Histamine Analogues Research Articles

Activation of protein kinase in the guinea pig fundic gastric mucosa by histamine

The effect of histamine, 1,4-methylhistamine and ethanol on cyclic AMP levels and protein kinase activation was measured in tissue strips from the fundic region of guinea pig gastric mucosa. Histamine induced a significant elevation of tissue cyclic AMP levels and also in situ activation of the protein kinase. 1,4-methylhistamine, an inactive analog of histamine, and ethanol had no effect on these two parameters. Results suggest that protein kinase activation is involved in the cyclic AMP-mediated action of histamine on the gastric fundic mucosa.

Methyl derivatives of histamine; interaction with histamine metabolism.

Several histamine analogs, with ring or side chain methyl groups, were tested for interaction with certain aspects of 14C-histamine metabolism. The physiological catabolite, denoted as 3-methylhistamine under the nomenclature we have adopted, is known to inhibit histamine methylation in vitro and in vivo. At low concentrations, all analogs inhibited histamine methylation by mouse brain homogenates; however 3-methylhistamine was completely ineffective against the highly active enzyme from rat didney, while 2-methylhistamine was most effective. None of the drugs showed a significant effect on in vivo formation of 14C-histamine by mouse stomach. All analogs had a definite effect on the distribution and fate of intravenously injected 14C-histamine. The 2-methyl analog was the strongest in vivo inhibitor of histamine methylation, and 3-methylhistamine next. The side chain N-methylated histamies altered uptake of 14C-histamine in some tissues but inhibited methylation weakly, if at all. Data on blood kidney and urine for 4-methylhistamine were unique, and suggested some effect on tubular reabsorption. 2-methylhistamine may prove to be the inhibitor of choice for in vivo studies on histamine methylation.

Effects of burimamide, an antagonist of H-2 histamine receptors, in the gastric fistula dog.

In 6 dogs with gastric fistula, burimamide, a histamine analog which blocks H-2 histamine receptors, was given in a dose of 500 μg/kg-hr as a background to step-dose responses with histamine (2–100 μg/kg-hr) or with betazole (50–5000 μg/kg-hr). The drug did not change the histamineresponsive H, electrolyte, or pepsin secretion, but did competitively inhibit both H+ and electrolyte responses to betazole, and reduced pepsin secretion by 90%. Three of the dogs in studies using pentagastrin (0.1–5.0 μg/kg-hr) had marked reduction in pepsin output but no effect on H+ or electrolytes by burimamide. With 2-DG stimulation in 3 dogs (1 dose, 100 mg/kg), burimamide had no effect on H+ or pepsin secretion. Larger doses of burimamide, 1–5 mg/kg-hr, produced side effects, especially retching and diarrhea, which precluded studies of these doses.

Stimulation of rat gastric adenylate cyclase by histamine and histamine analogues and blockade by burimamide.

Histamine, 4-methylhistamine, 3-(beta-aminoethyl)-1,2,4 triazole and betazole, in that order, stimulated adenylate cyclase prepared from rat gastric tissue in a dose-dependent manner. Burimamide, an H(2)-receptor blocking agent, in concentrations of 1-5 x 10(-6) M antagonized this effect. The data lend some support to the hypothesis that elevated levels of cyclic adenosine 3',5'-monophosphate may be involved in histamine-stimulated gastric secretions and that H(2)-receptors are associated with adenylate cyclase.

Pharmacological activity of new histamine analogues.

Pharmacological activity of new histamine analogues.

Actions of Metiamide, an H2-Histamine Receptor Antagonist, on Gastric H+ and Pepsin Secretion in Dogs

Metiamide, a thiourea analog of histamine, is an antagonist of the gastric histamine receptor (type H2). At doses of 0.2 and 0.5 mg per kg-hr, it acted as a potent competitive inhibitor of H+ secreted in response to step-doses of histamine, pentagastrin, and Urecholine. At a dose of 2.5 mg per kg-hr, metiamide almost completely inhibited histamine stimulation (acting uncompetitively), but had a less potent effect on pentagastrin and 2-deoxyglucose stimulated H+ secretion. By contrast, during metiamide administration, pepsin secretion stimulated by the cholinergic stimuli, Urecholine and 2-deoxyglucose, was further increased, while H+ secretion was inhibited. These data are difficult to explain on the basis of strict specificity of metiamide for the gastric H2-histamine receptor, and several possible postulates are discussed.

Blockade by burimamide of the effects of histamine and histamine analogues on cardiac adenylate cyclase.

Blockade by burimamide of the effects of histamine and histamine analogues on cardiac adenylate cyclase.

Stimulation of acid and pepsin secretion in the fistula dog by 4(5)-Methyl histamine, a specific h-2 agonist.

4-Methyl histamine, a ring analog of histamine, is a specific agonist for the H-2 receptor of the gastric parietal cell. Gastric H+ and pepsin responses to graded doses of 4-methyl histamine [4(Me)H] and to histamine in fistula dogs show that pepsin is stimulated about 4–5 times more strongly by 4(Me)H but that for H+ secretion, time of onset (10–20 min), rate of reaching peak secretion (45–90 min), peak output (10 mEq/15 min), rate of fade (30% in 2 hours), the dose giving near-maximum response (100 μg/kg-hr), and kinetic parametersVmax (45 mEq/hr) andKm (11.8 μg/kg-hr for 4(Me)H compared to 12.4 μg/kg-hr for histamine) do not serve to distinguish the two drugs with respect to the parietal cell. After infusion of 4(Me)H was stopped, H+ secretion declined exponentially with time, and the half-time of this slope was linearly proportional to dose. At all doses, this decay of response was several times slower than with histamine, representing the only difference from histamine as regards gastric acid secretion in the dog.

Mucosal cyclic AMP and secretion in the dog stomach.

