Is prostacyclin responsible for producing the hyperdynamic response during early sepsis?
OBJECTIVE
Although polymicrobial sepsis is characterized by an early hyperdynamic phase (2-10 hrs after cecal ligation and puncture [CLP]), followed by a late hypodynamic phase (20 hrs after CLP), it remains unknown whether prostacyclin or prostaglandin I2 (PGI2) plays a significant role in modulating the hyperdynamic state during early sepsis. The aim of this study was to determine whether inhibition of PGI2 synthesis prevents the occurrence of the hyperdynamic response during early sepsis.


METHODS
Prospective, controlled animal study.


METHODS
A university research laboratory.


METHODS
Adult male Sprague-Dawley rats were subjected to sepsis by CLP.


METHODS
Blood samples were collected at 2, 5, 10, or 20 hrs after CLP, and plasma concentrations of PGI2, in the form of its stable product 6-keto-PGF1alpha, were measured by radioimmunoassay. In additional studies, a PGI2 synthase inhibitor, tranylcypromine, was administered subcutaneously at the time of CLP and again at 3 hrs after CLP. At 5 hrs after the onset of sepsis, the maximal rates of the left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax) were determined by an in vivo heart performance analyzer. Microvascular blood flow in the liver, small intestine, and spleen was assessed by laser Doppler flowmetry.


RESULTS
Plasma concentrations of 6-keto-PGF1alpha increased significantly at 2-20 hrs after CLP. At 5 hrs after the onset of sepsis, +/-dP/dt(max) and microvascular blood flow in the tested tissues increased significantly. Inhibition of PGI2 synthase activity did not prevent the occurrence of hypercardiovascular responses under such conditions. Moreover, the administration of tranylcypromine significantly reduced circulating concentrations of 6-keto-PGF1alpha at 5 hrs after CLP.


CONCLUSIONS
Because inhibition of PGI2 production did not prevent the occurrence of the hyperdynamic and hypercardiovascular response during the early stage of sepsis, mediators other than PGI2 appear to play a major role in producing the hyperdynamic response under such conditions.
Wang
P
P
Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence 02903, USA. pwang@lifespan.org
Zhou
M
M
Cioffi
W G
WG
Bland
K I
KI
Ba
Z F
ZF
Chaudry
I H
IH
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D011464:Epoprostenol / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007421:Intestine, Small / Q000098:blood supply; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000502:physiology; D008099:Liver / Q000098:blood supply; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000503:physiopathology*; D013154:Spleen / Q000098:blood supply; D014191:Tranylcypromine / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D014191:Tranylcypromine; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase