Effects of IGN-2098, a new histamine H2-receptor antagonist, on gastric secretion and gastric and duodenal lesions induced in rats. Comparison with roxatidine]

A new compound, IGN-2098 [5,6-dimethyl-2-[4-<3-(1-piperidinomethyl) phenoxy>cis-butenylamino]-4-(1H)-pyrimidone.2HCl], was found to be a potential histamine H2-receptor antagonist in the guinea pig atrium. IGN-2098, given p.o., significantly and persistently (for more than 12 hr) inhibited the basal gastric secretion in pylorus-ligated rats. The agent also significantly inhibited the basal gastric secretion when given by the s.c.-, i.d.- or i.p.-route. Stimulated gastric secretion in fistula rats in response to histamine, carbachol or pentagastrin was also significantly inhibited with IGN-2098 given s.c. Pretreatment with IGN-2098 (p.o.) significantly protected the gastric mucosa against pylorus ligation-, water-immersion stress-, histamine-, indomethacin-, HCl.aspirin-, and HCl.ethanol-induced gastric lesions. In addition, the agent significantly protected the duodenal mucosa against mepirizole-induced ulcers. Based upon the ED50 values, the antisecretory effects on histamine, carbachol or pentagastrin-stimulated acid secretion were 6.0, 37.0 or 80 times more potent than roxatidine, respectively. As to the anti-lesion effects on HCl.aspirin-induced gastric lesions or mepirizole-induced duodenal ulcers, IGN-2098 was 8.1 or 14.8 times more potent than roxatidine, respectively. These results suggest that IGN-2098 will be a useful drug for the treatment of gastric and duodenal lesions in man.     

Effects of IT-066, a new histamine H2-receptor antagonist, on gastric acid secretion and experimental gastric ulcers in rats and dogs

We examined the effects of a new histamine H2-receptor antagonist, 3-amino-4-(4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino)-3- cyclobutene-1,2-dione hydrochloride (IT-066), on gastric acid secretion and the healing process of experimental ulcers in rats and dogs. Famotidine, a well-established H2-receptor antagonist, was used as the reference drug. Male Donryu rats (240-260 g) and Beagle dogs of both sexes (8-10 kg), having Heidenhain pouches, were used. IT-066 dose-dependently inhibited the basal gastric acid secretion of rats, and this inhibition significantly persisted for 12 hr. In addition, the agent significantly inhibited histamine-stimulated acid secretion in both normal rats and rats with acetic acid ulcers. IT-066, given p.o. twice daily for 2 and 3 weeks after ulceration, significantly accelerated both spontaneous and delayed healing (with indomethacin) of acetic acid-induced gastric ulcers in rats. The effects of IT-066 on acid secretion and ulcer healing were almost the same or slightly more potent than those observed with famotidine. IT-066, when given i.v. or p.o., dose-dependently inhibited the gastric acid secretion stimulated by histamine, pentagastrin, or carbachol in dogs. The antisecretory effects of the agent on histamine-stimulated acid secretion significantly persisted for more than 6 hr. These results indicate that IT-066 appears to be a promising antisecretory and anti-ulcer agent.     

Effects of 5-acetylspiro[benzofuran-2(3H),1'-cyclopropan]-3-one, a new anti-ulcer agent, on experimental acute and chronic ulcers

The effects of 5-acetylspiro[benzofuran-2(3H),1'-cyclopropan]-3-one (AG 629), a newly synthesized compound, on various experimentally induced ulcers were investigated. Oral or intraduodenal administration of AG 629 in a dose range of 25-100 mg/kg inhibited water-immersion stress ulcer, exertion ulcer, Shay ulcer, indometacin- and acetylsalicylic acid (ASA)-induced gastric ulcer, and indomethacin-induced small intestinal ulcer in rats, histamine-induced gastric ulcer in guinea pigs, and ASA-induced gastric ulcer in dogs, though it was not effective against cysteamine-induced duodenal ulcer in rats. AG 629 in doses of 6.3-25 mg/kg p.o. twice a day significantly promoted the healing of acetic acid- or thermal-cortisone-induced gastric ulcers and acetic acid-induced duodenal ulcers in rats. AG 629 (25-100 mg/kg i.d.) inhibited the secretion of gastric acid and pepsin in pylorus-ligated rats and the acid secretion stimulated by distension of the rat stomach with air, whereas this compound did not affect acid secretion stimulated by histamine, pentagastrin, carbachol or 2-deoxy-D-glucose. This study shows that AG 629 has both prophylactic and curative effects on various ulcers. The anti-ulcer effect of this agent seems to be mediated primarily by increasing mucosal resistance and secondarily by an antisecretory activity.     

Analysis of the actions of cimetidine and metiamide on gastric acid secretion in the isolated guinea pig gastric mucosa

Summary Cumulative dose-response curves for histamine were determined on acid secretion from the isolated guinea pig gastric mucosa. Two H₂-receptor antagonists—metiamide and cimetidine—behaved like competitive antagonists to histamine on gastric acid secretion in vitro. The isolated guinea pig gastric mucosa seems to be a suitable in vitro model for analysing the action of compounds on receptors involved in acid secretion.     

Studies on anti-ulcer effects of a new compound, zinc L-carnosine (Z-103)

We investigated the anti-ulcer effects of zinc L-carnosine (Z-103) using several acute experimental models of gastric and duodenal lesions in rats. Effects of Z-103 on various gastric functions, e.g., antacid (in vitro), anti-pepsin (in vitro), gastric secretion, mucosal potential difference (PD) and mucus contents were also examined. Z-103 given orally prevented development of gastric lesions induced by water immersion stress, histamine, HCl-aspirin, HCl-ethanol and also duodenal ulcers induced by mepirizole in a dose-dependent manner. In vitro, Z-103 had a greater antacid effect than sodium bicarbonate; and moreover, the potency of its anti-peptic action (IC50 = 8.7 mM) was higher than those of several other drugs (sodium bicarbonate, sucrose sulfate and aceglutamide aluminum). Intragastric treatment of Z-103 (100 mg/kg alone tended to increase PD, and it also significantly inhibited the decrease in PD induced by aspirin. In addition, pretreatment with Z-103 at 10 and 30 mg/kg (p.o.) significantly prevented the decrease in mucus contents in the gastric mucosa and also mucosal lesions by oral administration of ethanol. On the other hand, Z-103 was not so effective on both basal (pylorus-ligation preparation) and histamine-stimulated gastric secretion (Heidenhain pouch preparation). These results suggest that Z-103 is useful for the treatment of gastric and duodenal ulcers in humans.     

Antiulcer effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl] carbamoyl]methyl]-amino-N-methylbenzamide in experimental gastric and duodenal ulcers

Effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl] methyl]-amino-N-methylbenzamide (DQ-2511), a newly synthesized compound, were evaluated using various types of experimental gastric and duodenal ulcers in rats. Pretreatment with DQ-2511, over the dose range 30-300 mg/kg p.o., resulted in a dose-related inhibition of water-immersion stress-, serotonin-, acetylsalicylic acid (ASA)-, indometacin-, ethanol-, and 2-deoxy-D-glucose(2DG) plus indometacin-induced gastric ulcers as well as cysteamine-induced duodenal ulcers. The antiulcer potencies of DQ-2511 were equal to or greater than those of H2-receptor antagonist cimetidine in these ulcer models except for ASA- and 2DG plus indometacin-induced ulcers. The rate of healing of chronic gastric ulcers induced by acetic acid was significantly accelerated by DQ-2511 (100 and 300 mg/kg p.o.) but not by the same doses of cimetidine. DQ-2511, at doses of 30 mg/kg p.o. and above, produced a significant decrease in gastric acid and pepsin output in pylorus-ligated rats. In anesthetized rats with acute gastric fistulae, 30 mg/kg i.v. of DQ-2511 significantly inhibited gastric acid secretion stimulated by 2DG, whereas it did not affect gastric hyperacidity evoked by either carbachol, histamine or pentagastrin. At effective antiulcer doses, this compound produced a sustained increase in gastric mucosal blood flow in conscious, restrained rats. Based on these observations, DQ-2511 is characterized as a new antiulcer compound with beneficial effects on both gastric aggressive and defensive factors. Furthermore, these results indicate a possible superiority of DQ2511 over cimetidine in regard to its antiulcer potency and spectrum.     

Effect of ketotifen on acute gastric lesions and gastric secretion in rats.

Ketotifen, a histamine H1-receptor antagonist and mast cell stabilizer, significantly protected the rat gastric mucosa against lesions induced by necrotizing agents, histamine or compound 48/80. The agent significantly inhibited the basal gastric acid secretion, but had little or no effect on the histamine-stimulated secretion. The mucosal protective effect was observed even at a dose that had little or no effect on gastric acid secretion, suggesting that ketotifen exhibits so-called cytoprotective activity.     

Inhibitory activity of 2-benzimidazolylurea on gastric acid secretion in rats

2-Benzimidazolylurea (BIU) decreases gastric acid secretion. The antisecretive activity appears to be associated with antihistaminic and antimuscarinic effects. The antihistaminic activity of BIU appears from its inhibitory effects on betazole stimulated gastric acid secretion and from its inhibitory activity on the isolated guinea pig auricle stimulated by betazole. The antimuscarinic activity of BIU appears from several experiments: this molecule decreases gastric acid secretion stimulated by carbachol in rats, depresses the neostigmine-stimulated motility of duodenum in the anaesthetized cat, lessens the hypertonus of isolated guinea pig trachea caused by pilocarpine and also inhibits guinea pig ileum activity stimulated by acetylcholine. BIU probably depresses gastric acid secretion by interfering with both histamine and acetylcholine receptors.     

Effects of N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)-acetoxyacetamide hydrochloride (TZU-0460), a histamine H2-receptor antagonist, on gastric acid secretion and ulcer formation

N-(3-[3-(1-Piperidinylmethyl)phenoxy]propyl)-acetoxyacetamide++ + hydrochloride (TZU-0460) was compared with cimetidine for the effects on gastric acid secretion in dog and rat and on ulcer formation in rat. TZU-0460 as well as cimetidine, given i.v. or p.o., produced a dose-dependent inhibition of acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain gastric pouch dogs and gastric lumen-perfused rats. In dog, the relative potencies of TZU-0460 to cimetidine, given p.o. and i.v., were 6.2 and 5.1, respectively, in acid secretion stimulated by histamine, and those gained by i.v. route were 3.5 by pentagastrin and 4.2 by carbachol. In rat, however, relative potencies of TZU-0460 to cimetidine, given i.v., were 2.8, 2.2 and 1.6 in acid secretion stimulated by histamine, pentagastrin and carbachol, respectively. TZU-0460, given p.o., prevented the formation of gastric ulcers induced by exposure to stress, pylorus-ligation, both pylorus-ligation and acetylsalicyclic acid, indometacin or reserpine in rats. TZU-0460 was about twice as active as cimetidine on these experimental models of gastric ulcers. TZU-0460, given p.o., prevented the formation of duodenal ulcer induced by cysteamine in rats, whereas cimetidine failed to prevent it significantly.     

Effects of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride on acute gastric lesions, acid secretion in rats and on some hemodynamic parameters in cats

The effectiveness of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (AN12) on acute ulcer models and gastric acid secretion in rats was compared with the action of the histamine H2-receptor antagonist roxatidine (R). AN12 or R given orally, produced significant, dose-dependent decreases in stress- and indomethacin-induced ulcers. The ED50 value of AN12 and R were 0.40 (0.27-0.60) and 13.27 (9.13-19.29) mg/kg, respectively, for stress ulcers and 0.68 (0.17-2.61) and 25 mg/kg, respectively, for indomethacin ulcers. The length and number of ethanol-provoked gastric damages were significantly reduced by R (50 and 100 mg/kg p.o.) but not by AN12 (0.5-2 mg/kg p.o.). In pylorus-ligated rats, AN12 (2 mg/kg p.o.) and R (50 and 100 mg/kg p.o.) significantly inhibited basal gastric acid secretion, increased pH and decreased acidity. The influence of AN12 (2 mg/kg) on the volume of stomach juice was close to that of R (100 mg/kg), AN12 (0.1-1.0 mg/kg i.v.) did not significantly affect the hemodynamics of anesthesized cats. It is suggested that the influence of some CNS amine neurotransmitters may be included in part, in the effects of AN12.     

Stimulation 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 vitro

Summary There are experimental data indicating that cyclic AMP is involved in the regulation of gastric acid secretion in various mammalian species. In a broken cell preparation of guinea pig gastric mucosa the effects of some stimulants of gastric acid secretion on the activity of adenylate cyclase were studied. The basal adenylate cyclase activity was 483±43 pmoles cyclic AMP/mg proteinx10 min. The activity could be stimulated by histamine maximally 5-fold, by sodium fluoride (NaF) maximally 20-fold and by 5-guanylylimidodiphosphate (GMP-PNP) maximally 10-fold. Neither pentagastrin nor carbachol were able to stimulate the adenylate cyclase. Stimulants of adrenergic - or -receptors (phenylephrine, isoproterenol) were also ineffective.The activation of the adenylate cyclase by histamine was inhibited by the histamine H₁-receptor antagonists diphenhydramine and mepyramine as well as by the histamine H₂-receptor antagonist metiamide. On the other hand, the stimulatory action of NaF or GMP-PNP could be antagonized only by high concentrations of dipenhydramine or mepyramine while metiamide showed no antagonizing effect in this respect. Thus this preparation can be used as a tool to determine the activity and specificity of histamine H₂-receptor antagonists.     

Cholinergic-mediated gastric mast cell degranulation with subsequent histamine H1-and H2-receptor activation in stress ulceration in rats.

The effects of atropine, mepyramine, metiamide or NaHCO3 on gastric ulceration, gastric secretion and gastric mast cell degranulation were studied in stressed pylorus-occluded rats. The influence of dexamethasone pretreatment on stress ulcers in animals without pylorus occlusion (intact rats) was also examined. Stress produced a high glandular lesion incidence and ulcer index, and markedly lowered gastric secretion and glandular wall mast cell counts. Injected 0.5 h before stress, atropine, mepyramine or metiamide strongly antagonised ulceration. Atropine or metiamide, but not mepyramine, reduced gastric secretion. Only atropine prevented stress-induced mast cell changes. NaHCO3, given intragastrically before stress, did not prevent ulceration or mast cell degranulation despite complete neutralisation of gastric acid. Dexamethasone-induced gastric mucosal mast cell depletion could reduce stress ulceration. The findings show that stress degranulates stomach mast cells via a cholinergic pathway; released histamine from this source is largely responsbile for gastric ulceration through H1- and H2-receptor effects. Histamine H2-receptor-mediated gastric acid may play only a small contributory role in stress ulcers in rats. The antiulcer mechanisms of histamine H1- and H2-receptor blockade are discussed.     

Role of endogenous serotonin and histamine in the pathogenesis of gastric mucosal lesions in unanaesthetised rats with a single treatment of compound 48/80, a mast cell degranulator.

In unanaethetised rats with a single injection of compound 48/80, a mast cell degranulator (0.75 mg kg-1, i.p.), gastric lesions occurred with increased serum serotonin and histamine levels and reduced gastric mucosal blood flow at 0.5 h after the injection and developed at 3 h. Pretreatment with either cyproheptadine (a serotonin and histamine antagonist) or methysergide (a serotonin antagonist) prevented the formation of gastric mucosal lesions with attenuation of reduced gastric mucosal blood flow at 0.5 h after compound 48/80 injection, while pretreatment with either amitriptyline (a selective inhibitor of histamine release from mast cells), tripelennamine (a histamine H1-receptor antagonist), famotidine (a histamine H2-receptor antagonist) or cimetidine (a histamine H2-receptor antagonist) had no effect. Pretreatment with either cyproheptadine, methysergide, amitriptyline or tripelennamine prevented the development of gastric mucosal lesions at 3 h after compound 48/80 injection, while pretreatment with either famotidine or cimetidine had no effect. These results indicate that in unanaesthetised rats with a single compound 48/80 treatment, acutely released endogenous serotonin causes gastric mucosal lesions, while released endogenous histamine mainly contributes to the lesion development and that gastric acid plays little role in the pathogenesis of the compound 48/80-induced acute gastric lesions.     

法莫替丁、雷尼替丁、西米替丁的药理作用比较

Fam非竞争性地拮抗组胺对豚鼠心房和大鼠于官的作用.而Ran和Cim呈竞争性地拮抗作用。它们的pA_z值分别是6.24和8.26.5.16和7.22.4.08和6.17。Fam、Ran、Cim均呈剂量依赖性的减少大鼠基础胃酸和胃蛋白酶分泌,抑制组胺刺激性胃酸分泌.预防应激及消炎痛和组胺引起的急性胃粘膜损伤.促进醋酸所致的慢性胃溃疡的愈合.F am的作用强度为Ran的6～8 倍.Cim的30～40倍.此外Cim能明显增加戊巴比妥的催眠作用,Fam的作用弱于Cim·而Ran没有作用。     

Anti-ulcer and secretion-inhibitory properties of the tricyclic derivative doxepin in rats and dogs

The anti-ulcer and antisecretory properties of 3-(dibenz[b,e] oxepin - 11(6H)-ylidene)-N,N- dimethylpropylamine hydrochloride (doxepin) were investigated in a series of acute experiments in rats with gastric and duodenal ulcer. Acute gastric ulceration induced by immobilisation and stress (waterbath), and by non-steroidal anti-inflammatory agents, was reduced by doxepin to the same extent as by pirenzepine and cimetidine. Doxepin and cimetidine showed a weak but significant effect against serotonin-induced ulcers in the rat, but pirenzepine did not. Duodenal ulcer caused by increased acid production (pentagastrin plus carbachol induced) was suppressed by pirenzepine, doxepin and cimetidine. The inhibition of gastric secretion by doxepin was studied in anaesthetised rats and conscious dogs. In the Lai rat, doxepin decreased carbachol-induced secretion of hydrochloric acid more effectively than cimetidine. Doxepin was as ineffective as pirenzepine against histamine- or pentagastrin-induced secretion. In the dog with gastric fistula, doxepin inhibited the acid production induced by 2-desoxy-d-glucose more effectively, and for longer periods, than that induced by pentagastrin or histamine. In the dog with a Heidenhain pouch, doxepin reduced the acid secretion stimulated by pentagastrin and carbachol, and by histamine, less effectively and for a shorter time, than cimetidine. The antagonism of doxepin to the action of carbachol in the rat and that of 2-desoxy-d-glucose in the dog appears to be an important factor in its mode of action. To inhibit the secretion of saliva and to delay intestinal transport, a dose of doxepin 3-10 times greater than that required for anti-ulcerative and secretion-inhibitory effects was necessary.     

Effects of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion and gastroduodenal ulcers in rats.

We studied the effects of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion and gastroduodenal lesions in rats in comparison with those of omeprazole. TU-199 inhibited hog gastric H+, K(+)-ATPase activity and its potency was almost equal to that of omeprazole (IC50 = 6.2 and 4.2 microM, respectively). In vivo, TU-199 inhibited basal gastric acid secretion in pylorus-ligated rats in a dose-dependent manner (ED50 = 4.2 mg/kg p.o.). In gastric fistula rats. TU-199 (2.5 and 5 mg/kg i.d.) also inhibited gastric acid secretion stimulated by histamine, carbachol or tetragastrin. Furthermore, TU-199 prevented the formation of water-immersion restraint stress-, pylorus ligation- and indomethacin-induced gastric lesions, and mepirizole-induced duodenal ulcer in rats. These antisecretory and antiulcer effects of TU-199 were 2-4 times more potent than those of omeprazole. The results demonstrate that TU-199 potently inhibits the acid secretion and formation of ulcers in various experimental rat models via an inhibition of H+, K(+)-ATPase. These findings suggest that TU-199 may have a beneficial effect against peptic ulcer disease in humans.     

Studies on the H2-receptor antagonism of MK-208 in isolated rabbit gastric glands

Using isolated rabbit gastric glands, the H2-receptor antagonist MK-208 was investigated with respect to its effects on [14C]aminopyrine uptake as an index of gastric acid secretion. In addition to shifting the histamine concentration-response curve to the right in a parallel fashion, the antagonism produced by MK-208 was reversible, contrary to that previously seen in the guinea pig atria. These observations suggest that the H2-receptors responsible for mediating gastric secretion in the rabbit and the chronotropic response in guinea pig atria are different.     

Roxatidine acetate. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic potential in peptic ulcer disease and related disorders.

