Masayoshi Watanabe

ACID PHOSPHATASE ACTIVITY IN THE AORTA OF SPONTANEOUSLY HYPERTENSIVE RATS AND THE EFFECT OF VARIOUS ANTIHYPERTENSIVE DRUGS

In an attempt to obtain information about the arterial lysosomal enzymes in hypertension, we biochemically investigated acid phosphatase (Ac-Pase) activity in the aorta of spontaneously hypertensive rats (SHR) and the effects of various antihypertensive drugs. Ac-Pase activity in SHR was always higher than that in age-matched control rats. The enzyme activity tended to increase progressively with advancing age, a tendency which was more pronounced in SHR than in control rats. The aging process expressed by the Ac-Pase activity seems to be accelerated under hypertensive conditions. Antihypertensive drugs such as reserpine, hydrochlorothiazide, hydralazine and propranolol significantly suppressed the rise of blood pressure and decreased the aortic Ac-Pase activity in SHR. In particular reserpine and propranolol lowered Ac-Pase activity more effectively than it did blood pressure. Hypertension as well as catecholamine seem to be involved in the increase in the aortic lysosomal enzyme activity in SHR.

Behavioral and Electroencephalographic Studies of Beagles with an Eck's Fistula: Suitability as a Model of Hepatic Encephalopathy

Behavioral manifestations, electroencephalograms (EEGs) and visually evoked potentials (VEPs) were studied in beagles with Ecks fistula (portacaval shunt [PCS]), an established model of hyperammonemia, to determine whether they developed CNS disorders characteristic of hepatic encephalopathy. After PCS, behavioral changes occurred in the form of listlessness, sluggishness (altered gait, snapping and transient catatonia-like symptoms) and apparent blindness, which appeared in that order and progressed to coma and death in some animals. The EEGs from the frontal cortex showed a gradual decrease in voltage and frequency. Development of snapping and catatonia-like symptoms coincided with the occurrence of high voltage fast waves in the EEGs from the occipital cortex. In comatose Ecks fistula dogs. flattening of the EEGs was recorded from the frontal cortex and a lowered voltage was noted in the EEGs from the occipital cortex. After PCS, the latencies and amplitudes of the components of VEP were increased. The snapping and catatonia-like symptoms were markedly ameliorated by carbamazepine and the coma by flumazenil and thyrotropin-releasing hormone. These findings indicate that Ecks fistula dogs provide a useful model of hepatic encephalopathy.

実験的肝性昏睡ラットモデルにおける血中および脳内アンモニア濃度ならびに昏睡に対するラクチトール(NS-4)の作用

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 carbontetrachloride (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.

実験的肝性昏睡ラット脳波に対するラクチトール(NS-4)の改善作用について

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 (13-25 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.