Beneficial effect of cyclosporine A on traumatic hemorrhagic shock.
BACKGROUND
Vascular hyporeactivity plays an important role in severe trauma and shock. We investigated the beneficial effect of cyclosporine A (CsA) on traumatic shock and its relationship to vascular reactivity improvement and mitochondrial permeability transition pore (MPTP).


METHODS
Sodium pentobarbital-anesthetized rats were used to induce traumatic hemorrhagic shock by left femur fracture and hemorrhage, the beneficial effects of CsA (1, 5, and 10 mg/kg, intravenously) on animal survival, cardiovascular function, tissue blood perfusion, and mitochondrial function of vital organs were observed. In addition, hypoxia-treated vascular smooth muscle cells from normal rats were used to investigate the relationship of this beneficial effect of CsA to Rho-associated serine/threonine kinase (ROCK) and protein kinase C.


RESULTS
CsA prolonged the survival time and increased the 24-h survival rate of traumatic hemorrhagic shock (31%, 56%, and 56% in 1, 5, and 10 mg/kg CsA group versus 25% in lactated Ringer solution group). Five milligrams per kilogram of CsA had the best effect, which stabilized and improved the hemodynamics, increased the tissue blood flow, and improved the liver and kidney function including its mitochondrial function in shock rats. CsA had no significant influences on the production of inflammatory mediators and cardiac output after traumatic hemorrhagic shock. Further results indicated that CsA significantly improved the vascular constriction and dilation reactivity of superior mesenteric artery to norepinephrine and acetylcholine, which was antagonized by ROCK inhibitor, Y27632, but not by protein kinase C inhibitor, staurosporine. Further studies showed that CsA restored hypoxia-induced decrease of ROCK activity and inhibited the opening of MPTP in hypoxia-treated vascular smooth muscle cells.


CONCLUSIONS
CsA is beneficial for the treatment of traumatic hemorrhagic shock. The mechanism is mainly through improving the vascular reactivity, stabilizing the hemodynamics, and increasing tissue perfusion. This beneficial effect of CsA is related to the inhibitory effect of CsA on MPTP opening. ROCK is an important regulator molecule in this process.
Department of General Medicine, Medical Service Training Base, Third Military Medical University, Chongqing, China; State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
Yan
Y
Lei
State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
Xiaoyong
X
Peng
State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China. Electronic address: liangmingliu@yahoo.com.
Liangming
L
Liu
Department of Chemical Defense, Institute of Toxicology, Third Military Medical University, Chongqing, China.
Zhaojun
Z
Dong
State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China. Electronic address: lt200132@163.com.
Tao
T
Li
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D005260:Female; D006439:Hemodynamics; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000503:physiopathology; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D012774:Shock, Traumatic / Q000188:drug therapy* / Q000503:physiopathology; D054460:rho-Associated Kinases / Q000502:physiology
D016207:Cytokines; D019344:Lactic Acid; D016572:Cyclosporine; D054460:rho-Associated Kinases; D011493:Protein Kinase C
Cyclosporine A; Mitochondrial permeability transition pore; Rho-associated serine/threonine kinase; Traumatic hemorrhagic shock; Vascular hyporeactivity