Additional data on the function of hypothalamic histamine

In a preliminary study, the stimulatory effect of histamine on an adenylate cyclase system in a solubilized cell-free preparation of the rat hypothalamus was established. The effect was dose dependent, and the histamine concentration required for half-maximal activation (K _a) was determined at 0.1 M. At a 10-fold higher concentration, both chloropyramine, the classical histamine H₁ antagonist, and metiamide, the selective H₂-receptor blocker, partially blocked this action. Experiments carried out in hypothalamic slices showed a stimulatory effect of both the H₁-agonist, 2-(2-pyridyl)-ethylamine, and the H₂-antagonist, dimaprit, on adenylate cyclase in the range of histamine action. These effects could be reversed completely by the H₁-antagonist, mepyramine, and the H₂-receptor blocker, cimetidine.In an additional study, histamine, histamine agonists and antagonists were tested on the spontaneous and the potassium-activated outflow of³H-noradrenaline from rat hypothalamic slices. Histamine did not modify this outflow significantly, whereas the H₁-agonist, 2-(2-pyridyl)-ethylamine, produced a marked, dose-related increase in both the spontaneous and the potassium-stimulated release of noradrenaline. The H₂-receptor blocker, cimetidine, also exerted a moderate but statistically significant stimulatory effect in this system.In combination studies, the noradrenaline-releasing action of these compounds could not be reversed by the selectively acting histaminic or antihistaminic agents, showing that this effect does not relate to the histaminic or antihistaminic property of the compound.It is becoming clear that histamine exerts a direct stimulatory effect on hypothalamic adenylate cyclase. The noradrenaline-releasing potency of some histaminic and antihistaminic agents showed that these compounds might modify the clear histamine effects through the release of other transmitter amines.     

Evaluation of combined H1- and H2-receptor blocking agents in the treatment of seasonal allergic rhinitis

During an 8 wk period (September 23 to July 30) 23 patients with histories of late-summer allergic rhinitis received, on a random basis, alternating 2 wk courses of either chlorpheniramine (anti-H1), 12 to 48 mg/day, plus placebo, or anti-H1 in the same dose plus cimetidine (anti-H2), 300 mg t.i.d. Symptom (SX) and medication (MED) scores were recorded twice daily. After the season the immediate (ICR) and late (LCR) reactions to allergens and histamine were measured in six of these patients while on: (1) no drugs, (2) anti-H1 plus placebo, or (3) anti-H1 plus anti-H2 in the doses employed during the season. Mean weekly SX scores were significantly lower on anti-H1 plus anti-H2 compared with anti-H1 plus placebo during the sixth week of the study (p less than 0.001). MED scores were lower on the anti-H1 and anti-H2 combination than on anti-H1 alone during weeks four and five (p less than 0.02). In the six patients studied after the season, the ICRs were consistently smaller with the anti-H1 and anti-H2 combination, but the differences were only significant for the histamine-induced wheal (p less than 0.01). In this study of allergic rhinitis there appeared to be a small but statistically significant additive effect of anti-H2 to the clinical response to anti-H1. No additional side effects were noted.     

THE EFFECTS OF MA-XING-GAN-SHI-TANG ON RESPIRATORY RESISTANCE AND AIRWAY LEUKOCYTE INFILTRATION IN ASTHMATIC GUINEA PIGS

Ma-Xing-Gan-Shi-Tang (MXGST), a traditional Chinese medicine, has been used in treatment of the bronchial asthma for several centuries. However, the therapeutic mechanisms of this Chinese medicine are still far from clear. To understand the mechanism of anti-asthmatic property of MXGST, a guinea pig model of allergic asthma was used to investigate the effects of MXGST on Dermatophagoides pteronyssinus-induced early and late asthmatic responses and airway inflammation, and examine direct β₂-adrenoceptor agonist activity in guinea-pig isolated trachea. Administration of MXGST (10 g/kg) extracts significantly inhibited the antigen induced immediate asthmatic responses (IAR) in actively sensitized guinea pig. MXGST caused concentration-dependent relaxation in strips of guinea pig trachea contracted with carbachol, and ICI-118551, a selective β₂-adrenoceptor antagonist, significantly inhibit the relaxation caused by MXGST. Furthermore, examination of bronchoalveolar lavage fluid (BALF) revealed that MXGST significantly inhibited the increase in neutrophil in the airway at 1, 6 and 24 hr after antigen challenge. Histopathologic examination results showed that MXGST suppressed the neutrophil infiltration into lung tissue. In conclusion, we suggest that the anti-asthmatic effects of MXGST are mainly due to its stimulation of β₂-adrenoceptors on bronchial smooth muscle and its anti-inflammatory ability to inhibit the neutrophil into the airway. The precise mechanism of action of MXGST in asthma remains to be elucidated.     

