Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Figure 1 Proposed downstream signalling pathways of endothelium-dependent vasodilatation in splanchnic vasculature. Nitric oxide (NO) is a key mediator of mesenteric vasodilatation in cirrhosis. G protein-coupled receptor-mediated activation of G-proteins augments the production and activation of a number of vasodilatory pathways including endothelial nitric oxide synthase/nitric oxide (eNOS/NO), vasodilating prostacyclins, and metabolites of arachidonic acid (AA) metabolism which act as endothelium-derived hyperpolarizing factors such as epoxyeicosatrienoic acids (EETs) in vascular endothelial cells. The eNOS converts L-arginine to produce NO which diffuses into the vascular smooth muscle cells (VSMCs). In VSMCs, NO which activates membrane-bound guanylyl cyclase enzyme to release cyclic guanosine monophosphate from guanosine triphosphate, mediates vasodilatation by increasing K⁺ efflux via large-conductance and intermediate-conductance calcium-activated potassium channels and by decreasing Ca²⁺ influx via voltage-gated calcium channels, and by dephosphorylation of myosin light chain. In addition to NO, vasodilators such as prostaglandin I₂, derived from AA by the action of cyclooxygenase enzyme which activates membrane-bound adenylyl cyclase enzyme to release cyclic adenosine monophosphate from adenosine triphosphate, causes vasodilatation by increasing K⁺ efflux and dephosphorylation of myosin light chain. The EETs deriving from AA by the action of endothelial epoxygenases such as cytochrome P450 directly act on Ca²⁺ and K⁺ channels, causing hyperpolarization of VSMC membrane and subsequent vasodilatation. NO: Nitric oxide; GPCR: G protein-coupled receptor; eNOS/NO: Endothelial nitric oxide synthase/nitric oxide; AA: Arachidonic acid; EDHFs: Endothelium-derived hyperpolarizing factors; EETs: Epoxyeicosatrienoic acids; VECs: Vascular endothelial cells; VSMCs: Vascular smooth muscle cells; cGMP: Cyclic guanosine monophosphate; GTP: Guanosine triphosphate; BK_Ca2+: Large-conductance; IK_Ca2+: Intermediate-conductance; VGCCs: Voltage-gated calcium channels; PGI₂: Prostaglandin I₂; COX: Cyclooxygenase; cAMP: Cyclic adenosine monophosphate; ATP: Adenosine triphosphate; CYP450: Cytochrome P450.