Gastric histamine content and ulcer formation in rats with ethanol-induced injury. Effects of cinnarizine and flunarizine

The effects of the calcium antagonists cinnarizine and flunarizine on gastric histamine content and ulcer formation in rats with ethanol-induced injury were studied. Gastric ulcers were inflicted by oral application of 50% or 100% ethanol solution. Cinnarizine (20 mg/kg), flunarizine (10 mg/kg) and cimetidine (100 mg/kg) were administered orally 1 h before ethanol. Histamine was assayed fluorometrically. No effect of the tested drugs on 50% ethanol-induced gastric damage was observed. Cinnarizine and flunarizine inhibited 100% ethanol-induced lesion formation by 71% (p<0.01) and 20% (p>0.05), respectively. The inhibition exerted by cimetidine was 54% (p<0.05). Gastric histamine content was not affected by 50% ethanol, while 100% ethanol decreased it two-fold. None of the tested drugs induced significant changes in gastric histamine levels. No correlation was obtained between the ulceroprotective effect of the used calcium antagonists and the gastric histamine content in ethanol-induced injury.

     

Gastric histamine content and ulcer formation in rats with ethanol-induced injury. Effects of cinnarizine and flunarizine

The effects of the calcium antagonists cinnarizine and flunarizine on gastric histamine content and ulcer formation in rats with ethanol-induced injury were studied. Gastric ulcers were inflicted by oral application of 50% or 100% ethanol solution. Cinnarizine (20 mg/kg), flunarizine (10 mg/kg) and cimetidine (100 mg/kg) were administered orally 1 h before ethanol. Histamine was assayed fluorometrically. No effect of the tested drugs on 50% ethanol-induced gastric damage was observed. Cinnarizine and flunarizine inhibited 100% ethanol-induced lesion formation by 71% (p<0.01) and=" 20%=">p>0.05), respectively. The inhibition exerted by cimetidine was 54% (p<0.05). gastric=" histamine=" content=" was=" not=" affected=" by=" 50%=" ethanol,=" while=" 100%=" ethanol=" decreased=" it=" two-fold.=" none=" of=" the=" tested=" drugs=" induced=" significant=" changes=" in=" gastric=" histamine=" levels.=" no=" correlation=" was=" obtained=" between=" the=" ulceroprotective=" effect=" of=" the=" used=" calcium=" antagonists=" and=" the=" gastric=" histamine=" content=" in=" ethanol-induced=">     

Antiulcerogenic Effects and Possible Mechanism of Action of Quassia Amara (L. Simaroubaceae) Extract and Its Bioactive Principles in Rats

The effects of Quassia amara extract (Q. amara) and its bioactive principles-quassin and 2-methoxycanthin-6-one on gastric ulceration were studied in albino rats. Q. amara (200–800 mg/kg p.o.; 5–20 mg/kg i.p) and 2-methoxycanthin-6-one (12.5, 25.0 and 50.0 mg/kg p.o; 1, 2 and 4 mg/kg i.p) but not quassin (12.5, 25.0 and 50 mg/kg p.o; 1, 2 and 4 mg/kg i.p) significantly inhibited gastric ulceration induced by indomethacin (40mg/kg). Administration of Q. amara (800 mg/kg p.o and 20 mg/kg i.p) and 2-methoxycanthin-6-one (12.5 mg/kg p.o; 4 mg/kg i.p) caused between 77%–85% cytoprotection against indomethacin (40 mg/kg, i.p) — induced gastric ulceration. Quassin did not cause any significant change in indomethacin-induced gastric ulceration. The inhibition of gastric ulceration produced by Q. amara and 2-methoxycanthin-6 one was accompanied by significant dose-dependent decreases (P< 0.01) in total gastric acidity. To investigate the probable mechanism of action, the individual effects of the extract and its principles alone and in combination with histamine (1 mg/kg) or cimetidine (0.12 mg/kg) on gastric acid secretion in situ were studied. Q. amara (20 mg/kg) and 2-methoxycanthin-6-one (4 mg/kg) but not quassin significantly (P< 0.01) inhibited the basal and histamine-induced gastric acid secretion. Inhibition of gastric acid secretion by Q. amara and 2-methoxycanthin-6-one was accentuated by cimetidine. The results suggest that Q. amara and its bioactive principle, 2-methoxycanthin-6-one possess antiulcer activity probably acting via histamine H₂ receptor. This could be a potential source of potent and effective antiulcer agents.     

