Human gastric mucosal adenylate cyclase: Activation by histamine-H2-receptor stimulation and inhibition by cimetidine in vitro and in peptic ulcer patients

Summary Biopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H₂-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10^–7–10^–3 mol/l); maximal stimulation was obtained with concentrations of 10^–4–10^–3 mol/l, and half maximal stimulation with about 10^–5 mol/l. The selective H₁-receptor agonist PEA 10^–5 and 10^–3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10^–6 mol/l, a selective H₁-receptor antagonist, and cimetidine 10^–6 mol/l, a selective H₂-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10^–7 and 10^–5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10^–5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H₂-receptor blockade followed by inhibition of adenylate cyclase.     

Effect of some new histamine H2-receptor antagonists on the guinea-pig papillary muscle

Summary Several histamine H₂-receptor antagonists (cimetidine, ranitidine, oxmetidine and tiotidine) were tested for their activity on the papillary muscle of the guinea pig stimulated by histamine. All of the compounds exerted a competitive antagonism against histamine the order of potency being tiotidine > oxmetidine > ranitidine > cimetidine. Oxmetidine was the only drug which at high concentrations (10^–6 M) decreased the maximum response of histamine probably because of non specific effects of the molecule already described in the literature. As it was expected, the H₁-receptor antagonist, mepyramine, exerted a non-competitive antagonism.     

Synthese und kombinierte H1-/H2-antagonistische Aktivität von Mepyramin-, Pheniramin- und Cyclizin-Derivaten mit Cyanoguanidin-, Harnstoff- und Nitroethendiamin-Partialstrukturen

Synthesis and Combined Histamine H₁ - and H₂-Receptor Antagonist Activity of Mepyramine, Pheniramine, and Cyclizine Derivatives with Cyanoguanidine, Urea, and Nitroethenediamine Groups Compounds with combined histamine H₁- and H₂-receptor antagonist activity were synthesized by connecting H₁ and H₂-receptor substructures via cyanoguanidine, urea, or nitroethenediamine moieties. Loss of the strongly basic side-chain nitrogen results in a decrease of H₁-receptor activity compared to single reference compounds. At the guinea-pig right atrium (H₂-receptor model) compounds with mepyramine or cyclizine structure are also less active than the single references tiotidine, ranitidine, or lamtidine. Nevertheless substances with a pheniramine like partial structure proved to be potent histamine H₂-receptor antagonists at the atrium model (about 27 times more active than cimetidine).     

Characterization of histamine H2-receptors in human neutrophils with a series of guanidine analogues of impromidine

Summary Human neutrophils possess an NADPH oxidase which catalyzes superoxide (O _inf2 ^sup– ) formation and is activated by chemotactic peptides. Histamine inhibits O _inf2 ^sup–1 formation via H₂-receptors (Burde et al. 1989). We characterized the neutrophil H₂-receptor with a series of new guanidine-type H₂-agonists structurally derived from impromidine. Histamine inhibited O _inf2 ^sup– formation with an IC₅₀ value of 6.7 ± 1.2 M. Five aryloxy- and arylthioalkylguanidines were less potent and effective than histamine. Several arpromidine-like phenyl(pyridylalkyl)guanidines were either full or partial H₂-agonists. Some guanidines possess a three-membered carbon chain connecting the aromatic rings and the guanidine group; they were similarly potent and effective as histamine. Shortening or elongation of the carbon chain substantially decreased the potency and intrinsic activity of the guanidines. Halogenation of the phenyl ring did not substantially affect the potency and intrinsic activity of the compounds in comparison to the non-substituted parent compound. The H₂-antagonist, famotidine, competitively antagonized inhibition of O _inf2 ^sup– formation caused by the guanidine, arpromidine, with a pA₂ value of 6.84. The H₂-antagonist, cimetidine, differentially counteracted inhibition caused by partial and full H₂-agonists. Partial H₂-agonists antagonized the effects of histamine. The inhibitor of phosphodiesterases, 3-isobutyl-lmethylxanthine, additively enhanced the inhibitory effects of histamine and guanidines. The properties of the neutrophil H₂-receptor were compared with literature data concerning properties of the H₂-receptor of the guinea pig atrium. In the latter system, guanidines are full H₂-agonists with potencies of up to 125-fold of that of histamine. Our data indicate that guanidines inhibit O _inf2 ^sup– formation in human neutrophils via H₂-receptors. The structure/activity relationship for the neutrophil H₂-receptor substantially differs from the one for the H₂-receptor in the guinea pig atrium, suggesting that the neutrophil H₂-receptor has cell type-specific properties. Other possibilities to explain the differences between H₂-receptors in these systems are discussed. Send offprint requests to R. Seifert at the above address     

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.     

