Hisataka Ishiguro

Relationship between endothelin and thromboxane A2 in rat liver microcirculation

In our previous study, we determined changes in hepatic blood flow using a Laser Doppler blood flow meter after i.v. injection of endothelin-1 (ET-1) or endothelin-3 (ET-3) at 2 nmol/kg in rats and found that ET-3 caused greater decreases in blood flow than ET-1. In the present study, we determined how the arachidonic acid cascade, mainly thromboxane A2 (TXA2), is related to ET-1 and ET-3 using indomethacin (INDO), which inhibits the biosynthesis of prostaglandin (PG), and OKY-046, a selective inhibitor of TXA2 synthesis. In the first series of experiments, ET-1 and ET-3 were administered after inhibiting the biosynthesis of PG by s.c. injection of 2 mg/kg of INDO. While INDO failed to inhibit the slight decrease in hepatic blood flow induced by ET-1, it significantly inhibited the marked decrease in hepatic blood flow elicited by ET-3. In the next series of experiments, ET-1 and ET-3 were administered after administration of 20 mg/kg of OKY-046. OKY-046 showed no effects in animals treated with ET-1, as in those pre-treated with INDO, while it significantly inhibited the decreases in hepatic blood flow induced by ET-3. These findings suggest that ET-1 decreases hepatic blood flow due to its direct effects although to a lesser extent than ET-3, while ET-3 does so due not only to its direct effects but also to TXA2-mediated effects. It is therefore likely that in addition to ET family peptides, PG-mediated mechanisms are involved in the regulation of hepatic microcirculation by ETs.

ET-3 sensitive reduction of tissue blood flow in rat liver.

Changes in gastric mucosal and hepatic tissue blood flow were simultaneously determined using a laser-Doppler blood flow meter in rats given i.v. injection of endothelin-1 (ET-1) and endothelin-3 (ET-3), both at 2 nmol/kg. Gastric mucosal blood flow decreased significantly after administration of ET-1 compared to after administration of ET-3. Decreases in blood flow due to ET-1 were reversed by pre-treatment with 10 mg/kg of BQ-123 (sodium salt), an ETA receptor antagonist, to levels comparable to those induced by ET-3, but BQ-123 had no effects on decreases in blood flow due to ET-3. On the other hand, decreases in hepatic tissue blood flow by ET-3 were significant compared to those by ET-1. Decreases in hepatic tissue blood flow due to ET-1 were slightly inhibited by pre-treatment with 10 mg/kg of BQ-123, but it had no effect at all on decreases due to ET-3. These findings indicate that decreases in gastric mucosal blood flow are mainly caused by ET-1 via ETA receptors inhibited by BQ-123, while decreases in hepatic tissue blood flow are caused mainly by ET-3 via non-ETA receptors not inhibited by BQ-123. The fact that ET-3 decreases blood flow more significantly than ET-1 suggests the involvement of ET-3 selective receptors (ETc). The findings obtained in the present study indicate that complex mechanisms are involved in the regulation of tissue blood flow by ET, with different receptor subtypes and ET family peptides being involved according to the type of tissue.

Increase in hepatic tissue blood flow by teprenone

Abstract  The major objective of the present study was to evaluate mechanisms by which teprenone, a gastric mucosal protecting agent, increases hepatic mucosal blood flow using male Sprague‐Dawley rats. Hepatic and gastric blood flow was measured using a laser blood flow meter after administration of teprenone, dissolved in Tween 80, into the inferior vena cava. Teprenone itself increased hepatic and gastric blood flow. It also increased hepatic and gastric blood flow in rats with acute hepatic disorders due to carbon tetrachloride (CCL4) and improved histological changes, such as inflammatory cell infiltration and fatty changes in the liver. The fact that blood endothelin (ET) concentrations increased after administration of teprenone suggest that teprenone has great affinity for ETB receptors and shows ETB ‐receptor antagonist‐like effects. Hepatic blood flow decreased after administration of N‐nitro‐L‐arginine methyl ester, a nitric oxide (NO) synthetase inhibitor, suggesting that teprenone increases NO activity. Teprenone was thought to increase hepatic and gastric blood flow by different mechanisms, because it increased gastric mucosal prostaglandin E2 concentrations.

Effects of a gastric mucosal protecting agent in rats with liver cirrhosis

Male Sprague–Dawley rats were fed a 0.1% ethionine‐added choline‐deficient diet for 8 weeks to induce liver cirrhosis. At the same time 100 mg/kg/day teprenone was administered orally in order to evaluate its effects on the liver and gastric mucosal blood flow. Blood flow increased not only in gastric mucosa but also in liver tissues in the teprenone group. Serum transaminase levels and histopathologic findings of the liver also improved. These findings suggest that teprenone alleviates hepatocellular injuries. This effect may be partly attributable to cytoprotective effects of the catenoid isoprenoid moiety of teprenone on liver cells.

Effects of eicosapentaenoic acid on blood rheology in rats with fatty liver

Abstract A blood rheology study was conducted using Kikuchis microchannel method in male Sprague Dawley rats with fatty liver induced by choline deficiency. Effects of eicosapentaenoic acid (EPA) on blood rheology were also evaluated. Male Sprague Dawley rats given normal feed served as the control. One group was given choline-deficient feed for 4 weeks (EPA (−) group), while another was given EPA (1000 mg/kg) once daily for 4 weeks together with choline-deficient feed (EPA (+) group). The microchannel passage time was determined using 100 mL of whole blood during observation under a microscope with a video camera. The passage time increased significantly in the EPA (−) group compared with the control group, while it was significantly shorter in the EPA (+) group compared with the EPA (−) group. Changes in platelet aggregation and leukocyte adhesion were less in the EPA (+) group than in the EPA (−) or the control groups. EPA supplementation appeared to correct blood flow changes induced by choline deficiency in rats.