The effects of seven lectins with various sugar-specificities on histamine release from rat peritoneal mast cells induced by non-immunologic stimuli were studied. The non-immunologic stimuli used were three basic secretagogues, compound 48/80, bradykinin and PEI₆ (polyethylenimine with a molecular weight of 600). In this study, we observed inhibition of the histamine release by Macckia amurensis mitogen and Solanum tuberosum agglutinin (100 μg/ml at 371C for 10 min), which are specific for sialic acid-α2, 3-N-acetyl galactosamine (Siaα2, 3Ga1NAc) and N-acetyl glucosamine (G1cNAc) oligomers, respectively. The effects of Phytolacca americana mitogen and Sambucus sieboldiana agglutinin were different. Three lectins specific for mucin type oligosaccharides inhibited the histamine release induced by compound 48/80 but not that induced by bradykinin or PEI₆. Since bradykinin and PEI₆ additively enhanced the histamine release induced by compound 48/80, they partially shared the same signalling pathways. Glycoproteins with bisecting GlcNAc and Sia residues, as described previously (Jpn. J. Pharmacol. 57, 79-90, 1991), seemed to be one of the action sites for compound 48/80, bradykinin and PEI₆. In addition to the direct activation of the pertussis toxin-sensitive G proteins, we propose another mechanism of non-immunologic stimuli via specific glycoproteins on rat peritoneal mast cells. The apparent sugar residues involved were asparagine-linked oligosaccharides with Sia (especially Siaα2, 3Gal), GlcNAc oligomers and/or bisecting GlcNAc.

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We investigated the possible renal protective effects of KW-3902 (8-(noradamantan-3-yl)-1, 3-dipropylxanthine), a selective and potent adenosine A₁-receptor antagonist, against cephaloridine (CER)-induced acute renal failure (ARF) in rats. ARF was induced by intravenous injection of CER at a dose of 600 mg/kg body weight. KW-3902 at doses higher than 0.01 mg/kg (p.o.) dose-dependently attenuated the decrease of creatinine clearance and the increase of proteinuria in rats with CER-induced ARF. In contrast, furosemide and trichlormethiazide (TCM) increased urinary protein and aggravated the serum parameters. These results suggest that KW-3902 has some advantages over furosemide and TCM when used in combination with CER. In the diuretic study in the rats with established ARF induced by CER, KW-3902, furosemide and TCM caused a significant increase in sodium excretion, whereas acetazolamide was ineffective. These results suggest that the proximal tubule is functionally damaged in rats with CER-induced ARF, in accord with the histological observation demonstrating the degeneration of the proximal tubule. From the fact that KW-3902 induces diuretic action even in CER-induced ARF, it is suggested that KW-3902 acts, directly or indirectly, on the proximal tubule or other tubular sites in the kidney, resulting in the diuretic effect.

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Pharmacological characteristics of the canine isolated splenic artery were investigated by the cannula insertion method for observing vascular responses to vasoactive agents and periarterial nerve stimulation. Four α-adrenoceptor agonists and tyramine induced vasoconstrictions in a dose-dependent manner, and the order of potency was noradrenaline (NA) > phenylephrine > clonidine > methoxamine > tyramine. Xylazine (a selective α₂-adrenoceptor agonist) did not elicit any vasoconstriction. Several autacoids and KCl also constricted the splenic artery dose-dependently, and the order of potency was 5-hydroxytryptamine (5-HT) > ATP = histamine >> KCI. The dose-response curves for clonidine and NA were shifted to the right by bunazosin (a selective α1-adrenoceptor antagonist), but were not affected by midaglizole (a selective α₂-adrenoceptor antagonist). The parameters of electrical stimulation to elicit a clear and constant vasoconstriction were 0.2 msec of pulse duration, 6 V and 0.1 Hz. The vasoconstrictive responses to electrical stimulation at 6-12 V, 0.1-10 Hz and 0.2-1 msec of pulse duration were completely inhibited by tetrodotoxin (TTX) and strongly inhibited by guanethidine. The results in this study suggest that: 1) in contrast with other regional arteries, the canine splenic artery has an α₁-adrenoceptor-related and clonidine-sensitive vasoconstrictive response, 2) this artery has no functional postsynaptic α₂-adrenoceptors, 3) it may be easier to observe the vascular responses to vasoactive agents in the isolated and perfused arterial segments, and 4) the isolated and perfused canine splenic artery is useful as a preparation to study the sympathetic nerve transmission.

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Effects of short-term pretreatment with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) on the survival of neurons transplanted into the third ventricle in rats were studied. Septa from 16-day-old rat embryos were pretreated with growth factor containing medium for 30 min and transplanted into the third ventricle of adult rats. Twenty-one days after the operation, the recipient rats were perfused with 4% paraformaldehyde. Paraffin sections of the removed brains were made, and the sections were stained with cresylviolet. The number of neurons in the grafts was counted under a light microscope. Although pretreatment with NGF was not effective, bFGF at the concentration of 1 and 10 αg/ml enhanced the survival of transplanted septal neurons. These results suggest that short-term pretreatment with bFGF could increase the efficiency of neuronal transplantation.