Pharmacological characterisation of cardiovascular histamine receptors in man in vivo

Summary Data from pharmacological studies carried out in healthy subjects using systemic histamine or impromidine and their antagonists are reviewed. Exogenous histamine by rapid injection appears to stimulate only H₁-receptors. Chlorpheniramine alone antagonised the responses to histamine.The effects of cardiovascular H₂-receptor stimulation are demonstrated best by a sustained and large dose of histamine given by infusion. If it be considered desirable to antagonise all the cardiovascular responses to endogenous histamine, the available pharmacological data in man suggest this would be achieved best by a combination of an H₁- and H₂-receptor antagonist.     

Effects of ICI204,448, naloxone methiodide and levocetirizine on the scratching behavior induced by a κ-opioid antagonist,nor-BNI,in ICR mice

Objective: In this study, we aimed to study the effects of ICI204,448, naloxone methiodide and levocetirizine on the scratching behavior induced by intradermal injection of a ?-opioid antagonist, nor-binaltorphimine (nor-BNI), into the rostral back of ICR mice were investigated.

Materials and methods: Male ICR mice weighing 30?35 g were used. The number of scratching episodes were counted for 60 min after i.d. injection of nor-BNI.

Results: nor-BNI dose dependently increased in the number of scratching episodes in ICR mice. nor-BNI-induced scratching behavior was inhibited by not only nalfurafine but also ICI204,448, a peripherally selective ?-opioid agonist. Naloxone and naloxone methiodide, a peripherally restricted ?-opioid antagonist, also inhibited nor-BNI-induced scratching behavior. Scratching behavior induced by nor-BNI was inhibited by chlorpheniramine as well as levocetirizine, a third-generation H₁ antagonist that does not cross into the CNS.

Conclusion: These results suggest that scratching behavior induced by this ?-opioid antagonist, nor-BNI, is related to not only central but also peripheral opioid and H₁ receptors.     

Interaction of Aspergillus fumigatus Spores with Human Leukocytes and Serum

Serum was necessary for optimal phagocytosis of Aspergillus fumigatus spores by human leukocytes, and its opsonic capacity was greatly diminished by heat inactivation (56 C, 30 min). A germination assay, described in this report, was developed to study the fate of phagocytized spores. After incubation for 3 hr with normal leukocytes and serum, spores ingested by peripheral blood neutrophils and monocytes remained viable. Since we had previously found that myeloperoxidase (MPO), a lysosomal enzyme of human neutrophils and monocytes, exerted fungicidal activity against Candida albicans when combined with H₂O₂ and chloride or iodide, the effects of these substances on A. fumigatus spores were examined. Spore viability was not impaired by MPO alone, H₂O₂ alone, or KI alone, but high concentrations of KI and H₂O₂ in combination caused marked inhibition of subsequent germination. MPO imparted fungicidal activity to concentrations of KI and H₂O₂ that lacked any effect in its absence. NaCl, in combination with MPO and H₂O₂, was far less effective than the iodide salt against A. fumigatus. The relative ineffectiveness of chloride in this system could underly the apparent inability of human neutrophils to kill ingested A. fumigatus spores, despite their competence to kill C. albicans.     

Histamine H1- and H2-receptor involvement in eosinophil infiltration and the microvascular changes associated with cutanneous anaphylaxis

Several substances alter eosinophil motility, but the relative importance of these putative mediators in immediate hypersensitivity remains unclear. The present study has reinvestigated the role of histamine in type I allergic eosinophil infiltration, and the temporally associated microvascular events, by examining the effect of H₁-and H₂-receptor antagonist pretreatment. A combination of cimetidine and pyrilamine significantly reduced eosinophil accumulation, whereas neither antagonist alone was effective. Similarly, cutaneous hyperemia, measured indirectly as ear surface temperature, was reduced only by the cimetidine-pyrilamine combination. Pyrilamine partially attenuated the increase in microvascular permeability, but the addition of cimetidine provided no further reduction.It appears that histamine participates significantly in mediating both the microvascular changes and the eosinophil infiltration evoked by cutaneous anaphylaxis. The histaminergic component of increased microvascular permeability appears to be an H₁-receptor mediated phenomenon. However, blockade of both H₁-and H₂-receptor subtypes is required to inhibit the hyperemia and eosinophil infiltration responses.     

