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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/H2391    most recent ajpheart.00011.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chung, K. Y. Articles by Walker, J. W. Search for Related Content PubMed PubMed Citation Articles by Chung, K. Y. Articles by Walker, J. W.

Contractile regulation by overexpressed ET_A requires intact T tubules in adult rat ventricular myocytes

Molecular and Cellular Pharmacology Program and Department of Physiology, University of Wisconsin, Madison, Wisconsin

Submitted 4 January 2008 ; accepted in final form 6 March 2008

Endothelin (ET)-1 regulates the contractility and growth of the heart by binding G protein-coupled receptors of the ET type A receptor (ET_A)/ET type B (ET_B) receptor family. ET_A, the predominant ET-1 receptor subtype in myocardium, is thought to localize preferentially within cardiac T tubules, but the consequences of mislocalization are not fully understood. Here we examined the effects of the overexpression of ET_A in conjunction with T-tubule loss in cultured adult rat ventricular myocytes. In adult myocytes cultured for 3 to 4 days, the normally robust positive inotropic effect (PIE) of ET-1 was lost in parallel with T-tubule degeneration and a decline in ET_A protein levels. In these T tubule-compromised myocytes, an overexpression of ET_A using an adenoviral vector did not rescue the responsiveness to ET-1, despite the robust expression in the surface sarcolemma. The inclusion of the actin polymerization inhibitor cytochalasin D (CD) during culture prevented gross morphological changes including a loss of T tubules and a rounding of intercalated discs, but CD alone did not rescue the responsiveness to ET-1 or prevent ET_A downregulation. The rescue of a normal PIE in 3- to 4-day cultured myocytes required both an increased expression of ET_A and intact T tubules (preserved with CD). Therefore, the activation of ET_A localized in T tubules was associated with a strong PIE, whereas the activation of ET_A in surface sarcolemma was not. The results provide insight into the pathological cardiac conditions in which ET_A is upregulated and T-tubule morphology is altered.

cytochalasin D; inotropism; endothelin type A receptor; heart failure