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 ET(A)-receptor antagonist (30 mg x kg(-1) x day(-1), LU302146) or an ET(AB)-receptor antagonist (30 mg x kg(-1) x 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 alpha and delta were investigated by Western blot analysis using specific antibodies. In the SNX group, systolic blood pressure rose to 154+/-5 mmHg after 12 weeks. The ET(A) receptor antagonist prevented this increase in blood pressure, but ET(AB) antagonism did not. Left ventricular weight increased in SNX; this increase was inhibited by the ET(A) receptor antagonist. In comparison with the sham group, PKC isoform alpha increased by 19% in SNX animals. When the SNX animals were treated with ET(A) or ET(AB) antagonists, PKC isoform alpha levels decreased by 31%. PKC isoform delta levels decreased by 35% in SNX animals. Treatment with both ET(A) or ET(AB) antagonists increased PKC isoform delta levels to normal. In the myocardium of uraemic rats PKC isoforms are differentially regulated with an increase in alpha isoform but a decrease in delta isoform. ET receptor blockers normalize these PKC isoforms.