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

Abstract

BT. P2X purinergic receptormediated ionic current in cardiac myocytes of calsequestrin model of cardiomyopathy: implications for the treatment of heart failure. Am J Physiol Heart Circ Physiol 292: H1077-H1084, 2007. First published October 13, 2006; doi:10.1152/ajpheart.00515.2006.-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 ϭ 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 Ϯ 15.4 (SE) m 2 , n ϭ 6 mice vs. vehicle-treated mice: 358 Ϯ 27.8 m 2 , n ϭ 6 mice, P Ͻ 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 nucleotidaseresistant 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. ion channels; membrane current; mouse; heart RECEPTORS FOR PURINE nucleotides, known as P2 purinergic receptors, mediate a number of potent and possibly important biological effects in the cardiovascular system (20,22,29). The P2X ion channels are receptor channels activated by extracellular ATP, whereas the P2Y receptors are G proteincoupled receptors. Together, they represent two subfamilies of the P2 nucleotide receptors. Previous studies have shown that extracellular ATP can cause an ionic current in murine (27), rat (26), and guinea pig (21) cardiac ventricular myocytes. The receptor that mediates this current appears to be a P2X receptor, of which the P2X 4 receptor is an important subunit (27). Activation of P2X receptors leads to the opening of a nonselective cation channel permeable to Na ϩ , K ϩ , and Ca 2ϩ . The current is inward at negative membrane potentials, reverses near 0 mV, and becomes outward at positive potentials. The continuous activation of this receptor channel by endogenous extracellular ATP may assume an important b...

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