SALUTARY EFFECTS OF ATP-MGCL2 ON ALTERED HEPATOCYTE SIGNAL-TRANSDUCTION AFTER HEMORRHAGIC-SHOCK

Although previous studies indicate that hepatocyte Pt purinoceptors, m acrophage adenosine 3',5'-cyclic monophosphate (cAMP), and beta-adrene rgic receptors decrease after hemorrhage and that administration of AT P-MgCl2 after hemorrhage normalizes these parameters, it is not known whether other aspects of hepatocyte signal transduction processes, suc h as transmembrane coupling, are also affected by hemorrhage and, if s o, whether ATP-MgCl2 has any beneficial effects on signal transduction . To study this, rats underwent a 5-cm midline laparotomy (i.e., traum a induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of a maximum bleed-out volume was returned in th e form of Ringer lactate (RL). They were then resuscitated with three times the volume of shed blood with RL over 45 min followed by two tim es the volume with RL + ATP-MgCl2 (50 mu mol/kg body wt) or an equival ent volume of saline over 95 min. Hepatocytes were isolated at 4 and 2 7 h after resuscitation, and basal as well as stimulated levels of cAM P and inositol 1,4,5-trisphosphate (IP3) were determined. The results indicate that basal levels of cAMP decreased whereas IP3 increased aft er hemorrhage and resuscitation. Receptor-dependent stimuli (i.e., glu cagon and vasopressin) failed to elicit cAMP or IP3 accumulation after hemorrhage. In contrast, receptor-independent stimulation was not imp aired. ATP-MgCl2 treatment, however, prevented the decreased basal lev els of cAMP and IP3 and the ability of hepatocytes to respond to recep tor-dependent stimulation. Thus ATP-MgCl2 treatment of animals after t rauma-hemorrhage and resuscitation attenuates the impaired second mess engers cAMP and IP3 and their membrane transduction processes.