ARTICLESMucosal cyclic AMP and secretion in the dog stomachCC Mao, ED Jacobson, and LL ShanbourCC Mao, ED Jacobson, and LL ShanbourPublished Online:01 Oct 1973https://doi.org/10.1152/ajplegacy.1973.225.4.893MoreSectionsPDF (967 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByInhibitors of gastric secretion: Current progress7 December 2005 | British Journal of Surgery, Vol. 63, No. 10Intracellular Activation Events for Parietal Cell Hydrochloric Acid Secretion1 January 2011The adenylate cyclase-cyclic AMP-protein kinase system in different cell populations of the guinea pig gastric mucosaLife Sciences, Vol. 37, No. 12CYCLIC AMP AND GASTRIC ACID SECRETION IN THE DOGANZ Journal of Surgery, Vol. 52, No. 3A Role of Cyclic AMP in the Gastrointestinal Tract: Receptor Control of Hydrogen Ion Secretion by Mammalian Gastric MucosaHistamine Receptors and Cyclic NucleotidesCyclic nucleotide response to acid-secreting stimuli in guinea pig gastric mucosa in vitroGastroenterologia Japonica, Vol. 16, No. 4Cyclic nucleotides and the regulation of canine gastric acid secretionDigestive Diseases and Sciences, Vol. 24, No. 4Effects of Ethanol on Membrane TransportEffect of the phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711) on gastric secretion and gastric mucosal cyclic AMPNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 304, No. 1Effect of Ca2+, Mg2+, NaN3, cholinergic agents, and gastrointestinal hormones on the guanylate cyclase from guinea pig gastric mucosaGastroenterology, Vol. 74, No. 2Prostaglandins and Gastrointestinal Secretion and MotilityInterrelationships Between Histamine, Prostaglandins, and Cyclic AMP in Gastric Secretion: A HypothesisGastroenterology, Vol. 73, No. 4Cyclic nucleotide activity in gastrointestinal tissues and fluidsAnalytical Biochemistry, Vol. 78, No. 2Histamine, cyclic AMP, and gastric secretion in the dogThe American Journal of Digestive Diseases, Vol. 22, No. 1Cyclic adenosine monophosphate and human gastric acid secretionThe American Journal of Digestive Diseases, Vol. 22, No. 8Characterization of an adenylate cyclase system sensitive to histamine H2-receptor excitation in cells from dog gastric mucosaAgents and Actions, Vol. 6, No. 6Effects of Secretagogues on Oxygen Consumption, Aminopyrine Accumulation and Morphology in Isolated Gastric GlandsActa Physiologica Scandinavica, Vol. 97, No. 4Gastric acid secretionThe American Journal of Digestive Diseases, Vol. 21, No. 5Distribution of adenyl cyclase sensitive to histamine in rabbit gastric mucosaBiochemical Pharmacology, Vol. 25, No. 5Action of H 1 and H 2 Inhibitors on the Response of Histamine Sensitive Adenylyl Cyclase from Guinea-Pig MucosaEuropean Journal of Clinical Investigation, Vol. 6, No. 1Stimulation of adenylate cyclase of guinea pig gastric mucosa by histamine, sodium fluoride and 5?-guanylylimidodiphosphate and inhibition by histamine H1- and H2-receptor antagonists in vitroNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 296, No. 1Effects of Cyclic Adenosine 3':5'-Monophosphate and Related Agents on Acid Secretion by Isolated Rabbit Gastric MucosaGastroenterology, Vol. 69, No. 2Modulation of Stimulated Acid Secretion by Dibutyryl Cyclic Amp in the Dog StomachGastroenterology, Vol. 69, No. 1Action of Insulin on Some Other Organs and on DifferentiationCyclic Nucleotides and their Role in Gastrointestinal SecretionGastroenterology, Vol. 67, No. 5Rat gastric mucosal cAMP following cholinergic and histamine stimulationEuropean Journal of Pharmacology, Vol. 28, No. 2STIMULATION OF RAT GASTRIC ADENYLATE CYCLASE BY HISTAMINE AND HISTAMINE ANALOGUES AND BLOCKADE BY BURIMAMIDE19 July 2012 | British Journal of Pharmacology, Vol. 52, No. 1 More from this issue > Volume 225Issue 4October 1973Pages 893-896 Copyright & PermissionsCopyright © 1973 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1973.225.4.893PubMed4355179History Published online 1 October 1973 Published in print 1 October 1973 Metrics

Catecholamine metabolism and digital circulation after histamine and its analogue. Krypton clearance and calorimetric blood flow.

In 1959 (1) we reported the paradoxical effects on the digital circulation of histamine administered parenterally and of an orally ingested histamine analogue* (2). Both histamine and its analogue produced vasodilatation of the capillaries as manifested by flushing contrasted with vasoconstriction of the arteriovenous anastomoses (AVAS). It was postulated at that time that the AVA constricted in response to heat loss produced by histamine-mediated precapillary sphincter and hence capillary vasodilatation. The question as to whether the AVA constriction was a neural reflex or produced by some other mechanism such as the release of catecholamines (CM) from nerve endings and/or chrcmaff in tissues remained unanswered (3).

More drugs for meniere’s disease

Ménière’s syndrome is paroxysmal vertigo with tinnitus and sensorineural (perceptive) hearing loss. The hearing loss may be slowly progressive, fluctuating or sudden. Where no organic cause can be discovered the condition is called Ménière’s disease. The syndrome is found in patients with bone disease involving the otic capsule such as otosclerosis, osteitis deformans or late syphilis. It may also follow labyrinthine trauma or be associated with a wide variety of diseases interfering with the blood supply to the brainstem or inner ear. Endolymphatic hydrops has been demonstrated in all these conditions, and it is believed that it may occur also in Ménière’s disease. Other causes of the syndrome include inflammatory or demyelinating disorders or tumours involving the eighth nerve. Many drugs have been used to treat Ménière’s disease, but with little success. Drugs investigated in recent years include cinnarizine (an antihistamine which has been used for vertigo and motion sickness), betahistine (an orally active histamine analogue) and hydrochlorothiazide.