Pharmacological characterization of cardiac histamine receptors: sensitivity to H1-receptor antagonists

The ability of five prototypic antihistamines (diphenhydramine, promethazine, cyclizine, chlorpheniramine and tripelennamine) to modify the cardiac actions of histamine was studied in order to determine the reactivity of cardiac histamine receptors. Histamine, as a function of dose, increases the rate, the force of contraction, the coronary flow and the time of atrioventricular conduction of the isolated guinea pig heart. Each of the five prototypic antihistamines failed to inhibit histamine-induced stimulation of cardiac rate and contractility. at the same time these antihistamines did inhibit the negative dromotropic effect of histamine. Chlorpheniramine and diphenhydramine antagonized the coronary dilating effect of histamine.These results suggest that two types of histamine receptors may be present in the guinea pig heart: H₁-receptors, at the atrioventricular node and coronary vessels; H₂-receptors at the sinoatrial node and on the ventricular fibers. The activity of these prototypic antihistamines is consistent with their action exclusively on H₁-receptors.     

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.     

Separate receptors mediating the positive inotropic and chronotropic effect of histamine in guinea-pig atria

The direct positive inotropic effect of histamine was studied on paced left atrial preparations from guinea pigs. Histamine (10^?8 to 10^?4 M) increased the maximum tension developed in left atria incubated at 35°C and driven at 2 Hz. The maximum increase in tension was 60% of that observed with norepinephrine. Metiamide (3 × 10^?5 M; a specific H₂-receptor antagonist) did not alter the inotropic response of left atria to histamine. However, tripelennamine (a typical H₁-receptor antagonist) competitively shifted the histamine inotropic dose—response curve to the right at concentrations from 10^?8 to 10^?7 M. Higher concentrations (3 × 10^?7 and 10^?6 M) caused little further additional shift to the right. The positive chronotropic effect of histamine on spontaneously beating atria was competitively antagonized by metiamide (10^?6 and 3 × 10^?6 M). These results demonstrate that in guinea-pig atria histamine increases myocardial contractility by an interaction with receptors closely related to classical H₁-receptors while its chronotropic effects is mediated by interaction with H₂-receptors.     

Adenylate cyclase of the dog gastric mucosa: Stimulation by histamine and inhibition by metiamide

Summary The activity of the non-stimulated, basal adenylate cyclase of the dog gastric mucosa is reduced by the histamine H₂-receptor antagonist metiamide but not by the histamine H₁-receptor antagonist mepyramine. Histamine activates the adenylate cyclase only slightly. In the presence of 10^–5 M metiamide a concentration-dependent stimulation of the enzyme by histamine was found. These data indicate that endogenous histamine in dog gastric mucosal homogenate is contributing at least in part to what is measured as basal adenylate cyclase activity. This effect is mediated by H₂-receptor excitation and in earlier studies has prevented the demonstration of a stimulatory effect of exogenous histamine on this enzyme.Supported by a grant from the Deutsche Forschungsgemeinschaft     

Effects of the histamine H2-receptor blocking drugs burimamide and cimetidine on noradrenergic transmission in the isolated aorta of the rabbit and atria of the guinea-pig

1 In rabbit aortic strips, concentration-response curves to noradrenaline (NA) were shifted to the right in a parallel and concentration-dependent manner by the α-adrenoceptor blocking drug, phentolamine and also by the histamine H₂-receptor blocking drugs, burimamide and cimetidine. Responses to 5-hydroxytryptamine were not affected by these drugs.

2 Burimamide had the properties of a competitive antagonist of noradrenaline, possessing about one-hundredth the potency of phentolamine. Cimetidine was weaker than burimamide and did not fulfil the requirements for competitive antagonism of noradrenaline.

