Kazuhisa Gondo

The endothelin-1 binding site in rat liver tissue: Light- and electron-microscopic autoradiographic studies

BACKGROUND Endothelin (ET) is known as a vasoconstrictive substance. The receptors for ET have been shown in various organs. However, little is known about the endothelin-1 (ET-1) binding sites in the liver. The aim of this study was to examine ET-1 binding sites in the liver. METHODS ET-1 binding sites in rat liver were studied in vivo by light- and electron-microscopic autoradiography using 125I-ET-1. RESULTS Light-microscopic autoradiographic observation revealed strong localization of grains in the sinusoidal lining cells of the hepatic lobule and a small number of grains in the luminal space of the portal vein and central vein. In the hepatic lobule, more grains were located in the periportal region, and the quantity tended to decrease from the midzonal to the pericentral region. Electron-microscopic autoradiographic observation revealed grains in Ito cells and in the endothelial cells of the portal vein, central vein, and hepatic sinusoids. CONCLUSIONS These results suggest that ET-1 acts on Ito cells and on endothelial cells of the hepatic sinusoids, portal vein, and central vein and that its action is related to hemodynamics of the liver, particularly regulation of the microcirculation of the hepatic sinusoids.

High prevalence of anticardiolipin antibodies in hepatitis C virus infection: lack of effects on thrombocytopenia and thrombotic complications

Abstract: Hepatitis C virus (HCV) causes various extrahepatic immunologic abnormalities. Recently, an association between HCV infection and antiphospholipid syndrome, including thrombocytopenia, has been reported. However, the precise relationship between thrombocytopenia and anticardiolipin antibodies in patients with chronic HCV infection is not fully understood; likewise, the association of antiphospholipid syndrome and various liver diseases is not well understood. To evaluate the prevalence and importance of antiphospholipid antibodies in various chronic liver diseases, we determined the levels of anticardiolipin antibodies, platelet numbers, and levels of platelet-associated immunoglobulin G (PA-IgG) and thrombin-antithrombin III complex (TAT) in patients with chronic HCV infection, chronic hepatitis B virus (HBV) infection, and primary biliary cirrhosis (PBC). The prevalence of anticardiolipin antibodies in patients with HCV infection was significantly higher than that in control subjects or individuals with the other liver diseases examined. However, there was no significant correlation between anticardiolipin antibodies and platelet counts or TAT. The frequency of thrombotic complications was similar in anticardiolipin antibody-positive and -negative patients with chronic HCV infection. Further, sera from all but one anticardiolipin antibody-positive HCV patient were negative for phospholipid-dependent anti-β2 glycoprotein I antibodies. Our results suggest that anticardiolipin antibodies are frequently found in patients with chronic HCV infection, but they do not appear to be of clinical importance. Immunologic disturbances induced by HCV or prolonged tissue damage in systemic organs as a result of the extrahepatic manifestations of HCV infection may induce the production of antibodies to various cardiolipin-binding proteins or phospholipids.

Radiographic Evidence of Cholecystokinin Octapeptide Receptors in the Hamster Gallbladder

The distribution of Cholecystokinin receptors in the hamster gallbladder was investigated by 125I-labeled Bolton-Hunter-cholecystokinin octapeptide autoradiography. Light microscopic examination showed a marked accumulation of radiolabeled Cholecystokinin within the domain of the muscle layer of the gallbladder. The electron microscopic study further disclosed the presence of radiolabeling mostly in those areas corresponding to cell-to-cell junctions of smooth-muscle cells. Our results suggest that contraction of the gallbladder may primarily be induced by cholecystokinin interacting with its specific receptor in smooth-muscle cells. That Cholecystokinin receptors were more abundant in the junctional complexes of smooth-muscle cells suggests that Cholecystokinin may have a major role in muscle contraction of the gallbladder, which eventually produces an effective bile emptying.

Interferon accumulation in cirrhotic rat liver

SUMMARY. In patients with chronic hepatitis C, the therapeutic effect of interferon (IFN) is influenced by the progression of liver disease. In a previous study, we showed that 2′,5′‐oligoadenylate synthetase activity in the liver homogenate was significantly lower in cirrhotic rats than in controls after injection of murine IFN. To determine the reason for this decrease, we injected IFN into rats with thioacetamide‐induced cirrhosis and used microautoradiography with human lymphoblastoid interferon ([125I]LyIFN). Accumulation of [125I]LyIFN in cirrhotic rat livers was approximately half of that in control rats (2880±900 vs 5770±600mm2, P<0.01). In the cirrhotic rat livers there were few grains on the hepatocytes, but many on collagen fibres. These results suggest that binding of IFN to its hepatocyte receptors is hindered in the presence of cirrhosis. The decreased amount of IFN reaching hepatocytes may contribute to the poor responses to IFN seen in patients with cirrhosis.

