BKCa channel beta‐1 subunit deficiency exaggerates microcirculatory dysfunction and mortality in CLP‐induced septic mice.

BKCa channels in smooth muscle cells are composed of pore forming α‐subunits and accessory beta1‐subunits that modulate Ca 2+ sensitivity of α‐subunits. BKCa channels regulate arterial tone, and earlier studies in human and animals suggested that activation of BKCa channels may contribute to reduced arterial reactivity to norepinephrine in septic shock. Our recent studies suggested that activation of BKCa channels may protect against hypotension and mortality, since inhibition of BKCa channels exaggerates hypotension and mortality in endotoxemic mice. In current studies, we measured mean arterial pressure (MAP) and heart rate (HR) in cecal ligation/puncture (CLP)‐induced septic shock BKCa channel β1‐subunit knockout (KO) mice using radiotelemetry. After CLP, KO mice exhibited a more rapid fall in MAP, when compared to wild‐type (WT) mice. There was a HR‐independent shorter latency to mortality and higher mortality rate in KO compared to WT mice. 24 h after CLP, KO mice had more severe hypothermia and lower peripheral perfusion, measured in paw flow by scanning laser Doppler. Polymorphonuclear leukocyte infiltration was higher in liver tissues, but not in kidneys and intestine tissues from KO mice. KO mice demonstrated more severe small intestinal mucosal necrosis. Serum TNF‐α and IL‐6 levels in CLP‐KO mice were slightly higher than CLP‐WT mice 24 h post CLP. Our results confirmed that inhibition of BKCa channels does not protect against hypotension in septic shock. BKCa channel deficiency exaggerates mortality via microcirculatory dysfunction.