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ABSTRACT: BACKGROUND: Previous studies have demonstrated differences among organs in terms of shock-induced vascular reactivity and a role for adenosine A2A receptors (A2ARs) in protection against ischemia/reperfusion injury. However, the contributions of A2ARs to organ-specific vascular reactivity and the protection of vascular responsiveness following shock are currently unknown. METHODS: We investigated the role of A2ARs in different arteries, including the left femoral artery (LFA), thoracic aorta (TA), superior mesenteric artery (SMA), right renal artery (RRA), pulmonary artery (PA), and middle cerebral artery (MCA), in hemorrhagic-shock rats. RESULTS: The vascular reactivities of the LFA, SMA, RRA, and MCA increased slightly during early shock and then gradually decreased, whereas those of the PA and TA decreased from the start of shock. Different blood vessels lost vascular reactivity at different rates compared with controls; the LFA had the highest rate of loss (64.51%), followed by the SMA (44.69%), TA (36.06%), PA (37.83%), and RRA (32.33%), whereas the MCA had the lowest rate (18.45%). The rate of loss of vascular reactivity in the different vessels was negatively correlated with A2AR expression levels in normal and shock conditions. The highly selective A2AR agonist CGS 21680 significantly improved vascular reactivity, hemodynamic parameters, and animal survival, whereas the specific antagonist SCH58261 further decreased the shock-induced reduction in vascular reactivity and hemodynamic parameters. CONCLUSIONS: A2ARs are involved in the regulation and protection of vascular reactivity following shock. A2AR activation may have a beneficial effect on hemorrhagic shock by improving vascular reactivity and hemodynamic parameters.
Journal of Surgical Research 04/2013; · 2.25 Impact Factor
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ABSTRACT: Our previous and other studies have shown that hypotensive or hypothermic resuscitation have beneficial effects on uncontrolled hemorrhagic shock. Whether hypothermia can increase the beneficial effect of hypotensive resuscitation on hemorrhagic shock is not known.
Two-hundred and twenty Sprague-Dawley rats were used to make uncontrolled hemorrhagic shock. Before bleeding was controlled, rats received normotensive or hypotensive resuscitation (target mean arterial pressure at 80 or 50 mmHg) in combination with normal (37°C) or mild hypothermia (34°C) (phase II). After bleeding was controlled, rats received whole blood and lactated Ringer's solution resuscitation for 2 h (phase III). The animal survival, blood loss, fluid requirement, cardiac output, and coagulation functions, as well as vital organ function, mitochondrial function, and energy metabolism of liver, kidney and intestines, were noted.
Short-term, mild hypothermia before bleeding was controlled increased the beneficial effect of hypotensive resuscitation. Hypothermia further decreased blood loss, oxygen consumption, and functional damage to the liver, kidney, and intestines during hypotensive resuscitation, protected mitochondrial function and energy metabolism (activity of Na(+)-K(+)-ATPase), and further improved survival time and survival rate (hypothermic/hypotensive combined group: survival rate, 9/10; survival time, 616 min; normothermic/normotensive group: 1/10, 256 min; hypothermic/normotensive group: 4/10, 293 min). Hypothermia slightly inhibited coagulation function.
Mild hypothermia before bleeding is controlled can increase the beneficial effect of hypotensive resuscitation on uncontrolled hemorrhagic shock. The mechanism underlying the benefits of short-term hypothermia may be related to the decrease in oxygen consumption and metabolism, and protection of mitochondrial and organ functions.
Anesthesiology 04/2012; 116(6):1288-98. · 5.36 Impact Factor
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ABSTRACT: The authors previously found that 50-60 mmHg mean arterial blood pressure (MAP) was an optimal target resuscitation pressure for hemorrhagic shock before bleeding was controlled in rats. However, the optimal target resuscitation pressure for hemorrhagic shock after bleeding has been controlled has not been determined.
A model of uncontrolled hemorrhagic shock was initiated in anesthetized Wistar rats. After 1-h hypotensive resuscitation and bleeding was stopped, rats received fluid resuscitation to different target MAPs (50, 70, or 90 mmHg) with lactated Ringer's solution (LR), 6% hydroxyethyl starch (HES), LR+HES (2:1) or LR+whole blood (2:1) for 2 h. Animal survival, hemodynamic parameters, and vital organ functions were observed.
After bleeding had been controlled, mildly hypotensive resuscitation at a target MAP of 70 mmHg increased the survival time and survival rate compared with a target MAP of 50 mmHg and 90 mmHg (P < 0.05 or 0.01). Hemodynamic parameters, cardiac output, oxygen delivery, and vital organ function (including mitochondrial function) in 70 mmHg target MAP groups were better than in other two-target pressure groups (P < 0.05 or 0.01). Among the fluids tested, LR+whole blood (2:1) or LR+HES130 (2:1) had better effects than LR or HES alone at each level of target blood pressure.