Histamine receptors in unstimulated pancreatic exocrine secretion of the rabbit

Histamine H₂-receptor antagonists cimetidine and oxmetidine, H₂-receptor agonist dimaprit, H₁-receptor antagonist chlorpheniramine and H₁-receptor agonist 2-thiazolylethylamine were tested for their effects on unstimulated pancreatic exocrine secretion in anaesthetized rabbits fitted with an acute pancreatic cannula. Intravenous administration of H₁ agonist induces a dose-dependent increase in pancreatic secretion but H₁ antagonist have the opposite effects. Intravenous administration of H₂ antagonists induces effects similar the ones produced after H₁ agonist infusion. The implications of H₁ and H₂ receptors on exocrine pancreatic secretion are discussed.     

An adenosine A(2A) antagonist injected in the NTS reverses thermal prolongation of the LCR in decerebrate piglets

Hyperthermia prolongs the laryngeal chemoreflex (LCR). Under normothermic conditions, adenosine antagonists shorten and adenosine A_2A (Ad-A_2A) agonists prolong the LCR. Therefore, we tested the hypothesis that SCH-58261, an Ad-A_2A receptor antagonist, would prevent thermal prolongation of the LCR when injected unilaterally within the nucleus of the solitary tract (NTS). We studied decerebrate piglets aged 4–13 days. We elicited the LCR by injecting 0.1 ml of water into the larynx and recorded integrated phrenic nerve activity. The laryngeal chemoreflex was prolonged when the body temperature of each piglet was raised 2.5 °C, and SCH-58261 reversed the thermal prolongation of the LCR when injected into the NTS (n = 13), but not when injected in the nucleus ambiguus (n = 9). Injections of vehicle alone into the NTS did not alter the thermal prolongation of the LCR (n = 9). We conclude that activation of adenosine receptors, perhaps located on GABAergic neurons in the NTS, contributes to thermal prolongation of the LCR.     

Acceleration of rat brain beta-adrenoceptor subsensitivity following the coadministration of histamine receptor antagonists with imipramine

Systemic administration of isoprenaline to rats produced a dose-dependent increase in water drinking which was effectively blocked by propranolol. This dipsogenic effect was significantly inhibited by the subacute (4 days) administration of imipramine (18.1. mg/kg/day) together with either the H₁-histamine receptor antagonist, chlorpheniramine (0.1 or 1.32 mg/kg/day), or the H₂-histamine antagonist, cimetidine (1.91 mg/kg/day) or ranitidine (0.60 or 1.51 mg/kg/day). The oral subacute administration of imipramine alone had no significant effect on this behavior. However, chronic ingestion of imipramine alone (21 days) caused a significant reduction in the isoprenaline-induced behavior.It is concluded that the desensitization of central beta-adrenoceptors, as evidenced by inhibition of isoprenaline-induced drinking, can be accelerated following the oral subacute co-administration of imipramine with either H₁- or H₂-histamine receptor antagonists. It also seems that central histamine receptors may partially contribute towards the mechanism of antidepressant effect of imipramine.     

Histamine receptor blocking effects of cimetidine in the airways

We investigated the modification of histamine-induced bronchoconstriction by the H₂-antagonist cimetidine in conscious sheep. One hundred breaths of 5% histamine aerosol increased mean (SD) pulmonary resistance (R _L) by 5.6 (1.4) cmH₂O/1/sec. This increase inR _L was completely blocked by intravenous clemastine (0.5 mg), a specific H₁-antagonist, indicating that the histamine-induced bronchoconstriction was mediated by H₁-receptors. Intravenous cimetidine caused a dose-dependent enhancement of the histamine response between 1 and 1000 mg with a mean peak ΔR _L of 15.3 (5) cmH₂O/1/sec (P<0.05) at the 1000 mg dose, while it blocked the histamine response at a dose of 2400 mg [ΔR _L=1.9 (2) cmH₂O/1/sec,p=NS]. This paradoxic effect was not related to an anticholinergic mechanism as intravenous cimetidine (2400 mg) failed to block carbachol-induced (25 breaths of 1% solution) bronchoconstriction. We conclude that in the ovine airway, cimetidine is a selective H₂-histamine receptor blocker at lower tissue concentrations, and a combined H₂- and H₁-histamine receptor blocker at high tissue concentrations.     

