Protective effects of endothelin antagonists in chronic renal failure.

The present study suggests that ET-1 is involved in the pathogenesis of uraemic cardiac hypertrophy and in the progression of renal failure in rats with subtotal nephrectomy examined after an intermediate period of 12 weeks of renal failure. Furthermore, proteinuria is reduced by the selective ETA receptor antagonist more than by the unselective ETAB receptor antagonist, without reducing the blood pressure. ET receptor blockade might preserve renal function by reduction of protein excretion. In addition, ET receptor antagonists influence the aldosterone system. In our animal studies, the medication was well tolerated. Our study results provide a possible therapeutic approach using ET receptor antagonists for cardiac hypertrophy and renal protein excretion by blockade of endogenous ET-1. Further human studies are needed to show whether this protection of the heart and kidney might influence the survival and life expectancy of patients suffering from chronic renal failure, of patients on dialysis or after kidney transplantation.

Upregulation of cholesterol synthesis after acute reduction of low density lipoprotein by apheresis in normocholesterolaemic subjects: evidence for a threshold effect.

The influence of low density lipoproteins (LDL) in the plasma on the regulation of cholesterol biosynthesis is not clear. We studied the changes in plasma mevalonic acid (MVA) concentration and the lathosterol/cholesterol (L/C) ratio, which are well established indices of whole body cholesterol synthesis, in four normocholesterolaemic subjects after each had undergone LDL apheresis on two occasions. LDL apheresis of 75% of the calculated plasma volume reduced LDL-cholesterol by 44% to 1.5 +/- 0.2 mmol/l without changing plasma MVA levels or L/C ratios. Apheresis of 125% of the calculated plasma volume decreased plasma LDL-cholesterol by 69% to 0.9 +/- 0.2 mmol/l, with significant increases in plasma MVA and L/C ratio on the day after the procedure. These results imply that LDL-cholesterol is an integral part of the sterol regulatory pool and suggest that plasma levels cannot be lowered below 1-1.4 mmol/l in normal subjects without upregulating cholesterol biosynthesis.