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Yang, Shaolong, Douglas J. Koo, Mian Zhou, Irshad H. Chaudry, and Ping Wang. Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis. Am J Physiol Gastrointest Liver Physiol 279: G1274-G1281, 2000.--Although plasma norepinephrine (NE) increases and hepatocellular function is depressed during early sepsis, it is unknown whether gut is a significant source of NE and, if so, whether gut-derived NE helps produce hepatocellular dysfunction. We subjected rats to sepsis by cecal ligation and puncture (CLP), and 2 h later (i.e., early sepsis) portal and systemic blood samples were collected and plasma levels of NE were assayed. Other rats were enterectomized before CLP. Hepatocellular function was assessed with an in vivo indocyanine green (ICG) clearance technique, systemic levels of tumor necrosis factor (TNF)-[Alpha], interleukin (IL)-1[Beta], and IL-6 were determined, and the effect of NE on hepatic ICG clearance capacity was assessed in an isolated, perfused liver preparation. Portal levels of NE were significantly higher than systemic levels at 2 h after CLP. Prior enterectomy reduced NE levels in septic animals. Thus gut appears to be the major source of NE release during sepsis. Enterectomy before sepsis also attenuated hepatocellular dysfunction and downregulated TNF-[Alpha], IL-1[Beta], and IL-6. Perfusion of the isolated livers with 20 nM NE (similar to that observed in sepsis) significantly reduced ICG clearance capacity. These results suggest that gut-derived NE plays a significant role in hepatocellular dysfunction and upregulating inflammatory cytokines. Modulation of NE release and/or hepatic responsiveness to NE should provide a novel approach for maintaining hepatocellular function in sepsis. indocyanine green clearance; enterectomy; isolated, perfused rat liver; cecal ligation and puncture; inflammatory cytokines

Ba, Zheng F., Ping Wang, Douglas J. Koo, Mian Zhou, William G. Cioffi, Kirby I. Bland, and Irshad H. Chaudry. Testosterone receptor blockade after trauma and hemorrhage attenuates depressed adrenal function. Am J Physiol Regulatory Integrative Comp Physiol 279: R1841-R1848, 2000.--Although the testosterone receptor antagonist flutamide restores the depressed immune function in males after trauma and hemorrhage, it remains unknown whether this agent has any salutary effects on adrenal function. To study this, male rats underwent laparotomy and were bled to and maintained at a blood pressure of 40 mmHg until 40% of the shed blood volume was returned in the form of Ringer lactate. Animals were then resuscitated and fiutamide (25 mg/kg body wt) was administered subcutaneously. Plasma adrenocorticotropic hormone (ACTH) and corticosterone, as well as adrenal corticosterone and cAMP were measured 20 h after resuscitation. In additional animals, ACTH was administered and ACTH-induced corticosterone release and adrenal cAMP were determined. The results indicate that adrenal contents of corticosterone and cAMP were significantly decreased and morphology was altered after hemorrhage. Administration of flutamide improved corticosterone content, restored cAMP content, and attenuated adrenal morphological alterations. Flutamide also improved the diminished ACTH-induced corticosterone release and adrenal cAMP response at 20 h after hemorrhage and resuscitation. Furthermore, the diminished corticosterone response to ACTH stimulation in the isolated adrenal preparation was improved with flutamide. These results suggest that flutamide is a useful adjunct for improving adrenal function in males following trauma and hemorrhage. adrenal function; isolated perfused adrenal preparation; corticosterone; adenosine 3',5'-cycle monophosphate; adrenocorticotropic hormone

Yang, Shaolong, Mian Zhou, Douglas J. Koo, Irshad H. Chaudry, and Ping Wang. Pentoxifylline prevents,; the transition from the hyperdynamic to hypodynamic response during sepsis. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H1036-H1044, 1999.--The cardiovascular response to sepsis includes an early, hyperdynamic phase followed by a late, hypodynamic phase. Although administration of pentoxifylline (PTX) produces beneficial effects in sepsis, it remains unknown whether this agent prevents the transition from the hyperdynamic to the hypodynamic response during the progression of sepsis. To study this, male adult rats were subjected to polymicrobial sepsis by ceca] ligation and puncture (CLP). At 1 h after CLP, PTX (50 mg/kg body wt) or vehicle was infused intravenously over 30 min. At 20 h after CLP (i.e., the late stage of sepsis), cardiac output and organ blood flow were measured by radioactive microspheres. Systemic and regional (i.e., hepatic, intestinal, and renal) oxygen delivery (D[O.sub.2]) and oxygen consumption (V[O.sub.2]) were determined. Moreover, plasma levels of lactate and alanine aminotransferase (ALT) were measured, and histological examinations were performed. In additional animals, the necrotic cecum was excised at 20 h after CLP, and mortality was monitored for 10 days thereafter. The results indicate that cardiac output, organ blood flow, and systemic and regional D[O.sub.2] decreased by 36-65% (P [is less than] 0.05) at 20 h after CLP. Administration of PTX early after the onset of sepsis, however, prevented reduction in measured hemodynamic parameters and increased systemic and regional D[O.sub.2] and V[O.sub.2] by 50-264% (P [is less than] 0.05). The elevated levels of lactate (by 173%, P [is less than] 0.05) and ALT (by 718%, P [is less than] 0.05), as well as the morphological alterations in the liver, small intestine, and kidneys during sepsis were attenuated by PTX treatment. In addition, PTX treatment decreased the mortality rate from 50 to 0% (P [is less than] 0.05) after CLP and cecal excision. Because PTX prevents the occurrence of hypodynamic sepsis, this agent appears to be a useful adjunct for maintaining hemodynamic stability and preventing lethality from sepsis. cecal ligation and puncture; regional blood flow; cardiovascular responses; oxygen delivery; oxygen consumption; lactate