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This Article Full Text Full Text (PDF) All Versions of this Article: 580/1/327    most recent jphysiol.2006.126805v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dedkova, E. N. Articles by Lipsius, S. L. Search for Related Content PubMed PubMed Citation Articles by Dedkova, E. N. Articles by Lipsius, S. L. Related Collections Integrative

Loyola University Chicago, Stritch School of Medicine, Departments of
¹ Physiology
² Medicine, Maywood, IL 60153, USA

In this study we sought to determine whether contractile activity has a role as a signalling mechanism in the activation of intracellular nitric oxide (NO_i) production induced by electrical stimulation of cat ventricular myocytes. Field stimulation (FS) of single ventricular myocytes elicited frequency-dependent increases in NO_i that were blocked by the calmodulin (CaM) inhibitor 10 µM W-7 and partially inhibited by the phosphatidylinositol 3'-kinase (PI-(3)K) inhibitor 10 µM LY294002. Increasing extracellular [Ca²⁺] caused a concentration-dependent increase in FS-induced NO_i that was partially inhibited by LY294002. The negative inotropic agents BDM (5 mM) or blebbistatin (10 µM) decreased cell shortening and NO_i production without concomitant changes in L-type Ca²⁺ current (I_Ca,L) or [Ca²⁺]_i transients. The positive inotropic agents EMD 57033 or CGP 48506 (1 µM) increased cell shortening and NO_i production without concomitant changes in I_Ca,L or [Ca²⁺]_i transients. FS-induced NO_i production was decreased in myocytes infected (100 multiplicity of viral infection (MOI); 24 h) with a replication-deficient adenovirus expressing a dominant-negative mutant of protein kinase B (Akt) compared with cells infected with a control adenovirus expressing -galactosidase. FS-induced NO_i was partially inhibited by either endothelial (eNOS) or neuronal nitric oxide synthase (nNOS) inhibitors and completely blocked by simultaneous exposure to both. FS-induced [Ca²⁺]_i transients were increased by the nNOS inhibitor nNOS-I (0.24 µM), decreased by the eNOS inhibitor L-NIO (1 µM) and unchanged by exposure to both inhibitors. We conclude that in cat ventricular myocytes, FS-induced NO_i production requires both Ca²⁺-dependent CaM signalling and Ca²⁺-independent PI-(3)K–Akt signalling activated by contractile activity. FS activates NO_i production from both eNOS and nNOS, and each source of NO_i exerts opposing effects on [Ca²⁺]_i transient amplitude. These findings are important for understanding the regulation of NO_i signalling in the normal and mechanically failing heart.

(Received 15 December 2006; accepted after revision 18 January 2007; first published online 18 January 2007)
Corresponding author S. Lipsius: Department of Physiology, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153, USA. Email: slipsiu{at}lumc.edu

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