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 tissu e in vivo. The aim of this study was to investigate changes in express ion 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 endothel ins and their receptors during the development of cardiac hypertrophy, while radioligand binding was employed to quantify the amount of [I-1 25]ET-1 binding to cardiac membranes. Tissue and plasma concentrations of ET-1 were measured by radioimmunoassay. Results: In control sham o perated animals, ET-1 mRNA was similar to fivefold greater in atria th an in ventricles (P<0.05), but there were no atrioventricular differen ces in ET-2 or ET-3 mRNA. In the AV fistula rats there was a prompt th ree- to fourfold increase in ET-1 mRNA in atria and a progressive five - to sevenfold rise in ventricles during cardiac hypertrophy. There we re no changes in ET-2 or ET-3 transcript prevalences, except for a lat e rise (35 d) in ET-2 mRNA levels in left ventricle. Consistent with E T-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 tr anscript 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 E T(A)R gene. Conclusions: During cardiac hypertrophy in AV fistula rats there is increased activity of the endothelin system mediated princip ally by ET-1 and the ET(A)R subtype.