Yoshikazu Hinohara

Feeding suppression induced by intra-ventricle III infusion of 1,5-anhydroglucitol

1,5-Anhydroglucitol (1-DG) has been known as an antimetabolic glucose analogue. Using gas chromatography, 1-DG was found to be physiologically present in rat serum. In order to investigate its direct and long-term effects on feeding, 1-DG was infused during the light period into the rat third ventricle in doses of 3.0, 6.0 and 12.0 mumol/rat. Its effects were then compared to those of similarly applied 2-deoxy-D-glucose (2-DG). Following initial hyperphagia, both of these glucose-analogues produced suppressive effects on feeding during the subsequent day throughout the light and dark periods. On the third day after 2-DG injection reduction of feeding did not recover completely to the pretreatment baseline levels, but it did recover after 1-DG. Both 1-DG and 2-DG caused linear dose-related hypophagia, with the slope for 1-DG being about half of that for 2-DG. It is suggested that the delayed hypophagia which followed the initial hyperphagia produced by deoxyglucose was a result of sustained inactivation of the Na-pump due to intracellular ATP deficiency caused by accumulation of deoxy-glucose-6-phosphate.

Hypotensive effects and biotransformation of nicorandil, a new antianginal agent, administered to rats by different routes: comparison with nitroglycerin and isosorbide dinitrate.

The effects of nicorandil, N‐(2‐hydroxyethyl)nicotinamide nitrate (ester), in reducing systemic blood pressure (SBP) in rats were studied in comparison with isosorbide dinitrate and nitroglycerin. The drugs were administered to pentobarbitone‐anaesthetized rats by jugular vein (i.v.), portal vein (p.v.), intrajejunal (i.j.), intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Nicorandil was absorbed rapidly through all routes, and caused marked hypotension dose‐dependently. With isosorbide dinitrate and nitroglycerin, unlike nicorandil, the p.v. dose required to induce a vasodepressor response was significantly greater than that required to cause a comparable response after i.v. administration. In non‐recirculating rat liver perfusion experiments, nicorandil was reduced only 5–10% during a single passage through the liver, while nitroglycerin was reduced over 95%. In recirculating liver perfusion experiments, the progressive decrease of nicorandil in the blood recirculated was accompanied by a corresponding increase of SG‐86, a denitrate compound of nicorandil (its main metabolite). Sixty min after dosing, nicorandil was decreased by approximately 73% of the initial nicorandil blood concentration and SG‐86 was increased by approximately 70%. The extent of degradation of nicorandil in liver homogenates, examined by thin‐layer chromatography, was in the following order: rat = guinea‐pig > dog = monkey > pig. In these species a close inverse relationship is apparent between the rate of liver nicorandil degradation and hypotensive effects of nicorandil.

Effects of AN-132 and quinidine, antiarrhythmic agents, on plasma digoxin concentrations in rats

Abstract— The effects of AN‐132, 3‐(diisopropylaminoethylamino)‐2′,6′‐dimethylpropionanilide.2H3PO4, on chloroform‐induced arrhythmias and plasma digoxin concentrations have been compared with those of quinidine in rats. AN‐132 (0.01–3 mg kg−1) administered orally significantly inhibited the incidence of cardiac arrhythmias in a dose‐related fashion. A single dose of digoxin (1 mg kg−1) given orally for 7 consecutive days was followed, on day 8, orally by digoxin alone, or together with AN‐132 (50, 100 and 200 mg kg−1) or quinidine (25 and 50 mg kg−1). The AUC0‐24 and Cmax of plasma digoxin were enhanced significantly by co‐administration of quinidine, but not by AN‐132.

Cell-specific hypomethylation of the pepsinogen gene in pepsinogen-producing cells

The pepsinogen gene is hypomethylated in the stomach, in which it is expressed. For demonstration that this hypomethylation of the pepsinogen gene in the stomach reflects pepsinogen-producing cells, we analyzed fractions of dispersed mucosal cells with various contents of pepsinogen-producing cells prepared from guinea pig stomach by centrifugal elutriation. mRNA expression and the extent of hypomethylation of the pepsinogen gene in each fraction was closely correlated with the content of pepsinogen-producing cells. These results suggested hypomethylation of the pepsinogen gene in pepsinogen-producing cells and differential pepsinogen gene methylation in cell subpopulations in the stomach.

Effects of nicorandil and verapamil, antianginal agents, on plasma digoxin concentrations in rats and dogs

The effects of equihypotensive doses of nicorandil and verapamil on plasma digoxin concentrations have been assessed in rats and dogs. In a single digoxin dose study, digoxin (1 mg kg−1) alone, or in combination with nicorandil (5 mg kg−1) or verapamil (25 mg kg−1) was given orally to rats. When given chronically to rats, a single dose of digoxin (1 mg kg−1) orally for 7 consecutive days was followed, on day 8, by digoxin alone, or together with nicorandil (5 mg kg−1) or verapamil (25 mg kg−1). In dogs, a loading dose of digoxin (50 μg kg−1) was given orally on day 1, then 25 μg kg−1 was administered for the following 6 days. On day 8, digoxin (50 μg kg−1) was given with nicorandil (5 mg kg−1) or verapamil (20 mg kg−1). In rats, the AUC0–24 and Cmax of plasma digoxin were enhanced significantly by coadministration of verapamil, but not by nicorandil. In dogs, verapamil significantly increased the Cmax of plasma digoxin, but not the AUC. Nicorandil had no effect on either parameter.