Vascular ATP-sensitive potassium channels are over-expressed and partially regulated by nitric oxide in experimental septic shock.

Abstract

PURPOSE:

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.

METHODS:

Septic shock was induced in rats by peritonitis. Selective inhibitors of vascular K(ATP) (PNU-37883A) or BK(Ca) [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.

RESULTS:

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 K(ATP) channels, while expression of vascular BK(Ca) channels remained unchanged. Selective iNOS inhibition blunted the sepsis-induced increase in aortic NO, decreased NF-κB activation, and down-regulated vascular K(ATP) channel expression.

CONCLUSIONS:

Vascular K(ATP) but not BK(Ca) 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 K(ATP) channel inhibitors offer potential therapeutic perspectives for septic shock.

• Authors: Solène Collin, Nacira Sennoun, Anne-Gaëlle Dron, Mathilde de la Bourdonnaye, Chantal Montemont, Pierre Asfar, Patrick Lacolley, Ferhat Meziani, Bruno Levy
• Journal: Intensive care medicine (Intensive Care Med) Vol. 37 Issue 5 Pg. 861-9 (May 2011) ISSN: 1432-1238 [Electronic] United States
• PMID: 21369811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KATP Channels
• Phenylephrine
• Nitric Oxide

Topics

• Animals
• Blotting, Western
• France
• KATP Channels (drug effects)
• Male
• Mesenteric Arteries (metabolism)
• Muscle, Smooth, Vascular (metabolism)
• Nitric Oxide (metabolism)
• Phenylephrine (pharmacology)
• Polymerase Chain Reaction
• Rats
• Rats, Wistar
• Shock, Septic (complications, metabolism, physiopathology)