Postmarketing Surveillance of Rabeprazole in Upper Gastrointestinal Peptic Lesions in Japanese Patients with Coexisting Hepatic Disorders

BACKGROUND Many Japanese patients with hepatic disorders confirmed on diagnostic imaging and coexisting upper gastrointestinal (GI) peptic lesions receive treatment with proton pump inhibitors. Some pharmacotherapies used to treat peptic ulcers have been associated with adverse drug reactions (ADRs), including elevated liver enzyme levels. OBJECTIVE The aim of this study was to determine the tolerability and effectiveness of rabeprazole sodium in treating peptic lesions in patients with coexisting hepatic disorders. METHODS This open-label, practice-based, postmarketing surveillance investigation was conducted at 15 centers across Japan. Male and female patients aged ≥18 years with peptic lesions confirmed on upper GI endoscopy and with underlying hepatic disease were enrolled. Patients were randomly assigned to receive rabeprazole 10 or 20 mg PO (tablet) QD after a meal for up to 8 weeks. Tolerability was assessed using monitoring of the incidence of ADRs determined by direct patient questioning, spontaneous reporting, and laboratory assessment. All patients who received at least 1 dose of study drug were included in the tolerability assessment. Effectiveness was assessed at baseline and study end using the rates of achievement of improvement on endoscopy, relief of subjective/objective symptoms (rates of improvement in epigastric pain and heartburn), and global improvement. The effectiveness analysis included all patients with complete data before and after treatment. Subanalyses were conducted to determine the effectiveness of drug by identification of the proportion of patients with coexisting hepatic disorders (cirrhosis, chronic hepatitis, and other hepatic diseases [eg, alcoholic hepatitis, fatty liver]) and by peptic lesion (gastric ulcer, duodenal ulcer, stomal ulcer, and reflux esophagitis) who achieved improvement. RESULTS A total of 114 patients were enrolled; 108 patients were included in the tolerability analysis (81 men, 27 women; mean age, 59.9 years; 10-mg dose, 90 patients; 20-mg dose, 18 patients) and 98 patients were included in the analysis of effectiveness. Twenty-one ADRs occurred in 11 (10.2%) patients. Serious ADRs occurred in 2 patients (elevated bilirubin level and hepatic encephalopathy, 1 patient each). Administration of rabeprazole was discontinued in 5 patients due to the occurrence of the following ADRs: constipation (1 patient); epigastric pain (1); dyslalia, disorientation, tremor, sleep disorder, and hepatic encephalopathy (1); diarrhea (1); and elevated alkaline phosphatase and y-glutamyl transpeptidase levels (1). On endoscopy, the proportion of patients achieving improvement with either dose was 30/33 (90.9%). The relief rates assessed using subjective symptoms were 47/55 (85.5%) and 47/56 (83.9%) for epigastric pain and heartburn, respectively. The proportion of patients achieving global improvement with either dose was 80/98 (81.6%) patients (49/62 [79.0%] for cirrhosis, 11/16 [68.8%] for chronic hepatitis, and 20/20 [100.0%] for other hepatic diseases [alcoholic hepatitis, fatty liver]). CONCLUSION In this study in Japanese patients with hepatic disorders, rabeprazole was well tolerated and appeared effective for the treatment of upper GI peptic lesions.

Hepatic Innervation and Hepatic Sinusoidal Cells

The innervation of the human liver is distributed throughout the hepatic lobules from the portal spaces to the centralobular spaces. Nerve endings in the intralobular spaces are localized mainly in the Disse spaces, and are closely related to hepatic stellate cells (HSCs). Various neurotransmitters such as substance P exist in these nerve endings. Substance P induces contraction in HSCs. In addition, HSCs possess endothelin (ET) receptors, and contract in response to ET-1 treatment. Moreover, α-smooth muscle actin (α-SMA) is localized in the cytoplasm of HSCs. α-SMA is closely related to the contractility of smooth muscle cells. Nitric oxide (NO) inhibits the contraction of HSCs. HSCs thus appear to be involved in the regulation of hepatic sinusoidal microcirculation by contraction and relaxation. In the human cirrhotic liver, intralobular innervation is decreased or absent, but ET, ET receptors, and NO are overexpressed in the HSCs. These phenomena indicate that HSCs in the human cirrhotic liver may play an important role in the sinusoidal microcirculation through agents such as ET or NO rather than through intralobular innervation.