We used isolated superior mesenteric arteries (SMAs) from
hemorrhagic-shock rats and
hypoxia-treated vascular smooth muscle cells (VSMCs; mimicking the
shock state) to observe the effects of
platelet-derived growth factor (PDGF; Rac1 stimulator) and
NSC23766 (Rac1 antagonist) on vascular reactivity and the relationship with the
Rho kinase-
myosin light-chain phosphatase (MLCP) and
p21-activated kinase (PAK)-
myosin light-chain kinase (MLCK) signal pathway. The results indicated that the contractile responses of the SMAs and VSMCs were significantly increased at early
shock or after transient
hypoxia.
NSC23766 (Rac1 antagonist) further increased, whereas PDGF (Rac1 stimulator) decreased the contractile responses of SMAs and VSMCs. In the late period of
shock or prolonged
hypoxia, the contractile responses of SMAs and VSMCs were significantly decreased;
NSC23766 increased (whereas PDGF further decreased) the contractile response of the SMAs and VSMCs. Activation of Rac1 with PDGF significantly increased the activity of PAK and MLCP, and decreased
Rho kinase and MLCK activity and 20-kDa
myosin light-chain phosphorylation in VSMCs. The PAK inhibitor PAK-18 significantly antagonized the PDGF-induced decrease in MLCK activity, whereas the
Rho kinase antagonist
Y-27632 further enforced the PDGF-induced increase in MLCP activity. Simple fluid
resuscitation did not improve but in combination with
NSC23766 significantly improved vascular reactivity and animal survival at 24 hours. This suggested that Rac1 has an inhibitory effect on vasoreactivity after
shock. Rac1-mediated regulation of vascular reactivity is mainly through activation of PAK, inhibition of MLCK and inhibition of
Rho kinase, unpack the inhibition of
Rho kinase to MLCP. Rac1 may be a potential target to treat vascular hyporeactivity in many critical conditions.