Mildly hypotensive resuscitation is also needed for hemorrhagic shock after bleeding has been controlled, irrespective of whether crystalloids or colloids are used. The optimal target pressure was 70 mmHg in our rat model. A resuscitation pressure that is too low or too high cannot produce a good resuscitative effect.
Anesthesiology 11/2011; 116(1):103-12. · 5.36 Impact Factor
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ABSTRACT: Limited fluid resuscitation has been proven to have a good effect on uncontrolled hemorrhagic shock. Arginine vasopressin (AVP) and norepinephrine (NE) were used to treat vasodilatory or septic shock, and were used to reduce the fluid requirement for uncontrolled hemorrhagic shock. Based on their pressor and hemodynamic stabilization effects, it is speculated that AVP and NE may be a good treatment for uncontrolled hemorrhagic shock at early stage after hemostasis.
Experiments were conducted in two parts. Each part had control, lactated Ringer's solution (LR), whole blood, NE, arginine vasopressin (AVP), NE+AVP, and AVP+NE+whole blood. Rats (n = 8-10/group), respectively, received LR, whole blood, NE (1 μg/kg) and AVP (0.1 U/kg) infusion alone, or in combination after 60 min hypotensive resuscitation (50 mmHg). The volume in each group was two times the volume of shed blood.
Whole blood improved all observed parameters, particularly the tissue blood flow and mitochondrial function of liver and kidney, and the 12-h survival (50%). NE only increased the hemodynamics. 0.1 U/kg of AVP had a similar effect with whole blood on hemodynamics, tissue blood flow, mitochondrial function, and the 12-h survival. AVP+NE significantly improved all observed variables (P < 0.05 or 0.01), the 12-h survival was 70%. Whole blood further potentiated the beneficial effect of AVP+NE, and 12-h animal survival rate in this group was 80%.
AVP+NE is a good treatment for uncontrolled hemorrhagic shock at the early stage after hemostasis if blood is unavailable. Whole blood transfusion can potentiate this beneficial effect of AVP+NE.
Journal of Surgical Research 07/2011; 169(1):76-84. · 2.25 Impact Factor
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ABSTRACT: 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.
Journal of cardiovascular pharmacology 02/2011; 57(6):656-65. · 2.83 Impact Factor
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ABSTRACT: Studies have shown that permissive hypotension for uncontrolled hemorrhagic shock can result in good resuscitation outcome. The ideal target mean arterial pressure (MAP) and the tolerance time for permissive hypotension have not been determined.
To elucidate the ideal target MAP and tolerance time for permissive hypotension with uncontrolled hemorrhagic shock rats, the effects of different target MAPs (40, 50, 60, 70, 80, and 100 mmHg) and 60-, 90-, and 120-min permissive hypotension (50 mmHg) on uncontrolled hemorrhagic shock were observed.
Rats in normotensive groups (80 and 100 mmHg) had increased blood loss (101%, 126% of total blood volume), decreased hematocrit, decreased vital organ (liver and kidney) and mitochondrial function, and decreased animal survival rate (1 of 10). Rats in the 50- and 60-mmHg target MAP groups had decreased blood loss (52% and 69%, respectively), good hematocrit and vital organ and mitochondrial function, stable hemodynamics, and increased animal survival (8 of 10 and 6 of 10, respectively). Rats in the 40-mmHg target MAP group, although having decreased blood loss (39%), appeared to have very inferior organ function and animal survival (2 of 10). Animal survival (1 of 10) and vital organ function in the 120-min permissive hypotension group were significantly inferior to the 60- and 90-min groups. The 60- and 90-min groups had similar animal survival (8 of 10 and 6 of 10) and vital organ function.
A target resuscitation pressure of 50-60 mmHg is the ideal blood pressure for uncontrolled hemorrhagic shock. Ninety minutes of permissive hypotension is the tolerance limit; 120 min of hypotensive resuscitation can cause severe organ damage and should be avoided.
Anesthesiology 01/2011; 114(1):111-9. · 5.36 Impact Factor
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ABSTRACT: To investigate the effects of the balance in activity of RhoA and Rac1 on the shock-induced biphasic change in vascular reactivity and the related mechanism.
Vascular reactivity after hemorrhagic shock shows a biphasic change. RhoA and Rac1 are the main members of a family of Rho GTPases; whether and how they participate in the regulation of the biphasic change in vascular reactivity after shock is not known.
The relationship of the balance of the activity RhoA and Rac1 with the changes in vascular reactivity after hemorrhagic shock, the effects of artificially changing the balance of RhoA and Rac1 activity on vascular reactivity, and the roles of Rho kinase and p21-activated kinase (PAK) in RhoA/Rac1 regulation of vascular reactivity were observed in isolated superior mesenteric arteries (SMAs) from hemorrhagic shocked rats and hypoxia-treated vascular smooth muscle cells (VSMCs).