3 In guinea-pig isolated atria, in which noradrenergic transmitter stores were labelled with [³H]-noradrenaline, phentolamine (3 μM), burimamide (30 μM) and cimetidine (30 μM), in decreasing order of effectiveness, each enhanced stimulation-induced efflux of [³H]-noradrenaline, indicating that their blocking effects on prejunctional α-adrenoceptors in this tissue are in the same order of relative potency as on postjunctional α-adrenoceptors in rabbit aortic strips.

4 In the concentrations used (30 μM), neither burimamide nor cimetidine interfered with the neuronal uptake of noradrenaline. Burimamide, and to a much lesser extent, cimetidine, increased the resting efflux of [³H]-noradrenaline from guinea-pig atria.

5 The effect of clonidine, a partial agonist on prejunctional α-adrenoceptors in guinea-pig atria, in increasing stimulation-induced efflux of [³H]-noradrenaline when stimulated with 150 pulses at 5 Hz was blocked by cimetidine (30 μM) and reversed by phentolamine (3 μM) and burimamide (30 μM).

     

Possible Regulatory Role of Histamine in Human Platelet Function Examined by Thrombin-induced Serotonin Release

Abstract: The influence of histamine on human platelet function was studied by thrombin-induced serotonin release. The thrombin-induced ³H-serotonin release was confirmed to be a rapid process which does not require external calcium. Histamine was found to reduce the release of serotonin and the inhibition was abolished when H₁-plus H₂-antagonists were added together with histamine. H₁- and H₂-receptor stimulation was examined in two ways, by a combination of histamine with cimetidine or diphenhydramine and by the selective agonists 2-(2-pyridyl)-ethylamine and impromidine. In both instances H₁- and H₂-stimulation was found to reduce the platelet serotonin release. These results suggest a regulatory role of histamine in the platelet function by stimulation of platelet H₁- and H₂-receptors.     

Long-term increase of hippocampal excitability by histamine and cyclic AMP

The action of histamine (HA) on rat hippocampal CA1 pyramidal cells in vitro was investigated in slices perfused with solution containing 0.2 mM Ca²⁺/4.0 mM Mg²⁺. Extracellular recordings of the spontaneous discharges occurring under these conditions revealed that HA caused a long-lasting increase in cell firing. The HA-effects were dose-dependent, in that low concentrations of HA (0.1–0.5 μM) exhibited an initial transient depression of cell firing and practically no long-lasting action, whereas higher concentrations of HA (1–10 μM) exerted strong, non-declining increases. The H₁-receptor antagonist mepyramine (1 μM) blocked the initial depression of firing and attenuated the long-lasting HA-mediated excitation. Pure H₁-receptor activation, tested with the H₁-receptor agonist 2-(3-fluorphenyl)histamine (1–10 μM) depressed cell firing, similar to the low dose effects of HA. HA-induced excitations were prevented by the H₂-receptor antagonist cimetidine (10–50 μM), and mimicked by the very potent H₂-receptor agonist impromidine (1 or 3 μM) which was, however, less effective compared to equal concentrations of HA. H₃-receptor activation by R-α-methylhistamine had no significant effect on cell firing. Thus, histamine H₁ and H₂ receptors seem to cooperate in producing this long-lasting augmentation of excitability. 8-Bromo-cyclic AMP monophosphate (8-Br-cAMP, 50–100 μM) mimicked the long-term excitation, whereas the adenylyl-cyclase inhibitor 9-tetrahydro-2-furyladenine (THFA, 100–500 μM) or the PKA-inhibitor Rp-adenosine-3′5′-cyclic monophosphate (Rp-cAMPS, 10 μM) blocked it, indicating that the HA-mediated increase of excitability in the hippocampus is dependent on the adenylate cyclase/PKA-signal transduction cascade. -2-Amino-5-phosphonopentanoic acid (APV, 50 μM) significantly attenuated the magnitude of the HA-induced enhancement, indicating an NMDA receptor-dependent component. Other biogenic amines, acting through receptors positively coupled to adenylyl cyclase, elicited similar responses as HA, indicating common mechanisms by which these substances modulate excitability in CA1 pyramidal cells.     

The effects of H2-receptor antagonists on anaphylaxis in the guinea-pig.

