Both cGMP and peroxynitrite mediate chronic interleukin-6-induced negative inotropy in adult rat ventricular myocytes.
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.
Yu
Xin-Wen
XW
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street , Little Rock, AR 72205, USA.
Liu
Meei-Yueh G
MY
Kennedy
Richard H
RH
Liu
Shi J
SJ
D000818:Animals; D002469:Cell Separation; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D003864:Depression, Chemical; D006162:Guanylate Cyclase / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D013481:Superoxides / Q000378:metabolism
D015850:Interleukin-6; D013481:Superoxides; D030421:Peroxynitrous Acid; D006162:Guanylate Cyclase; D006152:Cyclic GMP