Modification of airway histamine-receptor function with methylprednisolone succinate

The purpose of the present study was to investigate whether glucocorticosteroids alter airway histamine-receptor function. We measured pulmonary resistance in six conscious sheep before and after inhalation challenge with 100 breaths of 5% histamine solution, without and with intravenous pretreatment with the specific H₁- and H₂-receptor antagonists. Inhalation of histamine (combined H₁ and H₂ stimulation) increased mean pulmonary resistance (R_L) to 290% of baseline (p < 0.05). Pretreatment with the H₂ antagonist, metiamide (selective H₁ stimulation), enhanced the effect of histamine, with a mean R_L increase to 760% of baseline (p < 0.05). Histamine challenge after pretreatment with the H₁ antagonist, chlorpheniramine (selective H₂ stimulation), decreased R_L to 40% of chlorpheniramine value (p < 0.05). A single intravenous bolus injection of methylprednisolone succinate (30 mg/kg) 30 min before histamine challenge suppressed the airway responsiveness to histamine. with a mean R_L increase to only 186% of baseline. After methylprednisolone, selective H₁-receptor stimulation with histamine elicited a blunted H₁-receptor response; mean R_L increased to only 248% of baseline. Both changes were significantly lower than that with histamine alone (p < 0.05). Methylprednisolone per se blunted the chlorpheniramine-induced increase in R_L, which made it difficult to evaluate H₂-receptor function (R_L decreased to 67% of postchlorpheniramine value). However, in the presence of increased airway tone with carbachol, selective H₂ stimulation with histamine decreased R_L to 26% of postcarbachol value (p < 0.05), thus excluding suppression of H₂ receptors. Methylprednisolone had no effect on carbachol-induced increase in R_L. In conscious sheep, methylprednisolone blunts airway responsiveness to histamine by suppressing H₁ receptors without significantly altering H₂ receptors or cholinergic-receptor function.     

A study about the possible characteristics of cardiovascular histamine receptors of the turtle

Histamine produced pressor, depressor or biphasic responses in the systemic blood pressure of the turtle. The pressor response or component reversed to depressor effect after the injection of mepyramine, an H₁ receptor blocker. It was thought that this response is mediated through the H₁ receptors. The depressor response or component was abolished by the treatment of metiamide, a new histamine H₂ receptor blocker. Also, the effect reversed after metiamide. These results indicated the presence of H₂ receptors in the turtle.     

Effects of local treatment with salmeterol and terbutaline on anti-IgE-induced wheal, flare, and late induration in human skin

The capacity of terbutaline and the long-acting β₂-agonist salmetcrol to suppress wheal-and-flare reactions (WFRs) to intradermal antihuman IgE and to histamine was evaluated in 36 healthy volunteers. We also exaniined effects of the two drugs on the subsequent late cutaneous reaction (LCR) to anti-IgE. Salmeterol (10^-10 10^-6 M) and terbutaline (10^-10 10^-5 M), injected intradermally 2 or 15 min before anti-IgE challenge, produced a dose-dependent inhibition of the WFRs to anti-IgE (liter 1:10000) with a maximal effect of ?60% (wheal) and ??75% (flare) by both drugs. On a molar basis, salmctcrol was approximately 10–100 times more potent than terbutaline in inhibiting the WFRs. Moreover, the wheal response to histamine (4 nmol) was antagonized by ?40% after prctrcatment with either salmeterol (10^-5 M) or terbutaline (10^-4 M). We found that both salmeterol and terbutaline exhibited anti-WFR activity for up to 24 h, salmeterol being significantly more potent in this regard. When selecting a 15-min pretreatment interval with equieffective anti-WFR doses from the first dose-response experiments (i.e., a salmetcrol: terbutaline ratio of 1:10), the WFRs to high-dose anti-IgE (titer 1:100) were inhibited by terbutaline (10^-5 M) by 25–30%, but not by salmeterol (10^-4). On the other hand. salmeterol attenuated (by up to ?35%) the subsequent LCR more effectively than terbutaline. As compared to the prctrcatment procedure, infiltration of the drugs (single doses) into the wheals 30 min after challenge with anti-IgE (titer 1:100) proved to be less effective on the development of LCRs. Taken together, salmeterol was found to express higher potency and have longer duration of action than terbutaline in inhibition of IgE-mediated inflammation in human skin.     

On the mechanism of histamine-induced bronchodilation in conscious guinea-pigs

The bronchodilatory effect of histamine was evaluated in a conscious guinea-pig model of cholinergically mediated bronchoconstriction. The H₁, bronchoconstrictor, property of histamine was masked using high doses of the H₁-antagonist chlorpheniramine (30 mg/kg), and the bronchodilatory activity evaluated by observing the increase in latency to collapse induced by aerosol methacholine. Under these conditions, histamine (1.0, 3.0 or 10.0 mg/kg, i.p.) delayed methacholine-induced collapse in a dose-dependent manner. Cimetidine, an H₂-receptor antagonist (10 to 100 mg/kg), did not delay collapse either in the presence or absence of an H₁-antagonist. However, when cimetidine was administered prior to histamine, the bronchodilatory activity of histamine was abolished. A similar abolition of histamine bronchodilation was observed if propranolol, abeta-adrenoceptor antagonist, was administered prior to histamine. Propranolol alone had no effect on methacholine-induced bronchospasm. These data suggest that the major bronchodilatory property of histamine may be mediated indirectly via catecholamine release through an H₂-receptor mechanism.     

Safety of a proteoliposome from Neisseria meningitides as adjuvant for a house dust mite allergy vaccine

The proteoliposome (PL) of Neisseria meningitidis serogroup B has been reported as a safe and potent vaccine adjuvant, inducing a T_H1-skewed response. The present study describes a pre-clinical safety evaluation of an allergy therapeutic vaccine candidate based on purified allergens from Dermatophagoides siboney house dust mite and PL as adjuvant, both components adsorbed onto aluminum hydroxide gel. Two separate studies of acute toxicity evaluation were performed in mice and rabbits, and two repeat-dose studies were conducted in non-sensitized and allergen-sensitized Balb/c mice, respectively. The study in sensitized mice intends to model a therapeutic setting. Aerosolized allergen challenge was used in both settings to model natural respiratory exposure. In the therapeutic setting, mice were administered with three doses containing 2?μg allergen at weekly intervals [subcutaneous route] and subsequently challenged with aerosolized allergen for 6 consecutive days. Parameters of general toxicity effects were assessed via measures of behavior, body weight, food and water consumption, and macroscopic evaluation of organs. Histological examination of organs and the injection site was performed. Potential immunotoxicity effects at the systemic level were assessed by blood eosinophil counting and serum allergen specific IgE by ELISA The vaccine did not produce general or functional toxic effects of significance, at a dose up to 100?μg allergen per kg body weight. An expected local reaction at the injection site was observed, which could be attributed mostly to the immunological effect of aluminum hydroxide. The models implemented here suggest an acceptable safety profile of this vaccine for testing in clinical trials of allergy immunotherapy.     

Effects of Acetylsalicylate on Alkalinization,Acid Secretion and Electrogenic Properties in the Isolated Gastric Mucosa

The effects of acetylsalicylate (ASA) on the in vitro secretory and electrical properties of Necturus and Rana temporaria gastric mucosa have been studied. The gastric antrum alkalinized the luminal surface, while in the fundus it is likely that acidification and alkalinization occur simultaneously and that net secretion is due to the dominance of one or other of these processes. The histamine H₂ receptor antagonist Metiamide was used to inhibit acid secretion for studies on fundic alkalinization in Rana temporaria. Submucosal application of 3 mM ASA for 30 min markedly reduced alkalinization in the antrum and the frog fundus. Following removal of ASA there was only partial recovery of this secretion. The drug caused slight inhibition of spontaneous acid secretion in Necturus fundus but not of histamine-stimulated acid secretion in the frog fundus. Following salicylate removal, the rate of acid secretion increased to a higher level than before administration in both tissues. There was a small flux of ASA across the mucosa which was greatest in the acid secreting frog fundus (4.38μmol cm^-2 min^-1) and least in the antrum (2.19μmol cm^-2 min^-1). Exposure of the gastric mucosa to ASA was generally associated with a fall in transmucosal electric potential difference and short-circuit current together with an increase in electrical resistance. It is proposed that the greater sensitivity of alkalinization to ASA is responsible for the apparent increase in the rate of acid secretion which occurred.     

