Altered L-type Ca2+ channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice

作者：Xu Hui^*; Garver Hannah; Fernandes Roxanne; Galligan James J; Fink Gregory D

来源：American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2014, 307(2): R138-R148.

DOI：10.1152/ajpregu.00117.2014

• BK beta 1-subunit knockout
• polymicrobial septic shock
• blood flow and tissue perfusion
• Ca2+ channel blocker
• polymorphonuclear neutrophil infiltration and tissue injury
• cytokines
• vascular BK and L-type Ca2+ channel function

We determined the contribution of vascular large conductance Ca2+ -activated K+ (BK) and L-type Ca2+ channel dysregulation to exaggerated mortality in cecal ligation/puncture (CLP)-induced septic BK channel beta 1-subunit knockout (BK beta 1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK beta 1-KO mice that were either untreated, given volume resuscitation (saline), or saline + calcium channel blocker nicardipine. Some mice were euthanized 24 h post-CLP to measure tissue injury and vascular and immune responses. CLP-induced hypotension was similar in untreated WT and BK beta 1-KO mice, but BK beta 1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK beta 1-KO mice), untreated CLP-BK beta 1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltrationindependent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT but not CLP-BK beta 1-KO mice. Saline + nicardipine-treated CLP-BK beta 1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK beta 1-KO mice. These improvements were absent in treated CLP-WT mice, although saline + nicardipine improved blood pressure similarly in both septic mice. At 24 h post-CLP, BK and L-type Ca2+ channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK beta 1-KO mice had blunted BK/enhanced L-type Ca2+ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK beta 1-KO mice by activating L-type Ca2+ channels leading to blood pressure-independent tissue ischemia.

• 出版日期2014-7-15