Detection and possible role of a chain methylated histamine metabolite(s) in guinea-pig stomach

Biologically active chain-methylated histamine analogues, N-methylhistamine and N,N-dimethylhistamine have been confirmed to exert a marked gastric acid secretory effect: 0.17 mg/kg of each produced a higher acid output in pylorus ligated guinea-pigs than 0.4 mg/kg of histamine. A chain-methylated histamine metabolite(s) hitherto described only in human urine, was detected in the stomachs of guinea-pigs pretreated with cortisone. Inhibition of the oxidative deamination of endogenous histamine by aminoguanidine also led to the detection of this substance(s) in guinea-pig stomachs. If, however, the methylation of histamine was inhibited by the aministration of chlorpromazine, the cortisone induced formation of chain-methylated metabolites was inhibited. In studies with labelled histamine cortisone was shown to decrease the ratio of 14C-histamine: total 14C-methylhistamine indicating that methylation occured to a greater extent in the stomachs of cortisone pretreated guinea-pigs than in the stomachs of control animals. It is suggested that cortisone treatment might increase the formation of a chain-methylated metabolite(s) by enhancing the activity of the methylating enzyme system and that the gastric acid hypersecretory effect of cortisone in guinea-pigs may be due at least in part to the increased formation of this active histamine metabolite(s).

Compensatory changes in renal electrolyte excretion to removal of gastric HC1 in normal and uremic man.

Renal compensatory changes were studied during gastric drainage in 4 normal men and in 3 patients with chronic glomerulonephritis. 4–500 ml gastric juice was removed daily during stimulation of HCl-secretion by a histamine analogue over a period of 4–7 days. In the normal subjects, the net effect of drainage was a loss of hydrogen ions nearly equivalent to the reduction in excretion of sodium ions, whereas urinary excretion of chloride was reduced corresponding to the amounts of chloride removed. Plasma bicarbonate concentration did not increase. In the uremic subjects, plasma bicarbonate increased from an average of 12 to 20 mEq/L. The reduction in renal excretion of chloride and sodium was less complete, and continued after gastric drainage when acidosis rapidly developed. Renal acid excretion was slightly reduced in both normal and uremic man. The reduction in potassium excretion corresponded to the gastric losses in both groups. The glomerular filtration rate remained unchanged. It is concluded that removal of HC1 stimulates renal tubular sodium reabsorption. An increase in renal secretion of potassium and hydrogen ions, as is usually observed after vomiting or HC1 removal in NaCl-deficient subjects, does not occur as long as sodium can be reabsorbed with chloride.

HISTALOG (AMETAZOLE HYDROCHLORIDE) AS A SUBSTITUTE FOR HISTAMINE IN DETERMINATION OF MAXIMAL ACID OUTPUT.

In evaluating gastric secretory function by the augmented histamine test, headache and excessive drowsiness are often encountered. Less commonly, nausea, faintness, and hypo tension may follow injection of the antihistamine or histamine. Thus a method which provides comparable secretory data with improved tolerance by the patient would be advantageous. Histalog (3-beta-aminoethyl pyrazole ; ametazole hydro chloride ; betazole), a histamine analogue, may be preferable to histamine acid phosphate because of fewer side-effects (Kirsner and Ford, 1955). Even large doses, administered without an antihistamine drug, apparently are better tolerated than a maximum dose of histamine (Ward et al., 1963 ; Zaterka and Neves, 1964). The present investigation sought to determine whether a standard dose of Histalog would yield one-hour acid outputs comparable with those after maximum histamine stimulation. The dose of 100 mg. of Histalog was selected because it was inferred from earlier work that it might be equivalent to a maximum dose of histamine (Ward et al., 1963). In addition, a detailed study was made of the incidence and severity of side-effects during the two types of test in order to determine whether the use of 100 mg. of Histalog might be preferable in clinical practice.

Relationship between early vascular responses and growth in the rat uterus: stimulation of cell division by estradiol and vasodilating amines.

