Influence of endothelin receptor antagonists on myocardial protein kinase C isoforms in uraemic cardiomyopathy

Abstract

Increased endothelin-1 (ET-1) levels were found in patients with chronic renal failure and these correlate with the severity of renal failure. Increased mortality due to cardiovascular problems is observed in patients with elevated ET-1 concentrations. The aim of this study was to find out the influence of ET-1 and ET receptor antagonists on myocardial protein kinase C (PKC) regulation in uraemic cardiomyopathy. Male rats were subtotally nephrectomized and treated with an ETA-receptor antagonist (30mg·kg-1·day-1, LU302146) or an ETAB-receptor antagonist (30mg·kg-1·day-1, LU302872) for 12 weeks. One group was left untreated (SNX) and one group was sham-operated (sham). Systolic blood pressure, myocardial weight and the changes of the protein kinase C isoforms in the heart were determined. PKC isoforms α and δ were investigated by Western blot analysis using specific antibodies. In the SNX group, systolic blood pressure rose to 154±5mmHg after 12 weeks. The ETA receptor antagonist prevented this increase in blood pressure, but ETAB antagonism did not. Left ventricular weight increased in SNX; this increase was inhibited by the ETA receptor antagonist. In comparison with the sham group, PKC isoform α increased by 19% in SNX animals. When the SNX animals were treated with ETA or ETAB antagonists, PKC isoform α levels decreased by 31%. PKC isoform δ levels decreased by 35% in SNX animals. Treatment with both ETA or ETAB antagonists increased PKC isoform δ levels to normal. In the myocardium of uraemic rats PKC isoforms are differentially regulated with an increase in α isoform but a decrease in δ isoform. ET receptor blockers normalize these PKC isoforms.