he antiulcer effects of OPC-12759, a novel antiulcer agent were compared with those of cetraxate in various experimental ulcer models and on gastric secretion in rats. OPC-1 2759 (0.3-30 mg/kg, b.i.d., p.o.) significantly accelerated the healing rate of acetic acid-induced gastric ulcer in a dose-dependent manner, while cetraxate did not. When administered orally at 0.3-30 mg/kg, b.i.d., for 7 days, pretreatment with OPC-12759 (0.3-30 mg/kg, b.i.d., p.o.) prevented the formation of acute gastric ulcers, induced by: restraint water immersion stress, aspirin, indomethacin, histamine, serotonin, platelet activating factor (PAF) and DDC. Cetraxate showed antiulcer activity against a part of the OPC-12759-positive gastric ulcer models. Given intraperitoneally at the single dosing range of 10-100 mg/kg, OPC-12759 inhibited the formation of these acute gastric ulcer models. OPC-12759 administered orally at 0.3-30 mg/kg, b.i.d., for 7 days did not inhibit basal gastric secretion in pylorus ligated rats. The results indicated that OPC-1 2759 possesses wide spectrum antiulcer activity as compared with cetraxate.
The effects of nociceptive stimuli on the metabolism of brain histamine (HA) were examined, because of a previous observation that the exposure of mice to electric foot shock increased the brain HA turnover. In mice, the exposure to tail pinch markedly increased the brain level of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, while the level of HA was not changed. The HA turnover, measured either by the accumulation of t-MH after pargyline injection or by the HA depletion after the treatment with α-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, was enhanced by the exposure to tail pinch, like the enhancement produced by the exposure to foot shock. The exposure of rats to tail pinch increased the t-MH level in the telencephalon and the midbrain. Other types of noxious stimuli, such as placing mice on a hot plate or subjecting mice to acetic acid-induced writhing, also significantly elevated the level of t-MH but not that of HA in the mouse brain. These results suggest that nociceptive stimuli produce an increase in the brain HA turnover.
The effects of external concentration of [Ca2+] ([Ca2+]0) on the modulation by indomethacin (IND) or prostaglandin E2 (PGE2) of the evoked release of acetylcholine (ACh) were investigated in the myenteric plexus of guinea pig ileum. An increase in the [Ca2+]0 from 0.45 to 3.6 mM depressed both the spontaneous and the nicotine-induced release of ACh, while the releases of ACh induced by electrical-field stimulation (EFS) or by high K+ were augmented. IND and PGE2 did not modify the release of ACh induced by EFS and high K+, at any given [Ca2+]0 tested. The nicotine-induced release of ACh was significantly inhibited by IND with no relation to [Ca2+]0, and these inhibitory effects of IND were prevented by PGE2. At 0.45 mM [Ca2+]0, the extent of the recovery by PGE2 was less potent than those at other [Ca2+]0. IND inhibited the spontaneous release of ACh at lower [Ca2+]0, and such inhibition was not observed in the presence of PGE2. Thus, the modulatory actions of PGE2 on the spontaneous and the nicotine-induced release of ACh may depend partially on [Ca2+]0.
The changes in plasma level of alpha-atrial natriuretic polypeptide (alpha-ANP) and the relaxing responses to exogenous alpha-ANP of strips of rat aorta pretreated with methoxamine were examined at one, four and eight weeks after myocardial infarction induced by left coronary ligation. Responses to a beta-adrenergic stimulant, isoprenaline, and sodium nitroprusside of the vessel pretreated with high potassium were also evaluated up to twelve weeks. Plasma concentrations of immunoreactive alpha-ANP, which were measured at one, four and twelve weeks, were significantly elevated in rats with myocardial infarction (MI-rats) as compared with sham-operated rats (sham-rats). The relaxation responses of the aorta to exogenenous alpha-ANP in MI-rats were significantly reduced at one and four weeks as compared with sham-rats. The difference was, however, !ess obvious at eight weeks. The responses to isoprenaline tended to be reduced from the 1st week to the 12th week, and the difference was significant at eight weeks, whereas those to methoxamine and sodium nitroprusside were unchanged. It is concluded that the MI-rats are partially resistant to the vasodilating effects of alpha-ANP and isoprenaline without any change in responses to the alpha-stimulant and sodium nitroprusside, although these changes are transient.
