Fig. 6. Model of Rho/Rho-kinase signaling pathway for mediating the contraction of vascular smooth muscle. Agonists bind to heterotrimeric G-protein–coupled receptors and activate Gα^12/13. After activation by Gα^12/13, GEFs catalyze the Rho · GDP · GDI complex to stimulate nucleotide exchange on Rho (GTP replaces GDP), followed by dissociation of Rho · GTP from GDI and translocation of Rho · GTP to the plasma membrane. In the presence of active Rho · GTP, Rho-kinase also transfers from the cytosol to the membrane and becomes active. Activated Rho-kinase subsequently phosphorylates MLCPh and depresses its activity, thus attenuating MLC dephosphorylation and increasing the level of phosphorylated MLC, and finally enhancing contraction of the smooth muscle without increasing [Ca²⁺]ⁱ. Rho-kinase likely also phosphorylates MLC directly. GTPγS is able to bind and activate Gα^12/13and Rho. Y27632 inhibits the translocation and activation of Rho-kinase. Gα^12/13and Rho are the likely targets of sevoflurane. A = agonist; [Ca²⁺]ⁱ= Ca²⁺concentration; Gα^12/13=^12/13subunit of heterotrimeric G-protein; GDI = guanosine nucleotide dissociation inhibitor; GDP = guanosine 5-diphosphate; GEFs = guanine nucleotide exchange factors; GTP = guanosine 5-triphosphate; GTPγS = guanosine 5′-[γ-thio]triphosphate; MLC = myosin light chain; MLCPh = myosin light chain phosphatase; R = receptor; SEV = sevoflurane. Dotted lines = inhibitory effect.