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

Abstract

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 β1-subunit knockout (BK β1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK β1-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 β1-KO mice, but BK β1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK β1-KO mice), untreated CLP-BK β1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltration-independent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT but not CLP-BK β1-KO mice. Saline + nicardipine-treated CLP-BK β1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK β1-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 β1-KO mice had blunted BK/enhanced L-type Ca2+ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK β1-KO mice by activating L-type Ca2+ channels leading to blood pressure-independent tissue ischemia.

BK channel β1-subunit deficiency exacerbates vascular fibrosis and remodelling but does not promote hypertension in high-fat fed obesity in mice

“…[8] Breeding and maintenance of BK β1-knockout mice have been described previously. [10,11] Pups of BK β1-knockout mice were weaned at 4 weeks. Mice were divided into two groups at the end of 4 weeks and fed either a control diet D12450B (10 kcal% fat) or high fat diet (high-fat) D12492 (60 kcal% fat, Research Diets, Inc.) adlibitum .…”

“…[10,11] After 12 weeks on the control or high-fat diet, radiotelemeters (PA-C10, Data Sciences International, St. Paul, Minnesota, USA) were implanted under isoflurane anesthesia (2-3%). After the mice recovered from surgery (> 3 days), BP and HR were sampled continuously for 10 seconds every 10 minutes.…”

“…The high-fat diet fed rodent models have been used extensively in studies on the pathophysiology of obesity-associated metabolic disorders, and are presumed to mimic the etiology of primary human diet-induced obesity[17-19, 22]. BK β1-knockout mice have been used by others to mimic the SMC BK channel deficiency known to occur in hypertension[10,12], septic shock[11], and metabolic disorder. [20]…”

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon

“…enteric nervous system; large conductance calcium-activated K ϩ channel; gastrointestinal motility; obesity A HIGH-FAT DIET (HFD) can cause obesity (35) that leads to an increased risk for the development of type 2 diabetes (13,17,33), heart disease (29, 33), and arthritis (25). Obesity is also associated with gastrointestinal (GI) dysmotility (15,35,41,63). GI motility is controlled largely by interactions between enteric neurons, interstitial cells of Cajal (ICCs), and smooth muscle cells (SMCs) but how obesity alters the function of these cells is poorly understood.…”

“…Obesity is also associated with gastrointestinal (GI) dysmotility (15,35,41,63). GI motility is controlled largely by interactions between enteric neurons, interstitial cells of Cajal (ICCs), and smooth muscle cells (SMCs) but how obesity alters the function of these cells is poorly understood.…”