The characteristics of cholecystokinin (CCK) receptors in rat pancreatic acini and in various regions of the brain were examined using synthetic CCK-8 or CCK-7 analogues. 3H-propionylated CCK-8 ([3H]CCK-8) was used as a ligand. 1) The pancreatic CCK receptor had a single high affinity binding component with a dissociation constant, Kd, of 0.76 nM and a maximum number of specific binding sites, BmaX, of 271.91 fmol/mg protein. On the other hand, the CCK receptor in the cerebral cortex had a Kd of 1.66 nM and a BmaX of 30.15 fmol/mg protein. 2) The order of the potencies of CCK-7 and CCK-8 analogues with a substitution at position 3 or 4 to displace [3H]CCK-8 specific binding to the pancreatic acini was as follows: CCK-8>CCK-7=SucCCK-7>Suc[Sar3]CCK-7>Suc[D-Trp3]CCK-7 >Suc[D-Ala3]CCK-7>[D-Trp4]CCK-8=[D-Ala4]CCK-8. This order of potencies of CCK analogues was greatly different from that in the cerebral cortex. 3) The carboxy-terminal tetra-peptide (CCK-4) and penta-peptide (CCK-5) had very weak potencies in displacing [3H]CCK-8 binding in the pancreatic acini, which were 20 to 30-fold less than their potencies in the cerebral cortex. These results suggest that the recognition sites for CCK analogues in the pancreatic and brain CCK receptors are different.
The actions of aminopyrine on rat gastric mucosal cyclooxygenase activity in vitro were investigated and compared with those of the cyclooxygenase inhibitors indomethacin and aspirin. Aminopyrine is a phenyl-pyrazolone derivative with potent analgesic and antipyretic properties, but is weakly ulcerogenic, while indomethacin and aspirin are known to cause considerable ulcerogenesis. Aminopyrine was less potent in its ability to inhibit cyclooxygenase activity. The inhibition by all three drugs decreased with an increase in the substrate concentration. Pre-incubation with the enzymes greatly increased the inhibitory action of indomethacin and aspirin, but only slightly increased that of aminopyrine. The inhibitory action of aminopyrine was reversible, whereas those of indomethacin and aspirin were irreversible. These findings are discussed in relation to the low incidence of gastrointestinal irritation caused by aminopyrine.
The actions of metaraminol on the secretion of fluid and glycoproteins from rat submandibular glands were investigated using phentolamine, propranolol and reserpine. Metaraminol at doses from 1 to 8 mg/kg (i.p.) increased the salivation and the amounts of protein in submandibular saliva in a dose-dependent manner. The salivation induced by metaraminol at 2 mg/kg was inhibited strongly by pretreatment with propranolol, whereas the salivation induced by metaraminol at 8 mg/ kg was inhibited strongly by phentolamine. Reserpine inhibited the secretion of fluid caused by both doses of metaraminol. The electrophoretic profiles of saliva evoked by metaraminol at 2 mg/kg revealed two main bands of glycoprotein, I and IV, which originated from the acinus, and the intensities of these bands were decreased by treatment with propranolol, whereas the major band in saliva induced by 8 mg/kg of metaraminol was glycoprotein III, which originated from the granular tubules. The intensity of band III was decreased by pretreatment with phentolamine. These results suggest that metaraminol, at small doses, stimulates mainly the β-adrenoceptor in the acinus, whereas at large doses, it prominently stimulates the α-adrenoceptors in the granular tubules, although metaraminol at small and large doses is able to stimulate α- and β-adrenoceptors in rat submandibular gland.
To induce crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis, male Sprague-Dawley rats were immunized with rabbit γ-globulin in Freund's complete adjuvant following i.v. injection of anti-GBM serum. At the same time, original type anti-GBM nephritis was induced in other rats by anti-GBM serum only. The animals with crescentic-type anti-GBM nephritis showed significantly higher platelet aggregabil.ity than that in rats with original-type anti-GBM nephritis at days 5, 10 and 40 after anti-GBM serum administration, respectively. To estimate the antinephritic effect of OKY-046, a thromboxane A synthetase inhibitor, it was given orally to rats at doses of 0.5, 2.5 or 20 mg/kg for 39 days after anti-GBM serum. OKY-046 (20 mg/kg) significantly inhibited the increase in both urinary protein and plasma cholesterol levels (40% and 35% vs. control, respectively). Moreover, when examined by light microscopy, this drug remarkably prevented histological involvement of the glomeruli. OKY-046 at 20 mg/kg had suppressed the hyperaggregability of platelets by 77% by day 40 as compared with the control, but doses of 0.5 and 2.5 mg/kg did not. It is concluded from these data that OKY-046 has beneficial effects on crescentic-type anti-GBM nephritis and may act through inhibition of not only platelet TxA2 but also glomerular TxA2 in its action to prevent histological alterations.
