P2X purinergic receptor-mediated ionic current in cardiac myocytes of calsequestrin model of cardiomyopathy: implications for the treatment of heart failure

• Type of Material: Article
• Authors: Jian-Bing Shen, University of Connecticut Health Center; Chunxia Cronin, University of Connecticut Health Center; Dmitry Sonin, University of Connecticut Health Center; Bhalchandra V. Joshi, National Institutes of Health; Maria Gongora Nieto, Emory University; David Harrison, Emory University; Kenneth A. Jacobson, National Institutes of Health; Bruce T. Liang, University of Connecticut Health Center
• Language: English
• Date: 2007-02-01
• Publisher: American Physiological Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2007 by the American Physiological Society
• Final Published Version (URL): http://dx.doi.org/10.1152/ajpheart.00515.2006
• Title of Journal or Parent Work: AJP - Heart and Circulatory Physiology
• ISSN: 0363-6135
• Volume: 292
• Issue: 2
• Start Page: H1077
• End Page: H1084
• Grant/Funding Information: This work was supported in part by National Heart, Lung, and Blood Institute Grant RO1-HL-48225 and a Ray Neag Distinguished Professorship (to B. T. Liang).; B. V. Joshi and K. A. Jacobson acknowledge support from the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.
• Keywords: Science & Technology; Cardiac & Cardiovascular Systems; OVEREXPRESSING CALSEQUESTRIN; HYPERTROPHY; EXTRACELLULAR ATP; membrane current; mouse; heart; CALCIUM; Peripheral Vascular Disease; EXPRESSION; ADENINE-NUCLEOTIDE ANALOGS; CONFORMATION; POTENCY ANTAGONIST; VENTRICULAR MYOCYTES; Physiology; MICE; Life Sciences & Biomedicine; Cardiovascular System & Cardiology; ion channels
• Research Categories: Health Sciences, General

Abstract

P2X purinergic receptors, activated by extracellular ATP, mediate a number of cardiac cellular effects and may be important under pathophysiological conditions. The objective of the present study was to characterize the P2X receptor-mediated ionic current and determine its role in heart failure using the calsequestrin (CSQ) model of cardiomyopathy. Membrane currents under voltage clamp were determined in myocytes from both wild-type (WT) and CSQ mice. The P2X agonist 2-methylthio-ATP (2-meSATP) induced an inward current that was greater in magnitude in CSQ than in WT ventricular cells. The novel agonist, MRS-2339, an N-methanocarba derivative of 2-chloro-AMP relatively resistant to nucleotidase, induced a current in the CSQ myocyte similar to that by 2-meSATP. When administered via a miniosmotic pump (Alzet), it significantly increased longevity compared with vehicle-injected mice (log rank test, P = 0.02). The improvement in survival was associated with decreases in the heart weight-to-body weight ratio and in cardiac myocyte cross-sectional area [MRS-2339-treated mice: 281 ± 15.4 (SE) μm2, n = 6 mice vs. vehicle-treated mice: 358 ± 27.8 μm2, n = 6 mice, P < 0.05]. MRS-2339 had no vasodilator effect in mouse aorta ring preparations, indicating that its salutary effect in heart failure is not because of any vascular unloading. The cardiac P2X current is upregulated in the CSQ heart failure myocytes. Chronic administration of a nucleotidase-resistant agonist confers a beneficial effect in the CSQ model of heart failure, apparently via an activation of the cardiac P2X receptor. Cardiac P2X receptors represent a novel and potentially important therapeutic target for the treatment of heart failure.