Lipolytic responses induced by intracerebroventricular administration of histamine in the rat

Histamine (10–50 g) administered intraventricularly in conscious rats induced an increase in serum-free fatty acids. The maximum, significant increase appeared 30–60 min after administration. Histamine H₁-receptor antagonists, mepyramine and chloropyramine, when injected 2 h prior to histamine, abolished considerably hyperlipaemic responses to histamine. H₂-Receptor antagonists, metiamide and cimetidine, given i.c.v. only moderately diminished the histamine-induced hyperlipaemia. Histamine injected i.c.v. also increased serum corticosterone levels considerably. This elevation was prevented significantly by the H₁-receptor antagonist, mepyramine, but not by the H₂-receptor blocker, cimetidine. It seems likely that histamine given i.c.v. induces lipolysis through the release of ACTH, one of the known lipid-mobilizing hormones. The central lipid-mobilizing mechanism after histamine depends more on activation of H₁- than H₂-receptors.     

Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury

Fatty liver has been linked to low aerobic fitness, but the mechanisms are unknown. We previously reported a novel model in which rats were artificially selected to be high capacity runners (HCR) and low capacity runners (LCR) that in a sedentary condition have robustly different intrinsic aerobic capacities. We utilized sedentary HCR/LCR rats (generation 17; max running distance equalled 1514 ± 91 vs. 200 ± 12 m for HCR and LCR, respectively) to investigate if low aerobic capacity is associated with reduced hepatic mitochondrial oxidative capacity and increased susceptibility to hepatic steatosis. At 25 weeks of age, LCR livers displayed reduced mitochondrial content (reduced citrate synthase activity and cytochrome c protein) and reduced oxidative capacity (complete palmitate oxidation in hepatic mitochondria (1.15 ± 0.13 vs. 2.48 ± 1.1 n m g⁻¹ h, P < 0.0001) and increased peroxisomal activity (acyl CoA oxidase and catalase activity) compared to the HCR. The LCR livers also displayed a lipogenic phenotype with higher protein content of both sterol regulatory element binding protein-1c and acetyl CoA carboxylase. These differences were associated with hepatic steatosis in the LCR including higher liver triglycerides (6.00 ± 0.71 vs. 4.20 ± 0.39 nmol g⁻¹, P = 0.020 value), >2-fold higher percentage of hepatocytes associated with lipid droplets (54.0 ± 9.2 vs. 22.0 ± 3.5%, P = 0.006), and increased hepatic lipid peroxidation compared to the HCR. Additionally, in rats aged to natural death, LCR livers had significantly greater hepatic injury (fibrosis and apoptosis). We provide novel evidence that selection for low intrinsic aerobic capacity causes reduced hepatic mitochondrial oxidative capacity that increases susceptibility to both hepatic steatosis and liver injury.     

Acid blockade by omeprazole or ICI 162846 in a chronic duodenal ulcer model

Oral treatment with the H₂-antagonist ICI 162,846 or omeprazole for five days inhibited both basal and pentagastrin stimulated acid secretion by 50% or more in mice. Either treatment increased the luminal secretion of histamine in the basal (12-fold) and stimulated (9-fold) states. Mice treated with the H₂-antagonist had a 27% reduction (p<0.05) in mural histamine in the acid-producing area of the stomach. Mice were treated so as to induce duodenal ulcers (abscopal model) and were then treated with the H₂-antagonist ICI 162,846, omeprazole or vehicle, orally for one week. Fewer duodenal ulcers were found in animals receiving drug treatments than in the oral vehicle group. Both the H₂-receptor antagonist and the proton pump blocker inhibit acid production; acid blockade by either drug is accompanied by a massive increase in secretion of histamine. This rise was associated with depletion of the gastric histamine store only with H₂-receptor blocker. Both means of acid inhibition reduced the formation of ulcers in this model.