The influence of estradiol and of vasodilating amines on hyperemia, edema production and growth in uteri of ovariectomized rats was determined. Estradiol (0.04 μg), histamine (0.3 mg), 5-hydroxytryptamine (serotonin, 0.2 mg), 3-(β-aminoethyl) pyrazole (Histalog, 0.2-0.3 mg) or saline was injected into the uterine lumina of rats maintained under controlled lighting and temperature. Solutions were pre-adjusted to pH 7.0. The experimental substances caused significant increases in uterine water content in 4 hr from a level of 79.5 % (saline) to 82–83% (serotonin, histamine) and 84% (estradiol). Histalog, a histamine analogue, produced negligible hydration. Cross sections of uteri from colchicine-treated rats sacrificed 24 hr after injection of control or experimental solutions were examined for evidence of growth stimulation. All luminal epithelial cells in metaphase as well as the total number of epithelial cells in each of 8–16 sections/rat were counted. Calculations of the number of cells in metaphase /1,...

On the Biological Methylation of Histamine. 5. Inhibition by Histamine Analogues.

On the Biological Methylation of Histamine. 5. Inhibition by Histamine Analogues.

A histamine analogue that does not cause itching.

Much of our knowledge about cutaneous vascular physiology stems from work with histamine. A variety of techniques have been utilized to investigate histamine-induced vasodilatation and whealing. Vascular studies with a very sensitive method in our laboratory have made it clear that itching, which frequently accompanies injection of histamine, has an untoward disruptive effect on delicate measurements. Accordingly, we sought a histamine-like compound devoid of pruritogenic activity. A series of histamine analogues had already been prepared by Lee and Jones. 1 One of these, betazole, had been shown to stimulate gastric secretion usually without causing undesirable effects in other organs. 2 We injected this drug intradermally in a few subjects and observed good wheals and flares but no pruritus. The injections were repeated. Pruritus occurred only once in over 100 random observations. Wheals appeared unabated in size or fluid content; erythema was not inhibited. Experiments were designed to help clarify the

A simple oral gastric secretory stimulant (betazole hydrochloride).

BETAZOLE hydrochloride (Histalog), a synthetic analog of histamine, has been employed for the past 6 years as the parenteral stimulant to gastric acid secretion in the standard 2-hour gastric analysis employed by this clinic. 1 With proper intragastric placement of the tube, doses of 0.1 mg. per kg. of body weight have been equal in potency to the previously employed 0.01 mg. per kg. of histamine diphosphate. The chief advantage has been the almost complete disappearance of headache and flushing, frequent and occasionally troublesome side effects following injection of histamine. Three years ago the oral preparation of betazole hydrochloride was made available and a comparison of the two forms of administration was undertaken. The purpose of this report is to compare the effectiveness of oral and intramuscular betazole hydrochloride as a stimulant to gastric acid secretion. Method Each subject was studied by the standard 2-hour gastric analysis. 2 The

Effect of 1,2,4-triazole ethylamine on gastric secretion.

3-(beta-aminoethylamine)-1,2,4-triazole, the triazole analogue of histamine, was found to be a potent excitant of gastric secretion, 0.42 mg of the triazole base being equivalent to 0.3 mg histamine in the dog. The action was slightly more prolonged than that of histamine. The evidence in this study along with earlier evidence strongly indicates that aminoguanidine (AG) acts additively with histamine, since AG inhibits the destruction of histamine. It was found that AG also augments the action of the triazole on gastric secretion, the mechanism of which is now uncertain.

Paradoxical effect of an orally ingested histamine analogue on capillaries and arteriovenous anastomoses of the human digit.

The effect on the circulation of an orally ingested histamine analogue was studied in nine human subjects, and of subcutaneously administered histamine phosphate in four human subjects. In the digit, a paradoxical effect was observed consisting of capillary and venular dilatation and constriction of arteriovenous anastomoses. The latter effect was probably a reflex response to heat loss caused by the generalized dermal capillary dilatation which was the direct effect of the drug. Submitted on March 18, 1959