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 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) mum(2), n = 6 mice vs. vehicle-treated mice: 358 +/- 27.8 mum(2), 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.
Shen
Jian-Bing
JB
Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, USA. bliang@uchc.edu
Cronin
Chunxia
C
Sonin
Dmitry
D
Joshi
Bhalchandra V
BV
Gongora Nieto
Maria
M
Harrison
David
D
Jacobson
Kenneth A
KA
Liang
Bruce T
BT
D000227:Adenine Nucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000209:etiology / Q000517:prevention & control*; D009202:Cardiomyopathies / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D058910:Purinergic P2 Receptor Agonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D058848:Receptors, Purinergic P2X4; D013873:Thionucleotides / Q000494:pharmacology
C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); D000227:Adenine Nucleotides; D001557:Benzenesulfonates; D002155:Calsequestrin; C548227:P2rx4 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D013873:Thionucleotides; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D000249:Adenosine Monophosphate; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; C008501:2-methylthio-ATP