FLUVASTATIN, A NEW INHIBITOR OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-AREDUCTASE, SUPPRESSES VERY-LOW-DENSITY LIPOPROTEIN SECRETION IN PUROMYCIN AMINONUCLEOSIDE-NEPHROTIC RATS

The effects of fluvastatin, a new inhibitor of 3-hydroxy-3-methylgluta ryl coenzyme A reductase, on the hyperlipidemia associated with nephro sis were studied. Nephrotic rats, induced by a single intraperitoneal injection of puromycin aminonucleoside (100 mg/kg body weight), had si gnificantly higher plasma triglyceride (TG), total cholesterol and apo protein (ape) B concentrations than controls. Fluvastatin was administ rated as a 0.01% solution in drinking water for 14 days to either norm al control or nephrotic rats. Concentrations of TG and apo B in plasma , and very low-density lipoprotein (VLDL) in nephrosis were completely normalized by the treatment with fluvastatin, but concentrations of c holesterol in plasma and each lipoprotein fraction were not altered by the treatment. The ratio of apo E to C in VLDL was significantly decr eased in nephrotic rats, but the fluvastatin treatment increased this ratio. TG secretion rate estimated by the Triton WR1339 method was sig nificantly increased in nephrotic rats, but was normalized by fluvasta tin. Percent composition of TG in newly secreted VLDL particles in pos t-Triton plasma was not decreased by fluvastatin treatment, suggesting that the number of newly secreted VLDL particles was reduced by the t reatment. Postheparin plasma lipolytic activities were not affected by the fluvastatin treatment. These results demonstrate that fluvastatin can effectively ameliorate the high concentration of VLDL by suppress ing the hepatic secretion in nephrotic rats, and suggest that an inhib ition of cholesterol biosynthesis suppresses VLDL secretion from the l iver.