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

Xu H, Garver H, Fernandes R, Galligan JJ, Fink GD. Altered L-type Ca channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice. Am J Physiol Regul Integr Comp Physiol 307: R138–R148, 2014. First published May 14, 2014; doi:10.1152/ajpregu.00117.2014.—We determined the contribution of vascular large conductance Ca -activated K (BK) and L-type Ca channel dysregulation to exaggerated mortality in cecal ligation/ puncture (CLP)-induced septic BK channel 1-subunit knockout (BK 1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK 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 1-KO mice, but BK 1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK 1-KO mice), untreated CLP-BK 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 1-KO mice. Saline nicardipine-treated CLP-BK 1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK 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 Ca channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK 1-KO mice had blunted BK/enhanced L-type Ca channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK 1-KO mice by activating L-type Ca channels leading to blood pressure-independent tissue ischemia.