title: BK large conductance Ca²+-activated K+ channel-deficient mice are not resistant to hypotension and display reduced survival benefit following polymicrobial sepsis.
abstract: 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 BKα subunit knockout (α, 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, BKα 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 BKα 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.
authors.affiliation: Institute of Hepatology and †Department of Medicine, University College, London, UK. a.o'brien@ucl.ac.uk
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: O'Brien
authors.forename: Deepti
authors.initials: D
authors.lastname: Terala
authors.forename: Nelson N
authors.initials: NN
authors.lastname: Orie
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.forename: Parjam
authors.initials: P
authors.lastname: Zolfaghari
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.forename: Lucie H
authors.initials: LH
authors.lastname: Clapp
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D007022:Hypotension / Q000188:drug therapy / Q000235:genetics*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology* / Q000401:mortality*; D019789:Tetraethylammonium / Q000627:therapeutic use
chemical_list: D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D019789:Tetraethylammonium