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1 Department of Pharmacology and Toxicology
2 Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA
3 Department of Physiology, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153, USA
Interleukin (IL)-6 has been shown to decrease cardiac contractility via a nitric oxide synthase (NOS)-dependent pathway during acute exposure. We previously reported that IL-6 decreases contractility and increases inducible NOS (iNOS) in adult rat ventricular myocytes (ARVM) after 2 h exposure. The goal of this study was to investigate the cellular mechanism underlying this chronic IL-6-induced negative inotropy and the role of iNOS. Pretreatment for 2 h with 10 ng ml–1 IL-6 decreased the kinetics of cell shortening (CS) and contractile responsiveness to Ca2+o ([Ca2+]o from 0 to 2 mM) in ARVM. We first examined whether IL-6 reduced Ca2+ influx via L-type Ca2+-channel current (ICa,L). Whole-cell ICa,L in ARVM was measured under conditions similar to those used for CS measurements, and it was found to be unaltered by IL-6. The sarcoplasmic reticular (SR) function was then assessed by examining postrest potentiation (PRP) and caffeine responsiveness of CS. Results showed that treatment with IL-6 for 2 h significantly decreased PRP, which was concomitant with a decrease in the phosphorylation of phospholamban. Following removal of IL-6, PRP and responsiveness to 10 mM caffeine were also reduced. Meanwhile, the IL-6-induced increase in nitric oxide (NO) production after 2 h (but not 1 h) was abolished by NG-monomethyl-L-arginine (L-NMMA) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT; a selective inhibitor of iNOS). Furthermore, IL-6-elicited suppressions of PRP and responsiveness to caffeine and Ca2+o were abolished by L-NMMA and AMT. Thus, these results suggest that activation of iNOS mediates IL-6-induced inhibition of SR function in ARVM during chronic exposure.
(Received 15 March 2005;
accepted after revision 21 April 2005;
first published online 21 April 2005)
Corresponding author S. J. Liu: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street MS 522-3, Little Rock, AR 72205, USA. Email: sliu{at}uams.edu
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  S. J. Liu Inhibition of L-type Ca2+ channel current and negative inotropy induced by arachidonic acid in adult rat ventricular myocytes Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1594 - C1604. [Abstract] [Full Text] [PDF]
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