Roxatidine acetate is a histamine H2-receptor antagonist which, after almost complete oral absorption (greater than 95%), is rapidly converted to its active metabolite, roxatidine, by esterases in the small intestine, plasma and liver. Roxatidine is a potent inhibitor of basal and stimulated gastric acid secretion in animals and humans and, like most other H2-receptor antagonists, has no anti-androgenic effects and does not interfere with the hepatic metabolism of other drugs. Large-scale trials have shown that roxatidine acetate 150mg per day is as effective as standard doses of cimetidine and ranitidine in the treatment of patients with duodenal or gastric ulcer, and that roxatidine acetate 75mg in the evening is likely to become a 'standard' regimen for the prevention of peptic ulcer recurrence. Preliminary data also suggest that roxatidine acetate may be useful in the treatment of reflux oesophagitis and stomal ulcer, and in the prevention of pulmonary acid aspiration. Roxatidine acetate is an H2-receptor antagonist which has been well tolerated in clinical trials. However, broader experience is required before definitive statements about tolerability relative to other H2-receptor antagonists can be made, and before the role of roxatidine acetate in the treatment of reflux oesophagitis and stomal ulcer, and the prophylaxis of acid aspiration pneumonitis, can be clearly defined.     

Pharmacological studies with the alpha 2-adrenoceptor antagonist midaglizole. Part III: Smooth muscle, gastrointestinal and miscellaneous systems.

Pharmacological properties of midaglizole (DG-5128, CAS 66529-17-7) on smooth muscle, gastrointestinal and miscellaneous systems were investigated in comparison with those of tolbutamide. 1. Isolated smooth muscle: Midaglizole inhibited the contractile responses of the ileum to nicotine, acetylcholine, serotonin and BaCl2, and especially the response to histamine (guinea pig). Tolbutamide also reduced the contractions. On spontaneous motility of the uterus (estrus, diestrus, pregnant), midaglizole produced an increase in tonus and frequency, and decrease in contractile amplitude (rat). Tolbutamide reduced the motility of the uterus. The contractile response of the vas deferens to norepinephrine was potentiated after midaglizole and tolbutamide (guinea pig). Midaglizole inhibited the contractile response of the trachea to histamine, whereas it had little or no effect on the response to acetylcholine (guinea pig). Tolbutamide reduced the responses to both spasmogens. 2. Gastrointestinal system: Midaglizole induced an increase in gastrointestinal transit (mouse) and potentiated the gastrointestinal motility (dog). Tolbutamide was without any effect on these parameters. Gastric emptying rate, gastric secretion and gastric mucosa were not influenced after midaglizole (rat). Tolbutamide decreased gastric secretion and produced injury of gastric mucosa. 3. Urine volume: Midaglizole and tolbutamide showed a diuretic activity (rat). 4. Anti-inflammatory activity: Midaglizole and tolbutamide inhibited carrageenin-induced paw edema (rat).     

Antiulcerogenic mechanisms of dehydrocrotonin, a diterpene lactone obtained from Croton cajucara.

The bark of Croton cajucara Benth, is used in Brazilian folk medicine as an infusion to treat gastrointestinal disorders. The aim of the present study was to assess the mechanisms involved in the antiulcerogenic activity of dehydrocrotonin (DHC), a diterpene isolated from C. cajucara bark. We studied the effects of DHC on pylorus ligature (Shay) in mice treated with the drug (100 mg/kg) by the intraduodenal route. DHC did not induce any alteration in gastric volume in Shay mice but modified the pH and total acid concentration of gastric juice. Incubation of gastric juice with DHC did not reduce gastric acidity compared to control. We also investigated the effects of DHC on the response to histamine of right atria isolated from guinea pigs and on the response to carbachol of stomach fundus strips from rats. The concentration-response curves for the chronotropic effect of histamine in guinea pig right atria were shifted to the right, with a significant decrease in the maximum response, in the presence of DHC. Similar results were obtained with DHC (30 microM) for the concentration-response curves to carbachol in the isolated rat stomach. The ability of DHC to increase PGE2 release from rat stomach mucous cells was also studied. We observed that DHC induced a significant increase in PGE2 production (60% compared to control). In addition, the effects of DHC on the healing of acetic acid-induced gastric ulcer in rats were evaluated 14 days after acid injection. Oral administration of DHC (100 mg/kg per day) for 14 consecutive days had no effect on gastric ulcer healing in rats. Thus, the protective effect of DHC on induced gastric lesions could be due to synergistic effects, e.g., an increase in PGE2 release and non-competitive antagonism of H2-receptors and of muscarinic receptors. Whereas the former result represents an increase in the protective factors, the latter one shows a decrease in the aggressive factors against the gastric mucosa.