Septic shock is a syndrome defined by persistently reduced blood pressure despite fluid resuscitation leading to multiple organ failure resulting from overwhelming infection. It is a major cause of intensive care admission and is associated with a high mortality rate. The phosphorylation state of myosin light chain (MLC) in smooth muscle cells directly controls the contractility of blood vessels and the maintenance of blood pressure. Activation of AMP-activated protein kinase (AMPK) by calcium/calmodulin dependent protein kinase kinase beta (CaMKKβ) has previously been reported to inhibit MLC phosphorylation, and induce vasodilation in mice.We investigated the involvement of CaMKKβ in blood pressure control using a model of endotoxin induced septic shock. Using implantable telemetry probes, we recorded aortic blood pressure in age-matched male wild-type (WT) and CaMKKβ knockout (CaMKK KO) mice under both basal conditions and during endotoxin induced sepsis. We showed that in mice with global deletion of CaMKKβ, basal blood pressure is increased compared with their wild-type littermates. In addition, when treated with intraperitoneally injected bacterial endotoxin, the lack of CaMKKβ appeared to confer protection against hypotension, with significantly higher blood pressure seen in CaMKK KO mice, as well as improved mobility and general physiological state, compared with WT mice. We found no indication of altered inflammatory response between CaMKK KO and WT mice after intraperitoneal endotoxin injection. We are addressing the role of CaMKKβ in vascular smooth muscle MLC phosphorylation and the potential for AMPK involvement in the signalling pathways.Our findings suggest that loss of CaMKKβ in mice protects against septic shock through the maintenance of blood pressure. Inhibition of CaMKKβ could be an alternative strategy to assist with the maintenance of blood pressure during sepsis. FundingUK Medical Research Council, Imperial College London, and National Institute for Health Research Biomedical Research Centre at Imperial College NHS Trust.