Modulation of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during cardiac allograft rejection1 2.
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.
Szabó
Gábor
G
Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
Bährle
Susanne
S
Braun
Martin
M
Stumpf
Nicole
N
Vahl
Christian F
CF
Hagl
Siegfried
S
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
D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases