Youichi Hara

Effects of prostaglandins and cyclic AMP on cytokine production in rat leukocytes

Prostaglandins E1, prostaglandin E2, 3-oxa-methano-prostaglandin I1 (SM-10906), a stable prostaglandin I2 analog, and dibutyryl cyclic AMP suppressed the production of tumor necrosis factor and interleukin-1 in lipopolysaccharide-stimulated rat pleural resident monocytic cells, whereas they enhanced the production of interleukin-6 and cytokine-induced neutrophil chemoattractant (CINC), a rat interleukin-8-like chemokine, in these cells. SM-10906 also inhibited the in vivo production of tumor necrosis factor and interleukin-1 in pleural exudates, when injected into the rat pleural cavity concomitantly with carrageenin. The cyclic AMP (cAMP) level in the lipopolysaccharide-stimulated resident cells was increased when the cells were incubated in the presence of prostaglandin E1, prostaglandin E2 or SM-10906. Prostaglandin I2 showed only slight effects. The addition of pentoxifylline, a phosphodiesterase inhibitor, to the incubation mixture increased the cAMP level and also enhanced the effect of prostaglandins, indicating that these regulating actions of prostaglandins may be exerted partly through a mechanism involving an increased intracellular cAMP level.

Gastric hyperacidity and mucosal damage caused by hypothermia correlate with increase in GABA concentrations of the rat brain.

The involvement of brain GABA mechanisms in acid secretion and maintenance of gastric mucosal integrity was studied in the anesthetized rat. Cold exposure lowered the rectal temperature and stimulated acid output in the anesthetized rat. The acid response to cold exposure was completely suppressed by surgical vagotomy. The substantial increase in brain GABA content evoked by pretreatment with aminooxyacetic acid (10 and 20 mg/kg s.c. x 3) significantly potentiated the gastric acid response to the cold exposure stress; suppression of the GABA content induced by semicarbazide (100 mg/kg s.c.) reduced the acid response to cold. Significant correlations were found between the brain GABA contents and the acid secretory activity and also between the GABA contents and the ulcer index of gastric lesions induced by the cold stress. These results indicate that hypothermia evoked by cold exposure stimulates gastric acid secretion and induces gastric lesions through central GABA mechanisms in the rat.

Effect of topical application of a stable prostacyclin analogue, SM-10902 on wound healing in diabetic mice

The mechanism of wound healing induced by topical application of an ointment containing a new stable prostacyclin analogue, SM-10902 ((+)-methyl[2-[(2R,3aS,4R,5R, 6aS)-octahydro-5-hydroxy-4-[(E)-(3S,5S)-3-hydroxy-5-methyl-1- nonenyl]-2-pentalenyl] ethoxy] acetate), was investigated in the full-thickness wounds of genetically diabetic mice (db/db mice). The db/db mice treated with SM-10902 ointment (1, 10 and 100 micrograms/g) showed greater decrease in wound lesion area not covered with epidermis and fewer complete healing days than those treated with ointment base, and the effects of this prostacyclin analogue were greater than those of lysozyme chloride ointment (50 mg/g, Reflap ointment). SM-10902 ointment increased skin blood flow in the central site of the wound with development of wound healing. Histological evaluation of wounds revealed that SM-10902 ointment increased the capillary number during the early stage of the wound-healing process. These results suggest that SM-10902 ointment promotes wound healing through the stimulation of angiogenesis and the improvement of blood flow in neovascularization of repairing wound and may be useful in the treatment of skin ulcers caused by peripheral circulatory insufficiency.

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.

Acid secretagogue mechanisms of a GABA-mimetic (PCPGABA) in the anesthetized rat: Effects of hypothermia

The secretagogue action of lipophilic, GABA-mimetic, beta-(p-chlorophenyl)-gamma-aminobutyric acid (PCPGABA) was studied in the rat in relation to body temperature. PCPGABA (2 to 8 mg/kg s.c.) stimulated acid output in the urethane-anesthetized rat whose core temperature ranged between 28 to 30 degrees C. However, this stimulatory effect of PCPGABA totally disappeared in the same animal whose rectal temperature was maintained at the normal unanesthetized level (37-39 degrees C), whereas the acid secretory responses to histamine and bethanechol were not modified with the change in the thermoregulation. This suggests that the thermoregulation mechanisms are implicated in acid secretagogue action of centrally acting gastric stimulants.