The physiology and pharmacology of the cough reflex were reviewed from the perspective that the cough response and its peripheral mechanisms have diversity, taking reported findings together with the results obtained from our own studies. It is clear that there was a remarkable difference in the magnitude of expiration and sound in coughing between the two types of coughs in guinea pigs: one is caused by mechanical irritation to the airway mucosa or citric acid inhalation and the other caused by inhalation of pharmacological agents such as capsaicin and substance P. Four types of stimulation, i.e., mechanical, physicochemical, chemical and pharmacological stimulation, were discussed with respect to the site and the mechanisms of action in the airway. Mechanical stimulants and chemical stimulants such as citric acid seem to act mainly on Aδ -fibers. However, it is unclear whether pharmacological agents act on C-fibers to produce cough. As to the difference in distribution of cough receptors in the airway, pharmacological differences were found between coughs caused by mechanical irritation on the laryngeal sites and the site of bifurcation of the trachea. Furthermore, capsaicin, applied by a topical spraying method newly developed by us, produced cough-like forced expiration when it was sprayed around the site of the bifurcation of the trachea. This response was not depressed by codeine, but depressed by ophiopogonin, a Chinese herbal antitussive; mephenesine; and a neurokinin A antagonist. Mechanisms of cough augmentation in bronchitic guinea pigs were also described briefly. In conclusion, the site of action of cough stimulants and the mechanisms of cough production are still controversial. To solve these problems, we need to develop new methods and strategies for studying the cough reflex.

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Follicle-enclosed Xenopus oocytes have endogenous glibenclamide-sensitive K⁺ channels that can be activated by K⁺ channel openers. Since the follicle-enclosed Xenopus oocytes can be easily voltage-clamped, the K⁺ channels are used as a model of the ATP/glibenclamide-sensitive K⁺ channels. So far, the effects of calmodulin antagonists, antiarrhythmics, anesthetics, antidepressants, histamine H₁-receptor antagonists, imidazolines and several hormones on the K⁺ channels of the oocytes have been reported. The pharmacological data on the K⁺ channels obtained from the oocyte-system may contribute to our understanding of the regulatory mechanism and physiological role of the ATP/glibenclamide-sensitive K⁺ channels.

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We investigated the effect of Onpi-to (TJ-8117) on the mesangial injury induced by anti-Thy-1 antibody. TJ-8117 (400 mg/kg/day, p.o.) given from the 1st day (from the day of injection of the anti-thymocyte serum) or 4th day (after mesangial proliferation), markedly inhibited the mesangial proliferation and hypercellularity in glomeruli. TJ-8117 prevented the increase in the number of PCNA or ED-1 positive cells in glomeruli. These results suggest that TJ-8117 is effective against glomerular disease with mesangial injury.

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Effect of LipoPGE₁ on liver injury caused by ischemia-reperfusion were compared with that of PGE₁-CD, cyclodextrin clathrated PGE₁, in rats. LipoPGE₁ (10μg/kg) and PGE₁-CD (10μg/kg) were gradually injected into the portal vein 5 min both prior to ischemia and prior to reperfusion. In only the group receiving injections of vehicle alone, rats died within 2 days after the episode of 90-min liver ischemia. The survival rate of all rats treated with LipoPGE₁ was higher than that of rats who received vehicle alone, which indicates that LipoPGE₁ pretherapy improved the survival of rats after liver ischemia-reperfusion. LipoPGE₁ markedly suppressed elevations of GOT, GPT, and LDH, lipid peroxide and aromatic amino acid levels in the plasma caused by ischemiareperfusion of the liver. When animals were given a single dose of LipoPGE₁ prior to reperfusion, LipoPGE₁ also suppressed elevations of GOT, GPT, LDH and lipid peroxide levels caused by 30min of liver ischemia followed by 12-hr reperfusion. These suppressive effects with LipoPGE₁ were stronger than those of PGE₁-CD. These findings suggest that LipoPGE₁ may have therapeutic applications in the treatment of hepatic injury.

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A water-extract (TJ-97) prepared from “Dai-bofu-to”, a “Kampo” medicine (Chinese traditional prescriptions composed of herbal drugs) was tested for its potency to modulate morphine withdrawal responses in animals. TJ-97 significantly attenuated naloxone-induced contraction of the segments of the ileum isolated from morphine-dependent guinea pigs in the absence and presence of atropine. TJ-97 also inhibited the contractile responses of the segments to electrical field stimulation at a low frequency and those to nicotine, but not those to exogenously applied ACh or substance P. The rats given i.p. TJ-97 and 30 min later challenged with naloxone showed significantly lowered frequency of excretion and diminished amount of feces, including soft stools (diarrhea), as compared with the saline-injected control rats. These findings suggest that TJ-97 inhibits the release of ACh and substance P or substance P-like peptide(s) from the nervous structures in the wall of the ileum.

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Encephalopathy caused by hepatic cirrhosis is often associated with portasystemic shunt and hepatic parenchymal injury. Together, these are known as a combined-type symptom. Two experimental hepatic comatose models with combined-type symptom were developed in rats. Both of these models involve the administration of ammonium acetate (500 mg/kg) into the cecum in portacaval shunted (PCS) rats. In addition, hepatic injury was induced in one model by carbon tetrachloride (CCl₄) and in the other by dimethylnitrosamine (DMNA). These model rats showed a higher increase in the concentration of ammonia in the blood and a higher incidence of coma as determined by the loss of the righting reflex than did rats subjected to a shunt only (PCS operation + ammonia loading) or hepatic parenchymal injury only (CCl₄ treatment + ammonia loading). The effect of lactitol, administered orally for 7.5 days, on the experimental hepatic coma was compared with that of lactulose. Lactitol significantly inhibited the increase in blood and brain ammonia concentration at doses of 3 and 6 g/kg/day and also reduced the incidence of coma. The effects of lactitol were similar to those of lactulose, a therapeutic agent for hepatic encephalopathy. Therefore, lactitol should be useful in the clinical treatment of hyperammonemia or hepatic encephalopathy.

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Electroencephalographic (EEG) studies were conducted to demonstrate the ameliorating effects of lactitol and its reference drug lactulose on the disturbance of consciousness caused by severe hepatic encephalopathy in rats permanently implanted with cortical electrodes. A novel experimental animal model of combined-type human hepatic encephalopathy was prepared by portacaval shunting followed by a single treatment with dimethylnitrosamine (30 mg/kg, i.p.). Lactitol or lactulose was orally administered twice a day for seven days and once on the morning of the eighth day. Ammonium acetate (500 mg/kg) was injected into the cecum 4 hr after the final administration of the drug. In control animals not treated with either drug, but in which hepatic encephalopathy had been induced, ammonium acetate induced a comatose state defined by a loss of the righting reflex accompanied by slowing or flattening of the cortical EEG. In control animals, significant increases in delta (1-3 Hz)-activity and significant decreases in beta (1325 Hz)-activity during coma were detected by means of EEG power spectral analysis. Lactitol at doses of 3 g/kg/day or higher or lactulose at 6 g/kg/day significantly suppressed these EEG changes. Both drugs also suppressed in a dose-dependent manner the loss of the righting reflex. Lactitol may therefore be useful for ameliorating the disturbance of consciousness in patients with hepatic encephalopathy.

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