The reactivity of SMAs and VSMCs to norepinephrine after shock or hypoxia was positively correlated with changes in the RhoA and Rac1 activity ratio. Artificially changing the balance in activity of RhoA and Rac1 significantly changed the shock-induced biphasic response of vascular reactivity. Specific antagonist of Rho kinase and PAK (Y-27632 and PAK-18) respectively abolished the effect of activation of RhoA and Rac1. Activation of RhoA significantly increased the activity of Rho kinase and inhibited the activity of Rac1 in SMAs. Rac1 activation significantly increased the activity of PAK and decreased the activity of RhoA.
The balance in the activity of RhoA and Rac1 participated in the biphasic vascular reactivity seen after hemorrhagic shock. RhoA and Rac1 regulation of the vascular reactivity after shock are closely related to Rho kinase and the PAK pathway. RhoA regulates vascular reactivity mainly through activation of Rho kinase and inhibition of Rac1. Rac1 regulates vascular reactivity mainly through inhibition of RhoA and activation of PAK. These findings have potential significance for the treatment of vascular hyporesponsiveness.
Annals of surgery 01/2011; 253(1):185-93. · 7.90 Impact Factor
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ABSTRACT: RhoA, an important member of the Rho family of GTPases, has been implicated in many cellular processes. Our pilot study found that RhoA participated in the regulation of vascular reactivity after shock, but the mechanism was incompletely understood. Whether RhoA regulates vascular reactivity through the Rho kinase-myosin light-chain phosphatase (MLCP) and Rac1-p21-activated kinase (PAK)-myosin light-chain kinase (MLCK) signaling pathway needs investigation. With isolated, superior mesenteric arteries from hemorrhagic-shock rats and hypoxia-treated vascular smooth muscle cells (VSMCs), the effects of U-46619 (RhoA agonist) and C3 transferase (RhoA antagonist) on vascular reactivity, and the relationship to the Rho kinase-MLCP and Rac1-PAK-MLCK signaling pathways were observed. The vascular reactivity of the superior mesenteric artery and the contractile response of VSMCs to norepinephrine after prolonged hemorrhagic shock and hypoxia (2 h) were significantly decreased. Activation of RhoA with U-46619 significantly increased shock or hypoxia-induced decreased vascular reactivity. These effects of U-46619 were abolished by Y-27632 (Rho kinase inhibitor) and PDGF (Rac1 stimulator). Y-27632 had a stronger antagonistic effect than PDGF. U-46619 increased the activity of Rho kinase and MLCK, enhanced the phosphorylation of 20-kDa myosin light chain, and decreased the activity of Rac1, PAK, and MLCP in VSMCs after hypoxia. Y-27632-antagonized U-46619 induced the decrease of MLCP activity and the increase of 20-kDa myosin light chain phosphorylation. PDGF-antagonized U-46619 induced decrease of PAK activity and increase of MLCK activity. RhoA has an important role in the regulation of vascular reactivity after hemorrhagic shock. The Rho kinase-MLCP and Rac1-PAK-MLCK signal pathways participate in the regulatory process of RhoA. Rho kinase-MLCP may be the main signaling pathway by which RhoA regulates vascular reactivity.
AJP Heart and Circulatory Physiology 08/2010; 299(2):H292-9. · 3.71 Impact Factor
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ABSTRACT: The reduced vascular reactivity after severe trauma or shock played an important role in the development and outcome of shock. Our previous study showed that protein kinase C (PKC) took part in the regulation of vascular reactivity after hemorrhagic shock. The objective of this study was to investigate the protective effects of activation of PKC on hemorrhagic shock and its related mechanism.
Sprague dawley rats were subjected to hemorrhagic shock (40 mm Hg for 2 hours). Effects of the PKC agonist, phorbol-12-myristate-13-acetate (PMA), and its inhibitor, staurosporine, on hemodynamic parameters were observed in vivo or in vitro. The hemodynamic parameters included mean arterial blood pressure, left intraventricular systolic pressure, the maximal change rate of left intraventricular pressure (+/-dp/dtmax), blood gases including pH, Po2, Sao2, and base excess, animal survival time, the vascular reactivity and calcium sensitivity of superior mesenteric artery, and mitochondrial function and blood flow of liver and kidney.
Intravenous administration of PKC agonist, PMA, at the concentration of 1 microg/kg significantly increased the mean arterial blood pressure, left intraventricular systolic pressure, +/-dp/dtmax, the pressor effect, and the contractile response of norepinephrine, it also improved the blood gases, and prolonged the survival time of shocked rats. In addition, the intravenous administration of PMA improved mitochondrial function and liver and kidney blood flow. A total of 10(-7) mol/L of PMA administrated in vitro significantly improved the vascular reactivity and calcium sensitivity of superior mesenteric artery to norepinephrine and Ca2+. These effects of PMA were abolished by the PKC specific inhibitor staurosporine (1 microg/kg in vivo or 10(-7) mol/L in vitro).
Activation of PKC has protective effects on hemorrhagic shock. The mechanism is related not only to its hemodynamic stabilization effect via improving vascular reactivity and calcium sensitivity but also to its effect on improving the perfusion and mitochondrial function of vital organs.
The Journal of trauma 04/2010; 68(4):865-73. · 2.48 Impact Factor
