Keijiro Takagi

Effects of cimetidine and atropine sulfate in gastric secretion and healing of gastric and duodenal ulcers in rats

Cimetidine, a new histamine H2-receptor antagonist (50 or 100 mg/kg) and atropine sulfate (15 mg/kg) given intraduodenally, markedly inhibited gastric secretion in pylorus-ligated rats. Cimetidine (100 or 200 mg/kg/day) given for 10 or 12 consecutive days orally in two divided doses, significantly promoted the healing rate of both gastric and duodenal ulcers induced in rats. Atropine (30 mg/kg/day) also significantly accelerated the healing of duodenal ulcers but failed to affect gastric ulcers.

A new model of stress ulcer in the rat with pylorus ligation and its pathogenesis.

Water-immersion stress for 7, 14, or 20 hr consistently induced linear or punctate stress ulcers (mucosal erosions) in the corpus of the stomach in intact rats. When the pylorus of the stomach had been ligated prior to stressing, the stress ulcers changed their morphological feature (mainly punctate and in one place elongated) and location (both in corpus and antrum). Histologically, the stress ulcer developed in the proximal antrum of pylorusligated rats and penetrated into the muscularis mucosa. Sodium bicarbonate, chlorpromazine, hexamethonium, atropine, metiamide, and bilateral vagotomy markedly inhibited the stress ulcers which developed in the pylorus-ligated rats. Phentolamine and propranolol hardly affected the development of stress ulcers. Amylopectine evoked a new type of stress ulcer in the corpus when it was given to the pylorus-ligated rats.

Relaxation of intestinal smooth muscle and calcium movements

The effects of papaverine, isoprenaline and N6,2′‐O‐dibutyryl 3′,5′‐cyclic adenosine monophosphate (DiBu.C‐AMP) on calcium movements in the taenia from the guinea‐pig caecum have been investigated and compared with the effects of phenylephrine. Papaverine and DiBu.C‐AMP antagonized the contraction of KCl‐depolarized muscle induced by CaCl2 and increased 45Ca‐efflux from the taenia. Papaverine also significantly depressed 45Ca‐uptake by this preparation. These findings suggest that papaverine impairs the availability of calcium to the contractile system and that there may be a correlation between relaxation and increase of 45Ca‐efflux. The action of DiBu.C‐AMP resembles that of papaverine but its potency is less.

Inhibitory effect ofl-glutamine on gastric irritation and back diffusion of gastric acid in response to aspirin in the rat

Abstractl-Glutamine given orally at 750 mg/kg significantly reduced the formation of gastric mucosal lesions induced by aspirin at 100 mg/kg at 1, 3, and 7 hours in pylorus-ligated rats.l-Glutamine markedly inhibited the loss of H+ and a corresponding increment of Na+ through the aspirin-damaged mucosal barrier, which suggests inhibition of acid back diffusion as the mechanism of action. In vagotomized rats, the diffusion of H+ from the instilled acid solution into the gastric mucosa and outflux of Na+ from the mucosa into the lumen was so strong that aspirin could not show any acceleration of a back diffusion of H+ in contrast to the aspirin-free group. However,l-Glutamine given with or without aspirin inhibited the back diffusion of H+ instilled into the vagotomized rat stomach.

Intracellular cyclic AMP level and intestinal smooth muscle relaxation

Abstract The intracellular level of cyclic AMP in the taenia from the guinea pig caecum was significantly increased by isoprenaline in a dose-dependent manner. Papaverine also increased the intracellular cyclic AMP level, but a synthetic antispasmodic agent, Aspaminol (1,1-diphenyl-3-piperidinobutanol hydrochloride) did not modify it. The results suggest that there are two mechanisms for the so-called papaverine-like actions. The increase in the intracellular cyclic AMP concentration produced by isoprenaline was prevented by propranolol. In taenia depolarized by KCl, papaverine caused relaxation but isoprenaline did not. This difference can be explained by the observation that the intracellular cyclic AMP level in the KCl-depolarized taenia is increased by papaverine but not by isoprenaline.

Studies of the mechanisms involved in the production of stress and stress-atropine ulcers in rats

Abstract The mechanism of the production of gastric ulcers induced in atropinized rats under stress was investigated and compared with that of stress-induced ulcers (S-ulcer). The etiology of the stress-atropine ulcer (A-ulcer) was found to be mainly due to the participation of adrenergic nerves since the ulceration was inhibited by ganglion blockers, adrenergic blockers, and reserpine, though vagotomy also inhibited the formation of A-ulcer. On the other hand, S-ulcer was inhibited by certain nervous system depressants, ganglion blockres, vagotomy and atropine; therefore, a certrally mediated cholinergic factor was suggested to be the main factor in the ulceration.

Mechanism of morphine block of electrical activity in ganglia of Auerbach's plexus

A study was made of the effect of morphine on electrical activity within single ganglia of Auerbachs plexus of guinea pig longitudinal muscle-myenteric plexus as monitored by means of external electrodes. Morphine produces a concentration dependent block of single spike activity. This effect is competitively antagonized by naloxone. The ED50 for morphine effect is about 7 X 10(-7) M. Naloxone and dextrorphan have no effect on electrical activity. Acetylcholine in the concentration range of 10(-7)--10(-5) M augments electrical activity of ganglia. Morphine has little if any effect on the enhanced stimulation produced by acetylcholine thus indicating that the drug does not act directly upon the ganglion. Our results suggest that a specific opiate receptor is present on the preganglionic nerve terminals and that morphine and other opiates block ganglionic transmission by inhibiting the release of preganglionic acetylcholine.

Photoaffinity labelling of the β-adrenergic receptors and receptor reserve for isoprenaline

Abstract The beta-adrenergic receptors in the taenia isolated from the guinea pig caecum were irreversibly inactivated by photoaffinity labeling with l-isoprenaline and 2-(2-hydroxy-3-isopropylaminopropoxy)iodobenzene. The photoinactivation was elimination in the presence of protectors of the receptors. Photoinactivation caused a considerable parallel shift in the concentration-action curve of l-isoprenaline. The results possibly point to a certain receptor reserve for l-isoprenaline.

COMPARISON OF THE EFFECTS OF VARIOUS STRESSES ON BIOGENIC AMINES IN THE CENTRAL NERVOUS SYSTEM AND ANIMAL SYMPTOMS

Publisher Summary Investigators have shown that physiological stress of various types are associated with changes of norepinephrine (NE), dopamine (DA), serotonin (5-HT), or acetylcholine (ACh) levels in the brain. The present study was performed to find out whether the levels of NE, DA, 5-HT and/or ACh in the brain were influenced equally by the different stressors, and how the deleterious effects on motor activity, motor coordination, exploratory movement, body temperature, body tone, and grip tone were produced after the exposure to the stressors. The correlation between the changes of animal symptoms and those of biogenic amine levels in the brain has been found. In the determination of brain NE, DA, and 5-HT, the mice were killed by decapitation after the exposure to stress. Two mouse brains were pooled for each determination. Brain amines were assayed.

Relationships between Ca2+ uptake by a microsomal fraction of guinea-pig taenia caecum and its relaxation

Abstract A microsomal fraction isolated from guinea-pig taenia caecum can accumulate calcium ions in the presence of ATP and MgCl 2 . This calcium-accumulating ability depends on the ATP concentration in the reaction mixture, and its pH optimum is near 7·8. Procaine and quinidine inhibit Ca 2+ accumulation by fraction and suppress the relaxation of this tissue induced by papaverine, isoprenaline and phenylephrine. These results suggest that Ca 2+ accumulation by the microsomal fraction isolated from guinea-pig taenia caecum plays an important role during the relaxation of this smooth muscle. Cyclic adenosine 3′,5′-monophosphate (cAMP) does not accelerate Ca 2+ accumulation by the microsomal fraction. The failure of cAMP to accelerate Ca 2+ uptake by this fraction implies that some unknown steps or factors may exist between the intracellular increment of cAMP and the following relaxation of taenia caecum .