Anti-Ulcerogenic Activity of the Methanol Root Bark Extract of Cochlospermum Planchonii (Hook f)

Cochlospermum planchonii (Hook f) is a common medicinal plant used in Nigeria traditional medicine for treatment of different ailments including ulcers. The anti ulcer activity of the root bark methanol extract of Cochlospermum planchonii was evaluated using different [ethanol, acetylsalicylic acid (aspirin), cold/restraint stress and pyloric ligation/histamine - induced ulcers and acid production] ulcerogenic models in rats at the doses of 250, 500, and 1000 mg/kg body weight using cimetidine (100 mg/kg) as a standard reference drug. The different doses of the extract and the reference drug significantly (p < 0.01) decreased all the ulcer parameters in a dose dependent manner in all the models used. The total number of ulcers were significantly (p < 0.05) decreased. The ulcer index was significantly (p < 0.004) reduced by the extract. Similarly, the percentage ulcer preventive index was also increased from 0% in the negative control up to 93.2% at the dose of 1000 mg/kg, while the percentage ulcer severity was dose dependently reduced by the extract. Furthermore, the extract significantly (p < 0.02) decreased free gastric HCl and total gastric acid. In conclusion, Cochlospermum planchonii methanolic root bark extract showed significant antiulcer activity in this study which may be as a result of its cytoprotective, antioxidant or antisecretory properties.     

Suppression of the Arthus reaction by Y-24180, a potent and specific antagonist of platelet-activating factor

A novel and potent antagonist of platelet-activating factor (PAF), Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobubylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine) was investigated for the effects on the skin reactions induced by chemical mediators and the Arthus reactions. In the rat dorsal skin, Y-24180 (0.1–10 mg/kg, p.o.) inhibited increase in vascular permeability by the intradermal PAF injection in a dose dependent manner and the inhibitory activity was 60 times more potent than that of WEB 2086. While even at doses as large as 10 mg/kg, p.o., it had no effect on vascular permeability in the rat skin induced by histamine, serotonin, bradykinin and leukotriene D₄. On a reversed passive Arthus reaction in rat dorsal skin, Y-24180 (0.1–1 mg/kg, p.o.) markedly inhibited vascular permeability in a dose dependent manner and the inhibitory activity was 15 times more potent than that of WEB 2086. Y-24180 also inhibited the Arthus dermal reaction in rabbits (0.03–0.3 mg/kg, p.o.) and guinea pigs (0.1–1mg/kg, p.o.). In addition Y-24180 (0.1–10 mg/kg, p.o.) significantly reduced the exudate volume and the number of infiltrated inflammatory cells in the reversed passive Arthus pleural reaction in rats. Furthermore, in rat passive Arthus pancreatitis, Y-24180 (0.3–10 mg/kg, p.o.) significantly inhibited the dye extravasation from the pancreas. These results provide strong evidence that endogenous PAF plays an important role as a mediator in the type III allergic inflammation.     

H2-receptor antagonist and gastric acid antisecretory properties of Wy-45,662

Investigations were carried out to delineate the biological activity of Wy-45,662, a new H₂-receptor antagonist. In the pylorus-ligated rat after intraduodenal administration, total acid output (TAO) over 4 hours was inhibited by Wy-45,662 with an ED₅₀ of 0.3 mg/kg as compared to ranitidine (ED₅₀=7 mg/kg) and cimetidine (ED₅₀=12 mg/kg); i.v. or i.m. administration increased Wy-45,662's potency 10-fold. In dogs with innervated gastric pouches Wy-45,662 inhibited food-stimulated TAO with ED₅₀'s of 0.35 mg/kg (p.o.), 0.045 mg/kg (i.v.) and 0.065 mg/kg (i.m.); cimetidine (ED₅₀=6mg/kg p.o.) and ranitidine (ED₅₀=1 mg/kg p.o.) were less potent. Wy-45,662 also inhibited pentagastrin- or histaminestimulated acid secretion in the conscious fistula rat. In vitro, Wy-45,662 antagonized the histaminestimulated a) positive chronotropism in guinea pig atria and b) [¹⁴C]aminopyrine uptake by rat gastric mucosal cells, confirming its H₂-receptor antagonist properties.     

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

The blockade of histamine receptors by repeated i.p. administration of 10–20 mg/kg of chloropyramine and tripelennamine, the potent H₁-receptor antagonists, or by the i.c.v. administration of 2 mg/kg of metiamide and cimetidine, the highly selective H₂-receptor antagonists, led to significant enhancement in the hypothalamic HD² (l-histidine carboxylase; EC 4.1.1.22.) activity and the histamine content; whereas the activation of the histamin H₁-receptor by 4 mg/kg i.e.v. doses of 2-pyridylethylamine, the specific histamine H₁ agonist, resulted in significant diminution in both the synthesis and level of this amine. These compounds either do not influence the hypothalamic HDin vitro or cause opposite effects in relatively high concentrations. After repeated administration of either agonists or antagonists, no significant alteration have been observed in the hypothalamic HNMT (histamine-N-methyl-transferase; EC 2.1.1.8.) activity. There were, however, two exceptions: 2 mg/kg i.c.v. doses of 2-methylhistamine and 4-methylhistamine produced remarkable inhibitions in the hypothalamic HNMT activity. These effects do not seem to correspond to the agonistic character of the compounds, but mask the indirect actions and create difficulties in the discovery of regulatory events.The regulatory influence which suppresses or stimulates the basal activity of HD under the activation or the inhibition of the functional state of histamine receptor, is assumed to be mediated through the cyclic AMP system.Parts of this paper were presented at the Eleventh Meeting of the European Histamine Research Society in Bled, May 9–12, 1982.     

Induction of gastric histamine synthesis by H2-receptor antagonists: Potentiation of their antisecretory activity by histidine decarboxylase inhibitors

The activation of histamine (HA) formation in rat stomach was measured after repeated administrations of histamine H₂-receptor antagonists and the potentiation of their antisecretory activity was examined in histidine decarboxylase inhibitor (HDI)-pretreated rats. 40 mg/kg of metiamide, given intraperitoneally (i.p.) 24, 16 and 2 h prior to the examination, produced approximately 50% increase in the amount of¹⁴C-histamine, formed from¹⁴C-histidine in the stomach, and an almost equal enhancement in the gastric histidine decarboxylase (HD) activity. An equal dose of the compound did not influence the endogenous histamine level in the glandular stomach whereas it caused a significant increase in the serum histamine content. By similar treatment, 10 mg/kg of cimetidine enhanced the newly formed histamine in the rat stomach by 57%. The potent HDI, 2-hydroxy-5-carbomethoxy-benzyloxyamine (GYKI-11 121) suppressed the metiamide- and eimetidine-induced increases in histamine synthesis to slightly above or below the control values. In pharmacological studies, the antisecretory activity of histamine H₂-receptor blockers could markedly be potentiated by HDI. In GYKI-11 121 and NSD-1055-pretreated rats, the inhibiting potency of metiamide and cimetidine on pentagastrin-stimulated gastric acid secretion, increased to approximately twice that of the original effect. Neither GYKI-11 121 nor NSD-1055 produced significant inhibition on pentagastrin-stimulated gastric acid secretion in the applied doses. These findings provided evidence for the feedback stimulation of gastric HA synthesis by H₂-receptor blockers and confirmed the role of HA in the gastric acid secretion. Potentiation of the antisecretory activity of H₂-receptor antagonists by HDI would be useful in the therapeutic application of these compounds.     