Prostaglandin (PG) H2 produced a transient contraction followed by a relaxation in helical strips of dog coronary, mesenteric and renal arteries contracted with PGF2α. The contraction was in the order of mesenteric>renal>coronary artery. Removal of endothelium abolished the contraction in these arteries and significantly potentiated the relaxation only in mesenteric arteries. The relaxation was greater in mesenteric arteries than in renal and coronary arteries, denuded of endothelium. PGI2-induced relaxations were not influenced by endothelium denudation. In the arteries contracted with K+, PGH2-induced relaxations were attenuated, compared to those contracted with PGF2α. Treatment with ON03708, an antagonist of vasoconstrictor PGs, abolished the PGH2-induced contraction and potentiated the relaxation in the K+-contracted arteries. The relaxant response was suppressed by diphloretin phosphate, a PG receptor antagonist, as was the response to PGI2. PGH2-induced contractions in dog coronary, mesenteric and renal arteries would be due to vasoconstrictor PGs produced preferentially in the endothelium. However, production of PGI2 from PGH2 in endothelial and subendothelial tissues do not appear to differ.
Urethane is a widely used anesthetic and yohimbine is a well-known α2-adrenergic antagonist. In fasted Wistar rats urethane at an anesthetic dose (1.25 g/kg, i.p.) caused an increase in plasma glucose, while pentobarbital at an anesthetic dose (40 mg/kg, i.p.) did not. Urethane caused no change in plasma glucose in adrenalectomized rats. The hyperglycemic effect of urethane was not inhibited by pretreatment with propranolol (1 mg/kg, p.o.) or prazosin (10 mg/kg, p.o.), but was reduced by pretreatment with phentolamine (10 mg/kg, p.o.) or yohimbine (10 mg/kg, p.o.). Urethane caused an elevation of plasma adrenaline, and yohimbine reduced the elevation. In addition, the pretreatment of yohimbine potentiated the urethane-induced increase in plasma insulin. These results indicate that yohimbine may inhibit the urethane-induced hyperglycemia that is mediated by the central and peripheral α2-adrenergic systems.
Effects of pyrazine derivatives on the day of the first opening of the vagina in juvenile female rats were studied. Tetraethyl and 2, 5-dimethyl pyrazine caused a significant delay in the first vaginal opening day of juvenile female rats, but no delay was noted in the case of 2, 5-diethyl or triethyl pyrazine. These results suggest that tetraethyl and 2, 5-dimethyl pyrazine cause delays in the onset of puberty in juvenile female rats.
In the HEPES-buffered physiological solution containing 20 mM bicarbonate ion, cocaine not only increased the sensitivity to norepinephrine but enhanced the maximal contractions to norepinephrine and methacholine in the rat vas deferens. Cocaine also potentiated the high potassium-induced contractions. In the solution without bicarbonate ion, such effects of cocaine were lost except for the sensitivity increase to norepinephrine. These results suggest that bicarbonate ion is crucial for the postjunctional stimulatory action of cocaine in the rat vas deferens.
The anti-inflammatory effects of phenolic dental medicaments were evaluated by mouse ear edema assay. p-Chlorophenol (PCP) inhibited edema when applied topically in dosages of 0.2 and 0.5 mg per site at 15 min before or 1.0 and 2.0 mg per site at 60 min after the application of croton oil. The inhibitory effects were also noted with eugenol, guaiacol, o-cresol, phenol and orally administered indomethacin (10 mg/kg). The involvement of the effects on prostaglandin biosynthesis in the anti-inflammatory effects of these compounds is discussed.
In guinea pig ileal muscle strips, trifluoperazine (TFP) inhibited the high K+-induced contraction with an IC50 of 1.9 μM and the Ca2+-induced contraction in skinned fiber with an IC50 of 44 μM. TFP decreased the high K+-induced increase in cytoplasmic Ca2+ level at the concentration 3 μM, which did not inhibit the contraction in skinned fiber. It is suggested that the inhibitory effect of TFP on the high K+-induced contraction is mainly due to the decrease in cytoplasmic Ca2+.
Using the cannula inserting method, effects of cooling (from 37°C to 27°C) on norepinephrine (NE)- and KCI-induced vasoconstrictions were investigated in isolated, perfused simian and canine femoral arteries and veins. KCI-induced constrictions were much greater in simian vessels than in canine vessels. NE-induced constrictions were similar in both arteries, but were greater in simian veins than in canine veins. In both arteries, NE- and KCI-induced vasoconstrictions were markedly depressed to almost the same degree by cooling. In both veins, the vasoconstrictions were not significantly affected by cooling.
Endothelin (ET), an endothelium-derived vasoconstrictor peptide, was injected into the jugular vein (i.v.) of guinea pigs anesthetized with urethane. Blood pressure was measured from a cannula inserted into the carotid artery. All experiments were carried out after treatment with adrenergic and cholinergic antagonists. ET showed a potent, dose-dependent pressor action in guinea pigs. However, the initial, transient depressor response which is observed in rats was not produced in guinea pigs. Nicardipine (0.1 mg/kg), a dihydropyridine Ca2+-channel blocker, significantly inhibited the ET-induced pressor response. These results suggest that ET causes a potent pressor response, which appears to be related to the activation of Ca2+ channels.