Hideo Honda

Calcium mobilization and phosphatidylinositol turnover in vas deferens smooth muscle of diabetic rats.

The study concerned Ca2+ channels that are receptor-operated by norepinephrine (NE) and mediate hyper-reactivity of vas deferens smooth muscle from rats with streptozotocin (STZ)-induced diabetes, and the mediatory responses of these channels, such as tension development, Ca2+ uptake and phosphatidylinositol (PI) turnover. The contractile responses induced by adrenoceptor agonists were significantly greater in diabetic rat vas deferens than in the controls. A greater Ca2+ uptake was induced by 10(-5) M NE in strips from diabetic rats than in the controls. The uptake of Ca2+ was completely inhibited by 10(-6) M prazosin but not by 10(-5) M verapamil. Enhancement of Ca2+ release by 10(-5) M NE was faster and greater in diabetic muscles than in the controls. The accumulation of [3H]inositol phosphates was increased 4-fold in the controls and 7-fold in diabetic muscles by 10(-5) M NE. This increase was completely inhibited by 10(-6) M prazosin but not by 10(-6) M yohimbine. The data suggest that vas deferens smooth muscle hyper-reactivity in diabetic rats is due to increased PI turnover mediated by alpha 1-adrenoceptors, to the release of intracellular bound Ca2+ and to an increase of Ca2+ uptake through receptor-operated Ca2+ channels.

Hyperactivity of Ca channels in vasa deferentia smooth muscle of diabetic rats

Contractile responses of strips of the prostatic end of vasa deferentia isolated from streptozotocin-treated diabetic rats were investigated with five agonists. Agonists induced similar biphasic responses in vasa deferentia from diabetic and age-matched control rats six to seven weeks after streptozotocin. Twitches were observed superimposed on contractions induced by the adrenergic agonists in strips from most of the diabetic rats. Strips from the diabetic rats developed significantly greater tension than those from the controls. Especially, strips from diabetics had remarkably greater dose-related responses to Ca, and greater Ca influx, than controls when tested in the presence of either KCl or clonidine. The results suggest that both voltage-dependent Ca channels and receptor-operated Ca channels contribute to potentiation of contractile responses in diabetes.

Effect of trimebutine maleate on the contractile response of the isolated ileum from diabetic rats

1. Tension of the isolated ileum from diabetic rats induced by streptozotocin was measured isometrically to study the mode of action of trimebutine maleate (TMB). 2. The hyperreactivity of contractile response to KCl was observed in the isolated ileum from diabetic rats. TMB inhibited the contraction induced by KCl and acetylcholine (ACh) in normal solution. 3. In Ca2+ free solution, the hyperreactivity of contractile response to KCl was attenuated, and TMB did not inhibit the contraction induced by KCl. In contrast, TMB inhibited the contraction induced by ACh even in Ca2+ free solution. 4. These results suggest that the hyperreactivity of contractile response to KCl in the ileum from diabetic rats is due to the enhancement of Ca2+ influx through voltage-dependent Ca2+ channel and that TMB inhibits the hyperreactivity of contractile response through the inhibition of Ca2+ movement by the cell.

Evidence that the Na+−Ca2+ exchange system is related to the antiarrhythmic action of disopyramide

1. Disopyramide induced a concentration-dependent decrease in action potential amplitude and Vmax, and prolonged action potential durations (APD50 and APD90) in ventricular muscle. 2. Na+-loaded membrane vesicles isolated from canine ventricular muscle rapidly accumulated Ca2+. 3. Monensin (10(-5) M) abolished Na+-dependent Ca2+ uptake, and Na+ enhanced Ca2+ efflux. 4. Na+-Ca2+ exchange by membrane vesicles was more active in preparations pretreated with disopyramide (10(-5) M) than in control membranes. 5. The results suggest that disopyramide changes Na+ influx from Na+ channel mediated to Na+-Ca2+ exchange mediated. This is verified in part by increased Ca2+ efflux.

[Acidified aspirin-induced gastric lesion in rats with hepatic cirrhosis produced by N-nitrosodiethylamine or carbon tetrachloride. Effect of aldioxa on gastric lesions].

Gastric lesion was induced by the oral administration of acidified aspirin in rats with hepatic cirrhosis produced by N-nitrosodiethylamine (NDA) or carbon tetrachloride (CCl4). Gastric lesion by acidified aspirin was aggravated in NDA-induced cirrhosis, but not in CCl4-cirrhotic rats. To clarify this difference in the susceptibility of the gastric mucosa, gastric mucosal blood flow and gastric emptying were measured by the hydrogen gas clearance method and beads method, respectively. Gastric mucosal blood flow was lower and gastric emptying was significantly delayed in NDA-induced cirrhotic rats as compared with the controls, but not in CCl4-induced cirrhotic rats. Gastric mucosal blood flow in NDA-induced cirrhotic rats was significantly decreased by the oral administration of acidified aspirin as compared with the controls. Aldioxa dose-dependently inhibited the gastric lesion formation by acidified aspirin and inhibited the decrease of gastric mucosal blood flow in NDA-induced cirrhotic rats. These results suggest that aggravation of gastric lesion induced by acidified aspirin in NDA-induced cirrhotic rats would be due to the decrease of gastric mucosal blood flow and delay of gastric emptying. In addition, aldioxa showed a protective effect against gastric lesions induced by acidified aspirin in NDA-induced cirrhotic rats, suggesting that this compound would have an inhibitory effect on gastric lesions that are accompanied by hepatic cirrhosis.

Pharmacological actions of iprazochrome on the vascular system

The pharmacological actions of iprazochrome (IC) on the vascular system were studied, and the following results were obtained: No death nor abnormal behaviors were observed in acute toxicity tests conducted on male and female mice and rats despite the administration of large doses of IC (10,000 mg/kg, p.o. and 80 mg/kg, i.v., respectively). IC inhibited dose-dependently platelet aggregation in vitro induced by arachidonate and ADP, whereas no effect was observed on ADP-induced respiratory depression in mice, which is closely related to platelet aggregation in vivo. The antiserotonergic actions of IC on the isolated external carotid arteries and femoral arteries in dogs observed in a noncompetitive manner were found to be 1/24 to 1/65 that of methysergide. On the other hand, IC showed no inhibitory effect on the paw edema of rats in vivo induced by serotonin. The inhibitory effect of IC on peritoneal dye leakage in mice was less than half that of phenylbutazone. IC prevented apoplexy in stroke-prone SHR (SHRSP) without lowering the blood pressure. Histological changes in the cerebrum of SHRSP were ischemic changes such as swelling of the neurons and shrinkage of the nuclei, mainly in the cerebral cortex and corpus striatum area.