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Since the nucleus accumbens has been hypothesized to centrally mediate the discriminative effects of psychomotor stimulants, the discriminative effects of methamphetamine (MA) as well as dopamine (DA) and noradrenaline (NA) were observed by intracerebral administration of these drugs into the nucleus accumbens in rats discriminating subcutaneous MA from saline. These rats were trained and main tained to discriminate between MA at 0.5 mg/kg, s.c. and saline under a fixed ratio 10 schedule for food reinforcement in a 2-lever operant chamber situation. Guide cannulae were implanted bilaterally into the nucleus accumbens. In the substitution tests, the drug was administered into the nucleus accumbens. MA at 10 μg per rat substituted for subcutaneous MA in 4 out of 5 rats but neither DA at 10-40 μg per rat (n=7) nor NA at 10-40 μg per rat (n=4) substituted for subcutaneous MA. On the other hand, the same drugs administered into the nucleus accumbens induced increased spontaneous motor activity as also observed in six other untrained rats. MA, DA or NA alone each at 10 μg per rat increased spontaneous motor activity. The discriminative effects of MA are considered to be mediated in the nucleus accumbens of rats. Although DA or NA alone administered into the nucleus accumbens showed similar increasing motor activity effects as those of MA, the discriminative effects of exogenous DA or NA alone administered into the same brain area were different from those of MA in the present experimental condition.

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The effects of KB-5492, a new anti-ulcer agent with selective affinity for the sigma receptor, on ethanol- and acidified aspirin-induced gastric mucosal damage were studied in vivo and in vitro and compared with those of 16, 16-dimethyl prostaglandin E₂ (dmPGE₂). In the in vivo study, KB-5492 (200 mg/kg, p.o.) as well as dmPGE₂ (0.01 mg/kg, p.o.) significantly prevented the acute macroscopic lesions in rat gastric mucosa induced by oral administration of either absolute ethanol or 80 mM aspirin in 150 mM HCl. The light microscopic examination revealed that KB-5492 almost completely prevented the deep mucosal lesions induced by these necrotizing agents. KB-5492 also prevented the exfoliation of surface epithelial cells, but its preventive effect was incomplete. In the in vitro study, gastric epithelial cells, isolated from the rat stomach, were cultured for 6 days until they reached confluency. Subsequently, ⁵¹Cr was incorporated into the cells. Both 10 mM aspirin (at pH 5.0) and 12.5% ethanol (at pH 7.4) induced damage to the cells and markedly increased ⁵¹Cr release from the cells. KB-5492 at 0.3 and 1 mM and dmPGE₂ at 0.3 and 1 μM significantly, but not completely, prevented both the aspirin- and ethanol-induced increases in ⁵¹Cr release from the cells. These findings indicate that KB-5492 as well as dmPGE₂ may exert a direct but limited protective effect on the surface epithelial cells in vivo.

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The effect of KB-5492, a new anti-ulcer agent with a selective affinity for the sigma-receptor, on aspirin-induced disruption of the gastric mucosal barrier was studied in rats. Intragastric instillation of aspirin at 200 mg/kg rapidly decreased the gastric transmucosal potential difference (PD) in anesthetized rats. The PD recovered gradually following the removal of aspirin from the instillation solution. Aspirin, administered orally at 200 mg/kg, also reduced the amount of gastric covering mucus and induced a decrease in gastric H⁺ concentration and an increase in gastric Na⁺ concentration in pylorus-ligated rats. KB-5492, administered intraduodenally at 200 mg/kg, significantly prevented the aspirin-induced decrease in PD and accelerated the recovery of PD. In addition, KB-5492 at 200 mg/kg significantly prevented the reduction of gastric covering mucus, the decrease in gastric H⁺ concentration and the increase in gastric Na⁺ concentration induced by aspirin. These effects were similar to those of 0.01 mg/kg of 16, 16-dimethyl prostaglandin E₂ (dmPGE₂). Teprenone at 200 mg/kg did not show any effect except for the inhibitory effects on the changes in gastric H⁺ and Na⁺ concentration. In the histological study, marked reduction of PAS-positive epithelial mucus and the exfoliation of surface epithelial cells were observed in the gastric mucosa exposed to aspirin. KB-5492 and dmPGE₂ almost completely prevented the former, whereas both drugs prevented the latter incompletely. These findings indicate that KB-5492 protects the gastric mucosal barrier against the disruption by aspirin, which may be mainly exerted by retention of the gastric covering mucus.

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Symptoms similar to the central anticholinergic syndrome are often seen after high dose fentanyl anesthesia. Therefore, the binding of fentanyl, alfentanil, pethidine and morphine to opioid and muscarinic receptors was investigated in rat brain homogenate with [³H]naloxone and [³H]QNB as the radioligands, respectively. Both pethidine and fentanyl inhibited [³H]QNB binding with K_i values in the micromolar range. Alfentanil and morphine had no affinity for muscarinic receptors. The ratio of the K_i values for muscarinic receptors versus opioid receptors was 2.5 for pethidine and 88 for fentanyl. It is concluded that binding of fentanyl to muscarinic receptors is likely to occur during high-dose fentanyl anesthesia.

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Pocket probing depth was correlated with the amount of salivary sialic acid in pilocarpine stimulated saliva in ODU plaque-susceptible rats (ODUS/Odu) (r=0.657, P<0.01), but not with the content of serum sialic acid. There was no difference in the amount of serum sialic acid content between ODUS/Odu and plaque-resistant rats. These results suggest that the amount of sialic acid in the saliva can be a useful index of the severity of periodontal disease.

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