EM 405: A new compound with analgesic and anti-inflammatory properties and no gastrointestinal side-effects

EM 405 has analgesic and antitussive effects, probably exerted by noradrenaline uptake inhibition and local anaesthetic actions. It showed anti-inflammatory, which may be due to anti-histaminic and indirect sympathomimetic properties.As oral application of EM 405 did not induce gastrointestinal side effects a possible ulcer preventing action was investigated. EM 405 reduced gastric ulcers induced by ethnology or indomethacin with ED₅₀ values of 45 and 26 mg/kg p.o. Stress-induced ulcer was inhibited with an ED₅₀ of 34 mg/kg. EM 405 reduced basal and stimulated gastric secretion by reducing volume as well as H⁺- and Cl^–-production. Therefore ulcer prevention by EM 405 may be explained by its inhibitory effects on gastric secretion. The results characterise EM 405 as a novel anti-inflammatory compound with ulcer-protective action.     

Effect of atropine and cimetidine combinations on pentagastrin stimulated maximal gastric acid secretion in man

Recently it has been reported that anticholinergics were able to increase the inhibitory effect on gastric secretion of specific histamine H2-receptor antagonists. The aim of the present study was to determine the degree of increased inhibition of gastric acid secretion and also to introduce an exact method for measuring the gastric acid output. Maximal gastric acid secretion provoked by continuous pentagastrin infusion 3.4-4.0 micrograms X kg-1 h-1) was dose-dependently inhibited by intravenous (i.v.) atropine (0.002; 0.003; 0.004 mg X kg-1) and cimetidine (1.0; 1.5; 2.0 mg X kg-1). A potentiated synergism was observed on the simultaneous administration of atropine and cimetidine, suggesting the good effect of a low dose combination of atropine and cimetidine in the therapy of peptic ulcer.     

Lack of influence of histamine H1-, and H2-receptor antagonists on histamine level in rat brain

The intraperitoneal administration of three antihistaminic drugs of H1 type: mepyramine, diphenyhydramine (each 5 and 30 mg/kg) and danitracen (2 and 10 mg/kg) did not modify histamine level in the rat brain after 2 h. Histamine H2-receptor antagonists: cimetidine (25-250 microgram) and metiamide (100 microgram) given directly into the brain had no significant effect on histamine content after 1.5 h. L-histidine (0.5 g/kg i.p.) increased after 1.5 h histamine level in various experiments by 50-75% above control. All antihistaminic drugs did not change significantly histamine level in the brains of L-histidine-treated rats though a slight but consistent tendency to decrease the L-histidine effect in the group of H2-receptor blocking drugs was observed.     

A study of the antiulcer mechanisms of propanolol in rats

Although propranolol has been shown to protect against enthanol and stress ulceration, the antiulcer mechanisms are still unclear. The present study examined the antiulcer mechanisms of propranolol in three different types of ulceration induced respectively by ethanol (60%), indomethacin (30 mg/kg) and stress (cold-restraint). Propranolol pretreatment in the highest dose (10 mg/kg) given either intraperitoneally (i.p.) or orally (p.o.) prevented gastric mucosal damage in these three ulcer models. The three doses of the drug (2.5, 5 or 10 mg/kg) dose-dependently decreased systemic blood pressure which was accompanied by a reduction of gastric mucosal blood flow. These findings suggest that the protection was unrelated to an improvement of local circulation in the stomach. However, propranolol preserved the mucus levels in the three types of ulcer models. The -adrenoceptor blocker also increased the basal gastric mucosal potential difference. These findings indicate that propranolol strengthens the mucosal barrier by the preservation of mucosal mucus and enhancement of the mucosal integrity in the stomach.accepted by R. O. Day     

Antiallergic effects of terfenadine on immediate type hypersensitivity reactions

Terfenadine dose-dependently inhibited rat homologous PCA (2.5-10 mg/kg, p.o.) and experimentally-induced asthma in guinea pigs (0.5-5 mg/kg, p.o.). Similarly, metabolites I and II dose-dependently inhibited experimentally-induced asthma but their respective potencies were approximately 1/2 and 1/15th that of terfenadine. These results suggest that the metabolites contribute to the antiallergic effects of terfenadine. In ex vivo, terfenadine (5-20 mg/kg, p.o.) also inhibited the release of both antigen-induced histamine and SRS-A from sensitized guinea pig lung samples and that of histamine from rat peritoneal mast cells. Terfenadine dose-dependently increased the cAMP content in rat mast cells and in the lungs; in the latter, the augmented cAMP is associated with an increase in adenylate cyclase activity, but not with the inhibition of phosphodiesterase activity. The above evidence indicates that the inhibitory effects of terfenadine on mediator release from mast cells are in some way related to its antiallergic effects, and that an elevated cAMP content may be effective to enhance mediator release inhibition.     

Antiallergic Effects of Terfenadine on Immediate Type Hypersensitivity Reactions

Terfenadine dose-dependently inhibited rat homologous PCA (2.5-10 mg/ kg, p.o.) and experimentally-induced asthma in guinea pigs (0.5-5 mg/kg, p.o.). Similarly, metabolites I and II dose-dependently inhibited experimentally-induced asthma but their respective potencies were approximately 1/2 and 1/15th that of terfenadine. These results suggest that the metabolites contribute to the antiallergic effects of terfenadine. In ex vivo, terfenadine (5-20 mg/kg, p.o.) also inhibited the release of both antigen-induced histamine and SRS-A from sensitized guinea pig lung samples and that of histamine from rat peritoneal mast cells. Terfenadine dose-dependently increased the cAMP content in rat mast cells and in the lungs; in the latter, the augmented cAMP is associated with an increase in adenylate cyclase activity, but not with the inhibition of phosphodiesterase activity.

The above evidence indicates that the inhibitory effects of terfenadine on mediator release from mast cells are in some way related to its antiallergic effects, and that an elevated cAMP content may be effective to enhance mediator release inhibition.     

Antiallergic Effects of Terfenadine on Immediate Type Hypersensitivity Reactions

Abstract

Terfenadine dose-dependently inhibited rat homologous PCA (2.5-10 mg/ kg, p.o.) and experimentally-induced asthma in guinea pigs (0.5-5 mg/kg, p.o.). Similarly, metabolites I and II dose-dependently inhibited experimentally-induced asthma but their respective potencies were approximately 1/2 and 1/15th that of terfenadine. These results suggest that the metabolites contribute to the antiallergic effects of terfenadine. In ex vivo, terfenadine (5-20 mg/kg, p.o.) also inhibited the release of both antigen-induced histamine and SRS-A from sensitized guinea pig lung samples and that of histamine from rat peritoneal mast cells. Terfenadine dose-dependently increased the cAMP content in rat mast cells and in the lungs; in the latter, the augmented cAMP is associated with an increase in adenylate cyclase activity, but not with the inhibition of phosphodiesterase activity.

The above evidence indicates that the inhibitory effects of terfenadine on mediator release from mast cells are in some way related to its antiallergic effects, and that an elevated cAMP content may be effective to enhance mediator release inhibition.     

Cimetidine increases the pancreatic response to histamine

The effects of histamine alone and histamine plus cimetidine on basal pancreatic exocrine secretion were determined in anaesthetized rabbits with an acute pancreatic cannula. Intravenous histamine administration (0.2–0.8n mol/kg/min) increased pancreatic enzyme secretion. A much greater stimulative effect on pancreatic (cimetidine 4 mol/kg/min). The results indicate that in the rabbit pancreas the stimulatory effect of histamine is mediated by H1 receptors.     

