Beneficial effects of activation of PKC on hemorrhagic shock in rats.
BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Fang
Yuqiang
Y
State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Li
Tao
T
Fan
XiaoQing
X
Zhu
Yu
Y
Liu
Liangming
L
D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000098:blood supply; D008099:Liver / Q000098:blood supply; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000201:enzymology / Q000503:physiopathology*; D019311:Staurosporine / Q000494:pharmacology; D015996:Survival Rate
D010703:Phorbol Esters; C119222:phorbol-12-myristate; D011493:Protein Kinase C; D019311:Staurosporine; D002118:Calcium