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ABSTRACT AIM: The downregulation of phospholamban (PLB) and FKBP12.6 as a result of β-receptor activation is involved in the pathway(s) of congestive heart failure. We hypothesized that the
endothelin (ET)-1 system may link to downregulated PLB and FKBP12.6. METHODS: Rats were subjected to ischemia/reperfusion (I/R) to cause heart failure (HF). 1 mg/kg isoproterenol (ISO) was
injected subcutaneously (sc) for 10 d to worsen HF. 30 mg/kg CPU0213 (sc), a dual ET receptor (ETAR/ETBR) antagonist was given from d 6 to d 10. On d 11, cardiac function was assessed
together with the determination of mRNA levels of ryanodine receptor 2, calstabin-2 (FKBP12.6), PLB, and sarcoplasmic reticulum Ca2+-ATPase. Isolated adult rat ventricular myocytes were
incubated with ISO at 1×10−6 mol/L to set up an _in vitro_ model of HF. Propranolol (PRO), CPU0213, and darusentan (DAR, an ETAR antagonist) were incubated with cardiomyocytes at 1×10−5
mol/L or 1×10−6 mol/L in the presence of ISO (1×10−6 mol/L). Immunocytochemistry and Western blotting were applied for measuring the protein levels of PLB and FKBP12.6. RESULTS: The worsened
hemodynamics produced by I/R were exacerbated by ISO pretreatment. The significant downregulation of the gene expression of PLB and FKBP12.6 and worsened cardiac function by ISO were
reversed by CPU0213. _In vitro_ ISO 1×10−6 mol/L produced a sharp decline of PLB and FKBP12.6 proteins relative to the control. The downregulation of the protein expression was significantly
reversed by the ET receptor antagonist CPU0213 or DAR, comparable to that achieved by PRO. CONCLUSION: This study demonstrates a role of ET in mediating the downregulation of the cardiac
Ca2+-handling protein by ISO. SIMILAR CONTENT BEING VIEWED BY OTHERS GLIBENCLAMIDE ALLEVIATES Β ADRENERGIC RECEPTOR ACTIVATION-INDUCED CARDIAC INFLAMMATION Article 04 August 2021
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Division of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China Yu Feng, Xiao-yun Tang, De-zai Dai & Yin Dai Authors * Yu Feng View author publications You can also
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can also search for this author inPubMed Google Scholar * Yin Dai View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to
De-zai Dai. ADDITIONAL INFORMATION Project supported by the National Natural Science Foundation of China (No 30670760). RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE
CITE THIS ARTICLE Feng, Y., Tang, Xy., Dai, Dz. _et al._ Reversal of isoproterenol-induced downregulation of phospholamban and FKBP12.6 by CPU0213-mediated antagonism of endothelin
receptors. _Acta Pharmacol Sin_ 28, 1746–1754 (2007). https://doi.org/10.1111/j.1745-7254.2007.00650.x Download citation * Received: 04 February 2007 * Accepted: 11 May 2007 * Issue Date: 01
November 2007 * DOI: https://doi.org/10.1111/j.1745-7254.2007.00650.x SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link
Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * heart failure *
endothelin receptor antagonists * phospholamban * FKBP12.6 * propranolol * CPU0213