title: Beta-adrenergic receptor-dependent and -independent stimulation of adenylate cyclase is impaired during severe sepsis in humans.
abstract: OBJECTIVE
  a) To investigate the functional consequences of sepsis on the beta-adrenergic signal transduction in human circulating lymphocytes; b) to appreciate sepsis-associated catecholamine and cytokine release.
  
  
  METHODS
  Experimental, comparative study.
  
  
  METHODS
  Research laboratory in a university hospital.
  
  
  METHODS
  Healthy controls (n = 10); critically ill patients who were not septic (n = 7); septic patients with severe sepsis or septic shock (n = 11).
  
  
  RESULTS
  Experiments were carried out using freshly isolated peripheral blood mononuclear cells (PBMC). We measured beta-adrenergic receptor (betaAR) number and affinity, and intracellular cAMP content at baseline and after the pharmacological stimulation of each component of the beta-adrenergic complex: betaAR with isoproterenol, Gs-protein with sodium fluoride (NaF), adenylate cyclase with forskolin. Catecholamine (adrenaline, noradrenaline) and cytokine (TNFalpha, IL-1alpha, IL-1beta, IL-6) serum levels were measured. In both septic and non-septic patients we observed a similar 40 % down-regulation of betaARs compared to controls, and a reduced basal and isoproterenol-stimulated cAMP accumulation (p < 0.05). The cAMP production elicited by NaF or forskolin was lower in septic patients than in the controls (p < 0.01). Forskolin-stimulated cAMP accumulation was significantly lower in septic patients than it was in non-septic ones (p < 0.001). Catecholamine serum concentrations were increased in the two patient groups without any significant difference. Elevated cytokine serum levels were detected in 45% of the septic patients (versus 14% of non-septic patients p < 0.05).
  
  
  CONCLUSIONS
  Patients presenting with severe sepsis or septic shock have extended postreceptor defects of the beta-adrenergic signal transduction. This finding suggests a heterologous desensitization of adenylate cyclase stimulation.
authors.affiliation: Service de Réanimation Médicale, Hôpital de l'Archet, Nice, France. gbernard@unice.fr
authors.forename: G
authors.initials: G
authors.lastname: Bernardin
authors.forename: A D
authors.initials: AD
authors.lastname: Strosberg
authors.forename: A
authors.initials: A
authors.lastname: Bernard
authors.forename: M
authors.initials: M
authors.lastname: Mattei
authors.forename: S
authors.initials: S
authors.lastname: Marullo
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002395:Catecholamines / Q000097:blood*; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012772:Shock, Septic / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002395:Catecholamines; D016207:Cytokines; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D000262:Adenylyl Cyclases