SELECTIVE INCREASE IN ENDOTHELIN-1 AND ENDOTHELIN-A RECEPTOR SUBTYPE IN THE HYPERTROPHIED MYOCARDIUM OF THE AORTO-VENACAVAL FISTULA RAT

Objective: At present little is known about the factors that regulate the expression of the endothelins and their receptors in cardiac tissue in vivo. The aim of this study was to investigate changes in expression of the endothelins (ET-1, ET-2, and ET-3) and their receptors (ET(A)R and ET(B)R) in the hypertrophied heart of the aorto-venocaval (AV) fistula rat. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify cardiac mRNA expression of the endothelins and their receptors during the development of cardiac hypertrophy, while radioligand binding was employed to quantify the amount of [I-125]ET-1 binding to cardiac membranes. Tissue and plasma concentrations of ET-1 were measured by radioimmunoassay. Results: In control sham operated animals, ET-1 mRNA was similar to fivefold greater in atria than in ventricles (P<0.05), but there were no atrioventricular differences in ET-2 or ET-3 mRNA. In the AV fistula rats there was a prompt three- to fourfold increase in ET-1 mRNA in atria and a progressive five- to sevenfold rise in ventricles during cardiac hypertrophy. There were no changes in ET-2 or ET-3 transcript prevalences, except for a late rise (35 d) in ET-2 mRNA levels in left ventricle. Consistent with ET-1 mRNA measurements, immunoreactive endothelin levels were increased by 7 d in atria, but not in ventricles. In control rat hearts, ET(A)R mRNA levels were similar in atria and ventricles, but the prevalence of ET(B)R was similar to sevenfold greater in the former. ET(A)R mRNA prevalence increased with hypertrophy in all chambers, while ET(B)R transcript levels were raised only in the right ventricle. There was no significant difference in [I-125]-ET-1 binding between atrial samples from 35 d control and 35 d AV fistula rats, suggesting rapid turnover of endothelin receptors balanced by increased transcription from the ET(A)R gene. Conclusions: During cardiac hypertrophy in AV fistula rats there is increased activity of the endothelin system mediated principally by ET-1 and the ET(A)R subtype.