Histamine has been shown to inhibit a variety of immune responses including the antigen-induced, IgE mediated, release of histamine from sensitized human leucocytes and from sensitized monkey and dog mast cells. The inhibitory action of histamine appears to be mediated by action at a histamine H2-receptor. In in vitro experiments the H2-receptor antagonist metiamide has been shown to block this histamine effect and it has been suggested that H2-receptor antagonists could intensify immediate hypersensitivity reactions in vivo. The effects of the H2-receptor antagonist metiamide and cimetidine have been studied in in vitro and in vivo models of anaphylaxis in the guinea-pig. The amount of extracellular histamine found after antigen challenge is greater when an H2-receptor antagonist is present during the incubation of mast cells with antigen. Bronchoconstriction induced by antigen in sensitized guinea-pig is exacerbated only by high doses of cimetidine. Possible explanations for the mechanism of action involved are discussed.     

The Cardiovascular Effects of Thyrotropin-Releasing Hormone (TRH) are Attenuated by Cimetidine in Rats

Abstract: The modulation of cardioventilator effects of thyrotropin-releasing hormone (TRH) by histaminergic mechanisms was studied in anaesthetized rats pretreated with histamine receptor antagonists. TRH (1–10. nmol/kg) into the lateral cerebral ventricle dose-dependently elevated mean arterial pressure, heart rate and stimulated respiration. The respiratory stimulating effect of TRH remained unchanged after pretreatments with histamine H₁-receptor antagonist diphenhydramine or H₂-receptor antagonists cimetidine and ranitidine, while the TRH-induced hypertension and tachycardia were attenuated by cimetidine. This antagonism was not due to an interation between TRH and cimetidine at their central binding sites, since there was no displacement of [³H]MeTRH binding in the presence of cimetidine nor did TRH displace [³H]cimetidine in rat brain homogenates. Inability of diphenhydramine to modify the cardiovascular effects of TRH indicates that these effects are not due to histamine liberation, as cardiovascular stimulation after central administration of histamine is mainly mediated via H₁-receptors. The antagonism of the cardiovascular responses to TRH by cimetidine was not due to blockade of H₂-receptors, since another potent H₂-receptor antagonist ranitidine was unable to affect the cardiovascular effects of TRH. Therefore, we suggest that cimetidine exerted antagonism of TRH by some non-specific action.     

Structure-activity relationship of imidazolidine derivatives related to clonidine at histamine H2-receptors in guinea-pig isolated atria

1 Cumulative concentration-response relationships for the chronotropic effects of histamine, oxymetazoline, clonidine and thirteen clonidine-like imidazolidine derivatives were examined in isolated spontaneously beating guinea-pig atria.

2 The following compounds induced positive chronotropic effects: histamine, clonidine (2,6-dichloro-phenyliminoimidazolidine) and the 2,6-dibromo, 2,6-dimethyl, 2,6-diethyl, 2,6-dihydroxy, 2,4,6-trimethyl, 3,4-dihydroxy and 2-methyl-5-fluoro analogues of clonidine. These compounds appeared to act as partial agonists on histamine H₂-receptors, with potencies ranging from one tenth to one hundredth and intrinsic activities from approximately 20% to 75% of those of histamine.

3 The following compounds did not induce positive chronotropic effects but rather decreased the atrial rate, usually at high concentrations: oxymetazoline and the 2,3-dichloro, 4-dichloro, 5-dichloro, 2-chloro-4-methyl, 2-methyl-5-chloro, 2,4,6-trichloro analogues of clonidine.

4 The effects of histamine were antagonized by cimetidine, the pA₂ value being 6.68 (s.e. mean = 0.16, n = 3), and also in a concentration-dependent manner by clonidine. Cimetidine antagonized the response to clonidine in a concentration-dependent manner; however, high concentrations of cimetidine depressed the maximal response to clonidine and the slope of the concentration-response curve was no longer parallel to the control curve.

5 The effects of the other compounds which induced positive chronotropic effects were also antagonized by cimetidine (1 μmol/l); however, the effect of the 3,4-dihydroxy derivative was unaffected by cimetidine (1 μmol/l) but was abolished by propranolol (0.3 μmol/l).

