Fig. 1

The principal mechanisms involved in the regulation of vascular tone during vasoplegia as well as treatment options at the central, cellular, and intracellular levels. Central level. Inflammatory triggers such as tumor necrosis factor α (TNF, interleukin (IL)-1 and IL-6 activate the neuro-immune system. This activation leads to norepinephrine, epinephrine, cortisol, vasopressin, and indirectly angiotensin II production in order to counteract vasoplegia. Overactivation of this system may be treated at this integrative level with α₂ agonists and selective β₁ blockers. Cellular level. G-protein-coupled receptors are predominantly involved in vascular smooth muscle cell contraction: α₁ adrenoceptors (α ₁ AR), vasopressin 1 receptors (V1R), and angiotensin type 1 receptors (AT-R1). These receptors activate phospholipase C (PLC) with generation of inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidyl inositol 4,5 bisphosphate (PiP ₂ ). DAG stimulates protein kinase C (PKC), which in turn activates voltage-sensitive calcium channels, while IP3 activates sarcoplasmic reticulum calcium channels. α₁ARs increase intracellular calcium by receptor-operated calcium channels (ROCC) stimulation. Available treatments at this level are epinephrine, norepinephrine, dopamine, phenylephrine, selepressin, vasopressin (V1), and angiotensin II. Adrenomedullin primarily acts on endothelial cells. Intracellular level. Translocation of nuclear factor-κB (NF-κB) into the nucleus induces pro-inflammatory cytokine production. These cytokines enhance inducible nitric oxide synthase (iNOS) expression and overproduction of NO. This molecule activates cyclic guanosine monophosphate production as a mediator of vasodilation. Available treatments at this level are glucocorticoids (at different steps), β₁ blockade, and methylene blue. Vascular sensitive calcium channel (VSCC)