Journal
SHOCK
Volume 35, Issue 5, Pages 485-491Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0b013e31820860f5
Keywords
Large conductance calcium-activated potassium (BK) channels; BK alpha null mice; sepsis; tetraethylammonium chloride; hypotension; echocardiography; mortality
Funding
- University College London Hospitals
- British Heart Foundation [PG/07/078/2355]
- Wellcome Trust
- (UK) Medical Research Council
- Department of Health's NIHR Comprehensive Biomedical Research Centre
- MRC [G0500712, G0600500] Funding Source: UKRI
- Medical Research Council [G0500712, G0600500] Funding Source: researchfish
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Nitric oxide-mediated activation of large conductance calcium-activated potassium (BK) channels is considered an important underlying mechanism of sepsis-induced hypotension. Indeed, the nonselective K-channel inhibitor, tetraethylammonium chloride (TEA), has been proposed as a potential treatment to raise blood pressure in septic shock by virtue of its ability to inhibit BK channels. As experimental evidence has so far relied on pharmacological inhibition, we examined the effects of channel deletion using BK alpha subunit knockout (alpha(-/-), Slo(-/-)) mice in two mouse models of polymicrobial sepsis, namely, intraperitoneal fecal slurry and cecal ligation and puncture. Comparison was made against TEA treatment in wild-type (WT) mice. Following slurry, BK alpha(-/-) and WT mice developed similar degrees of hypotension over 10 h with no difference in cardiac output as assessed by echocardiography between groups. Tetraethylammonium chloride raised blood pressure significantly in septic WT mice, but had no effect on survival. However, following cecal ligation and puncture, a significantly reduced survival was seen in both BK alpha(-/-) mice and (high-dose) TEA-treated WT mice compared with untreated WT animals. In conclusion, the BK channel does not appear to be integral to sepsis-induced hypotension but does affect survival through other mechanisms. The pressor effect of TEA may be related to effects on other potassium channels.
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