title: Modulation of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during cardiac allograft rejection1 2.
abstract: BACKGROUND
  This study investigated the changes of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during acute cardiac transplant rejection.
  
  
  METHODS
  Isogeneic Lewis to Lewis and allogeneic Dark Agouti (DA) to Lewis rat cardiac transplants were studied 3 and 5 days after heterotopic intraabdominal transplantation (n=6/group). Myocardial blood flow (MBF), left ventricular systolic pressure (LVSP), maximum pressure development (+dP/dt), and end-diastolic pressure (LVEDP) were measured using an intraventricular balloon. Contractile response to dobutamine (5 microg/kg/min) was also assessed. In separate groups beta-adrenergic receptor density and adenylyl cyclase activity were measured in the grafts, in the recipients' native hearts and in native hearts of sham-operated controls.
  
  
  RESULTS
  During mild to moderate rejection cardiac function indices remained unchanged, although MBF and contractile response to dobutamine decreased significantly (P<0.05) in the allogeneic group. The beta-adrenergic receptor density was significantly (P<0.05) increased in both isografts and allografts and in the native hearts of allografted recipients in comparison to native hearts of controls. Adenylyl cyclase activity showed a significant decrease (P<0.05) only in allografts. During severe rejection, LVSP and +dP/dt decreased and LVEDP increased in allografts in comparison to isografts (P<0.05). This was accompanied by a significant decrease in MBF, contractile response to dobutamine, beta-adrenergic receptor density, and adenylyl cyclase activity (P<0.05).
  
  
  CONCLUSIONS
  Both microcirculatory disturbances and primary alteration in adenylyl cyclase activity may contribute to decreased contractile reserve in mild to moderate cardiac allograft rejection, whereas beta-adrenergic receptor density seems to be also influenced by cardiac denervation. Severe rejection leads to systolic and diastolic heart failure with complex dysregulation of the beta-adrenergic receptor/adenylyl cyclase pathway and impaired microcirculation.
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
authors.forename: Susanne
authors.initials: S
authors.lastname: Bährle
authors.forename: Martin
authors.initials: M
authors.lastname: Braun
authors.forename: Nicole
authors.initials: N
authors.lastname: Stumpf
authors.forename: Christian F
authors.initials: CF
authors.lastname: Vahl
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hagl
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003326:Coronary Circulation / Q000502:physiology; D003971:Diastole; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology*; D008297:Male; D009200:Myocardial Contraction; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013599:Systole; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic; D016277:Ventricular Function, Left
chemical_list: D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases