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J Physiol Volume 566, Number 2, 341-353, July 15, 2005 DOI: 10.1113/jphysiol.2005.087478
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Both cGMP and peroxynitrite mediate chronic interleukin-6-induced negative inotropy in adult rat ventricular myocytes

Xin-Wen Yu1, Meei-Yueh G Liu2, Richard H Kennedy3 and Shi J Liu1,2

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

We previously showed that chronic exposure to interleukin (IL)-6 decreases contractile and sarcoplasmic reticular (SR) function assessed by postrest potentiation (PRP) via a nitric oxide (NO)-dependent mechanism in adult rat ventricular myocytes (ARVM). Cyclic GMP (cGMP) has been associated with NO-associated negative inotropic effects of IL-6 during acute exposure; however, its role in chronic cardiac effects of IL-6 remains unclear. The present study examined the roles of cGMP and peroxynitrite (ONOO–) in chronic IL-6-induced negative inotropy in ARVM. After ARVM were exposed to IL-6 for 2–24 h, intracellular cGMP contents were time dependently increased; this was mimicked by a NO donor and abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase (sGC), or Rp-8-Br-cGMP, an inhibitor of cGMP-dependent protein kinase G (PKG). Meanwhile, the IL-6-induced decrease in PRP at 2 h was blocked by ODQ or Rp-8-Br-cGMP. By contrast, ODQ or Rp-8-Br-cGMP only attenuated the inhibition of PRP induced by IL-6 after 24 h exposure. Furthermore, IL-6 time dependently increased superoxide anion production and ONOO– formation; the latter was abolished by 5,10,15,20-tetrakis-(4-sulphonatophenyl)-porphyrinato iron (III) (FeTPPS), an ONOO– decomposition catalyst. Interestingly, FeTPPS had no effect on the IL-6-elicited decrease in PRP at 2 h, but attenuated it after 24 h exposure. Moreover, inhibition of sGC/cGMP/PKG, but not ONOO– formation, abolished the IL-6-induced inhibition of kinetics of myocyte contraction during 24 h exposure. We conclude that while the sGC/cGMP/PKG pathway was the primary mechanism for chronic IL-6-induced negative inotropy at 2 h, both sGC/cGMP/PKG and ONOO–, at least in part, mediate the IL-6-induced inhibition of SR function after 24 h exposure.

(Received 24 March 2005; accepted after revision 28 April 2005; first published online 5 May 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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