Effects of dithiocarb and (+)-catechin against carbon tetrachloride-alcohol-induced liver fibrosis

Treatment of male rats with carbon tetrachloride (CCl₄, 2 × weekly 0.2 ml/kg p.o.) and a 5% alcohol solution, instead of drinking water, for 4 weeks led to marked increases in serum enzyme activities (GOT, GPT, SDH), hepatic triglyceride and hydroxyproline content. Diethyl dithiocarbamate (dithiocarb, 200 mg/kg p.o.) simultaneously applied with CCl₄ totally suppressed the elevation in serum enzyme activities and hepatic hydroxyproline concentration, and partially suppressed that of the triglyceride content. (+)-Catechin (50–300 mg/kg p.o.). simultaneously applied with CCl₄ had no influence on the enhanced serum enzymes, but depressed the augmented content of both hepatic triglyceride and hydroxyproline in a dose-dependent way. The most effective dose with respect to the reduction of the hydroxyproline concentration was 100 mg/kg (+)-catechin; the highest dose (300 mg/kg), however, enhanced the CCl₄-alcohol-induced hydroxyproline augmentation.     

Comparison of inhibitory effects of atropine, cimetidine, and atropine plus cimetidine on the indomethacin-provoked gastric mucosal erosions in rats

20 mg/kg-1 indomethacin suspended in 1% carboxymethyl-cellulose solution was given subcutaneously into rats to provoke gastric mucosal erosions during 5 h. Dose-dependent inhibitions of indomethacin erosions were observed following different doses of atropine (0.025; 0.2; 1.0 mg/kg-1) and cimetidine (2.5; 10; 50 mg/kg-1) administered intraperitoneally (25%; 38%; 81% and 0%; 42%; 89% respectively). More pronounced inhibitory effects have been obtained with the combinations of both drugs (51%; 68%; 92%). In particular there was a remarkable potentiated synergism in the lowest doses of atropine and cimetidine (51%, against 0% and 25%). These results provide further evidence of synergism of histamine H2-receptor blockers and anticholinergics, which combinations would be useful, for example, in peptic ulcer therapy.     

Peripheral hypotensive and central hypertensive effects of cimetidine

Rapid intravenous (i.v.) injections of high doses (16–128 mol/kg) of cimetidine induced a short-lasting (5–15 min) hypotension in anaesthetized rats. Diastolic pressure was reduced more than systolic pressure, suggesting vasodilatation. Heart rate was not affected. Diphenhydramine pretreatment (100 mol/kg i.v.) did not antagonize the hypotensive effect of cimetidine. However, in the presence of diphenhydramine, cimetidine induced bradycardia. Intracerebroventricular administration of cimetidine or metiamide (2 mol/rat) increased the blood pressure and heart rate. It is concluded that the hypotension after i.v. cimetidine is mediated by peripheral mechanisms. Since diphenhydramine pretreatment had no antagonistic effect cimetidine-induced hypotension could not be due to indirect H₁-receptor stimulation caused by histamine liberation.     

H2-receptor antagonists protect against aspirin-induced gastric lesions in the rat

Gastric mucosal lesions were produced in rats by dosing orally with aspirin, 300 mg/kg. Predosing orally with either ranitidine or cimetidine inhibited this lesion formation; the respective ED₅₀ values were 0.8 and 3.9 mg/kg p.o. Oral ranitidine also inhibited lesion formation in the presence of exogenous 160 mM HCl, with an ED₅₀ value of 23.2 mg/kg p.o. Subcutaneous injection of ranitidine inhibited the formation of aspirin-induced lesions both in the presence and in the absence of excess HCl. The ED₅₀ values were respectively 3.4 and 0.9 mg/kg s.c. Mepyramine maleate (5 mg/kg p.o.) alone had no effect on gastric lesion formation, and did not influence the level of inhibition produced by ranitidine either in the absence or presence of exogenous acid.