Vascular ATP-sensitive potassium channels are over-expressed and partially regulated by nitric oxide in experimental septic shock
- 274 Downloads
To study the activation and expression of vascular (aorta and small mesenteric arteries) potassium channels during septic shock with or without modulation of the NO pathway.
Septic shock was induced in rats by peritonitis. Selective inhibitors of vascular KATP (PNU-37883A) or BKCa [iberiotoxin (IbTX)] channels were used to demonstrate their involvement in vascular hyporeactivity. Vascular response to phenylephrine was measured on aorta and small mesenteric arteries mounted on a wire myograph. Vascular expression of potassium channels was studied by PCR and Western blot, in the presence or absence of 1400W, an inducible NO synthase (iNOS) inhibitor. Aortic activation of the transcriptional factor nuclear factor-kappaB (NF-κB) was assessed by electrophoretic mobility shift assay.
Arterial pressure as well as in vivo and ex vivo vascular reactivity were reduced by sepsis and improved by PNU-37883A but not by IbTX. Sepsis was associated with an up-regulation of mRNA and protein expression of vascular KATP channels, while expression of vascular BKCa channels remained unchanged. Selective iNOS inhibition blunted the sepsis-induced increase in aortic NO, decreased NF-κB activation, and down-regulated vascular KATP channel expression.
Vascular KATP but not BKCa channels are activated, over-expressed, and partially regulated by NO via NF-κB activation during septic shock. Their selective inhibition restores arterial pressure and vascular reactivity and decreases lactate concentration. The present data suggest that selective vascular KATP channel inhibitors offer potential therapeutic perspectives for septic shock.
KeywordsSeptic shock Cardiovascular failure Potassium channels Nitric oxide Inhibitors
The authors thank W.A. Coetzee and N.Q. Shi for critical reading of the article and for providing antibodies. This work was supported by Inserm and by a grant from the French Society of Intensive Care (SRLF).
- 14.Sennoun N, Baron-Menguy C, Burban M, Lecompte T, Andriantsitohaina R, Henrion D, Mercat A, Asfar P, Levy B, Meziani F (2009) Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries. Am J Physiol Heart Circ Physiol 297:H277–H282PubMedCrossRefGoogle Scholar
- 16.Morrissey A, Rosner E, Lanning J, Parachuru L, Dhar Chowdhury P, Han S, Lopez G, Tong X, Yoshida H, Nakamura TY, Artman M, Giblin JP, Tinker A, Coetzee WA (2005) Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature. BMC Physiol 5:1PubMedCrossRefGoogle Scholar
- 17.Nacira S, Meziani F, Dessebe O, Cattan V, Collin S, Montemont C, Gibot S, Asfar P, Ramaroson A, Regnault V, Slama M, Lecompte T, Lacolley P, Levy B (2009) Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress. Crit Care Med 37:246–255PubMedCrossRefGoogle Scholar
- 23.O’Brien A, Stidwill RP, Clapp LH, Singer M (2008) Variable effects of inhibiting iNOS and closing the vascular ATP-sensitive potassium channel (via its pore-forming and sulfonylurea receptor subunits) in endotoxic shock. Shock 31:535–541Google Scholar
- 27.Kuo JH, Chen SJ, Shih CC, Lue WM, Wu CC (2008) Abnormal activation of potassium channels in aortic smooth muscle of rats with peritonitis-induced septic shock. Shock 32:74–79Google Scholar
- 31.Levy B, Collin S, Sennoun N, Ducrocq N, Kimmoun A, Asfar P, Perez P, Meziani F (2010) Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med 36:2019–2029Google Scholar
- 37.Morelli A, Lange M, Ertmer C, Broeking K, Van Aken H, Orecchioni A, Rocco M, Bachetoni A, Traber DL, Landoni G, Pietropaoli P, Westphal M (2007) Glibenclamide dose response in patients with septic shock: effects on norepinephrine requirements, cardiopulmonary performance, and global oxygen transport. Shock 28:530–535PubMedGoogle Scholar