6 In general, phenyliminoimidazolidine derivatives with 2,6-substitution on the phenyl ring are active on histamine H₂-receptors, whereas derivatives with 2,3-, 2,4- or 2,5-substitutions are weakly active or inactive. Thus the restriction imposed on the free rotation of the phenyl ring about the carbon-imino nitrogen bond by the introduction of two ortho substituents appears to result in increased agonist activity on the histamine H₂-receptor. The introduction of substituents in the 3, 4 or 5 positions in the phenyl ring may lead to compounds sterically hindered from combining with the histamine H₂-receptor.

7 There is no apparent relationship between the activities of clonidine-like imidazolidine derivatives as agonists on histamine H₂-receptors and their hypotensive activities (as reported in the literature).

     

The effects of histamine on responses of the rabbit ear artery to electrical stimulation and to exogenous noradrenaline

1 The effects of a subconstrictor dose of histamine (9 × 10^-7 mol/l) on the responses of the isolated perfused ear artery of the rabbit to electrical stimulation (E.S.) and to exogenous noradrenaline (NA) were investigated.

2 Both intraluminal (I/L) and extraluminal (E/L) histamine potentiated responses to E.S. and to I/L NA to the same extent.

3 Mepyramine alone (2.5 × 10^-6 mol/l) had no effect on the response of the ear artery to either stimulus, but in the presence of this concentration of mepyramine, the potentiation by histamine of the response to I/L NA was significantly decreased and that to E.S. was replaced by inhibition.

4 The H₁-receptor agonist, 2(2-pyridyl) ethylamine, applied I/L potentiated responses to I/L NA at both concentrations used (5.1 and 51 × 10^-7 mol/l), but only potentiated the effects of E.S. at the higher concentration.

5 The H₂-receptor antagonist, metiamide (4 × 10^-6 mol/l), alone did not alter the extent of potentiation of responses to either E.S. or I/L NA by histamine. This suggests relatively weak H₂-receptor activity in the rabbit ear artery. In the presence, but not the absence of metiamide, the potentiation by histamine of the I/L NA response was reversible, an observation suggesting an interaction between metiamide and the non-reversible component of the potentiating effect of histamine.

6 These results are interpreted in terms of postsynaptic H₁-receptors which potentiate and presynaptic H₂-receptors which inhibit contractile responses in the ear artery.

     

Histaprodifen, methylhistaprodifen, and dimethylhistaprodifen are potent H1-receptor agonists in the pithed and in the anaesthetized rat

Selective H₂- and H₃-receptor agonists, exhibiting an at least tenfold higher potency than histamine itself at the respective receptors, have been known for several years. Selective H₁-receptor agonists with a potency exceeding that of histamine have become available only recently; the most potent are methylhistaprodifen and dimethylhistaprodifen [N ^α-methyl- and N ^α,N ^α-dimethyl-2-(3,3-diphenylpropyl)histamine, respectively] with 3.4- and 2.4-fold higher potencies than histamine in vitro (in the guinea-pig ileum). The aim of the present study was to examine whether these compounds and the parent compound histaprodifen are potent H₁-receptor agonists in the pithed and in the anaesthetized rat. In pithed, vagotomized rats diastolic blood pressure was decreased by 2-(2-thiazolyl)ethanamine i.v. (which was used as a reference H₁-receptor agonist) and by histaprodifen, methylhistaprodifen, and dimethylhistaprodifen; the maximum decrease was about 45 mmHg for each compound, and the potencies, expressed as pED₅₀, the negative logarithm of the dose (in mole per kilogram body weight) eliciting a half-maximal response, were 7.23, 7.55, 8.43 and 8.12, respectively. The dose/response curves of the four compounds were shifted to the right to about the same extent by the H₁-receptor antagonist dimetindene (1 μmol/kg i.v.). The vasodepressor response was not affected by combined i.v. administration of the H₂- and H₃-receptor antagonists ranitidine and thioperamide, by combined i.v. administration of the α₁- and α₂-adrenoceptor antagonists prazosin and rauwolscine, and by the β-adrenoceptor antagonist propranolol i.v. but was attenuated by the inhibitor of NO synthase, N ^ω-nitro-l-arginine methyl ester i.v. In anaesthetized rats 2-(2-thiazolyl)ethanamine, histaprodifen, methylhistaprodifen and dimethylhistaprodifen i.v. also decreased diastolic blood pressure in a manner sensitive to dimetindene i.v. Our data show that histaprodifen and, in particular, methyl- and dimethylhistaprodifen are highly potent H₁-receptor agonists in vivo. Received: 3 September 1998 / Accepted: 23 October 1998     

Role of endothelium and nitric oxide in histamine-induced responses in human cranial arteries and detection of mRNA encoding H1- and H2-receptors by RT-PCR

1. Histamine induces relaxation of human cranial arteries. Studies have revealed that the relaxant histamine H₁-receptor predominates in human cerebral and the H₂-receptor in temporal arteries, while H₁- and H₂-receptors are of equal importance in the middle meningeal artery. The purpose of the present study was to examine the role of the endothelium and nitric oxide in histamine-induced responses and to show the presence of mRNA encoding H₁- and H₂-receptors in human cranial arteries.
2. Electrophoresis of polymerase chain reaction (PCR) products from human cerebral, middle meningeal and temporal arteries, demonstrated products corresponding to mRNA encoding both H₁- and H₂-receptors in arteries with and without endothelium. The amplified PCR products were sequenced and showed 100% homology with the published sequences of these histamine receptors.
3. A sensitive in vitro system was used to study vasomotor responses to histamine. In precontracted cerebral, middle meningeal and temporal arteries with and without endothelium, histamine caused a concentration-dependent relaxation with I_max values between 87% and 81% and pIC₅₀ values between 8.14 and 7.15. In arteries without endothelium the histamine-induced relaxation was significantly less potent (I_max values between 87% and 66% and pIC₅₀ values between 7.01 and 6.67) than in cranial arteries with an intact endothelium.
4. The addition of histamine to arteries without endothelium and pretreated with the histamine H₂-antagonist, cimetidine (10⁻⁵ M), caused a concentration-dependent contraction of the cranial arteries with E_max values between 86% and 29% and pEC₅₀ values between 7.53 and 6.77. This contraction was blocked by the histamine H₁-receptor antagonist, mepyramine (10⁻⁷ M), and even turned into a relaxation with I_max values between 84% and 14% and pIC₅₀ values between 7.42 and 5.86.
5. The nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME, 3×10⁻⁵ M) significantly inhibited the relaxant response to histamine in cerebral and temporal arteries (pIC₅₀ values between 7.43 and 7.13). The combined treatment with L-NAME (3×10⁻⁵ M) and cimetidine (10⁻⁵ M) caused a further displacement of the concentration-response curve (pIC₅₀ values between 7.14 and 6.57) and decreased the maximum relaxant responses in all three cranial arteries (I_max values between 62% and 39%).
6. In conclusion, this is the first study which show mRNA encoding histamine H₁- and H₂-receptors in human cranial arteries. The results indicate that histamine-induced relaxation of human cranial arteries is partially mediated via an endothelial H₁-receptor coupled to the production of nitric oxide and partially via a H₂-receptor associated with the smooth muscle cells. In addition, there is evidence for a contractile H₁-receptor in the smooth muscle cells in these arteries.

     

Modulation of the delayed K+ current by histamine in guinea pig ventricular myocytes

Summary The effects of histamine on delayed K⁺ current (I_K) were investigated in patch-clamped single guinea pig ventricular myocytes. Histamine increased I_K with a maximal fractional response of 2.7 and a k_d of 9.4 × 10^–7 mol/l. At a concentration of 10^–8 mol/l, histamine did not increase I_K significantly, but increased I_Ca by 52% ± 12%. The voltage-dependence of I_K activation, the reversal potential and the time course of the I_K tail decay were not changed by histamine. Under pretreatment with 10^–4 mol/l of ranitidine, neither histamine (10^–6 mol/l) nor 2-pyridylethylamine (10^–4 mol/l) caused any sizable increase in I_K. When the cell was pretreated with a saturating dose of isoproterenol (10^–6 mol/l), histamine did not additively enhance I_K. The I_K enhancement by 3 × 10^–7 mol/l histamine was partially antagonized by concurrent exposure to 5 × 10^–6 mol/l carbachol. Whereas, use of a higher concentration of histamine (10^–6 mol/l) obscured the inhibitory effect of carbachol. It is concluded that histaminergic action of I_K is attributed exclusively to H₂ receptor-mediated reactions involving G_s protein and adenylate cyclase. Send offprint requests to Y. Habuchi at the above address     

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.