Mikio Sawada

Unusual concentration of urine and prevention of polydipsia by fungal prenylphenols in doca hypertensive rats

When deoxycorticosterone acetate (DOCA)-loaded uninephrectomized rats were fed on standard laboratory pellet diet and 1% saline for 5 weeks, caloric homeostasis became abnormal resulting in (a) hyperlipidemia, (b) cholesterol deposit in the heart, (c) significant reduction of triglycerides in the aorta, heart and liver and (d) a 60% increase in the cardiac free fatty acids (FFA) on one hand and a 50% reduction of the hepatic FFA on the other. These facts suggest that the hypertension severely reduces hepatic lipogenesis, whereas the cardiovascular system depends much more on FFA as a metabolic fuel than on glucose. This idea is supported by the deficiency in total body potassium (K) and decrease in serum immunoreactive insulin (IRI) which occur in the hypertension. These alterations were attenuated by the fungal prenylphenols, 4-0-methylascochlorin (MAC) and ascofuranone (AF). The protective effect seems to be partly attributable to the counteraction to DOCA. In addition, the agents caused a specific increase of renal water reabsorption. MAC treatment resulted in a particularly marked reduction of saline intake and excretion of unusually thick urine with 2.8 times higher sodium (Na) concentration than in the DOCA/saline control rats.

Alteration of cholesterol metabolism by 4-0-methylascochlorin in rats

The effect of 4-0-methylascochlorin (MAC), an experimental hypocholesterolemic agent, on cholesterol metabolism was investigated in rats in two separate experiments. The administration of MAC for 2 and 6 consecutive weeks at daily doses of 100–135 mg/kg resulted in reduction in serum cholesterol levels of 16% after 2 weeks of treatment in the first experiment, and 13% after 6 weeks in the second experiment in comparison to the corresponding controls. MAC administered at a daily dose of 100 mg/kg for 2 weeks showed a significant increase in the biliary excretion of bile acids and cholesterol in bile-duct cannulated rats with or without the administration of taurocholate. In the second experiment, MAC treatment for 6 weeks produced a marked increase in the fecal output of acidic sterols during a 2 to 6-week period. MAC treatment also further enhanced hepatic cholesterol 7α-hydroxylase in the rats. Therefore, it appears that the mechanism of serum cholesterol lowering due to MAC is related to the enhancement of hepatic bile acid synthesis and the increase in biliary and fecal excretion of bile acids.

Enhanced excretion of fecal neutral sterols and the hypocholesterolemic property of 4-O-methylascochlorin in mice.

The hypocholesterolemic property of experimental agent 4-O-methylascochlorin (MAC) was examined in male mice. MAC exerted hypocholesterolemic activity without hepatomegaly in mice given MAC mixed in a standard laboratory diet for a week. MAC also significantly reduced plasma total cholesterol (p-TC) in mice when it was administered immediately after meals by gastric intubation in controlled feeding. However, the oral administration through gastric tube was completely ineffective on p-TC in mice with empty stomach. These results suggest a close relationship between hypocholesterolemic efficacy and the timing of diet intake. Hypercholesterolemia also induced by a high fat-cholesterol diet was unaffected by MAC when it was given mixed with the diet.From the isotopic study, three plausible mechanism were proposed for the mode of action: (I) enhanced output of biliary cholesterol, (II) inhibition of intestinal cholesterol absorption followed by an increment of fecal neutral sterols and (III) modulation of chol...