects, and the severity of arrhythmias evoked by the challenge of sensitized hearts with specific antigen. Nordimaprit and the selective H1-receptor agonist 2-pyridyl-ethyl-amine (2-PEA) did not modify the patterns of cardiac anaphylaxis. The positive inotropic and chronotropic responses of the isolated heart to exogenous histamine appear to be partly reduced in the presence of dimaprit. The H2-receptor agonists decrease the amount of histamine released during cardiac anaphylaxis which is increased by cimetidine, while nordimaprit and PEA were ineffective, indicating an inhibitory function afforded by H2-receptors in cardiac anaphylaxis.