Abstract 1546: P2X Purinergic Receptor-mediated Ionic Current in Cardiac Myocytes of Calsequestrin Model of Cardiomyopathy. Implications for the Treatment of Heart Failure
P2X Purinergic receptors, activated by extracellular ATP, mediate a number of cardiac cellular effects and may be important under pathophysiologic 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-meSATP induced an inward current that was greater in magnitude in CSQ than in WT ventricular cells. The novel agonist, MRS2339, an (N) methanocarba derivative of 2-chloroAMP relatively resistant to nucleotidase, induced a current in the CSQ myocyte similar to that by 2-meSATP. When administered via a mini-osmotic pump (Alzet), it significantly increased longevity as compared to vehicle-injected mice (Log Rank Test, p<0.02). The improvement in survival was associated with decreases in heart weight/body weight ratio and in cardiac myocyte cross-section area (MRS2339-treated mice: 281 ± 15.4 μm2, SE, n=6 mice vs. vehicle-treated mice: 358 ± 27.8 μm2, n=6 mice, P<0.05). MRS2339 had no vasodilator effect in mouse aorta ring preparations indicating that its salutary effect in heart failure is not due to any vascular unloading. The cardiac P2X current is up-regulated 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.