Molecular mechanism of contractile dysfunction in cardiac allograft rejection.
Alterations in the beta-adrenergic receptor adenylyl cyclase pathway are well known in heart failure. To determine if an alteration in this pathway occurs during the reversible phase of cardiac allograft rejection, we used a rat heterotopic heart transplant model. Lewis rats received either isografts or Lewis Brown Norway allografts. Cardiac grafts and native hearts were explanted 4, 5, or 6 days later. Receptor-mediated modulation of adenylyl cyclase activity was investigated using isoproterenol, forskolin, and the muscarinic and adenosine receptor agonists carbachol and R-N6-(C2-phenyl-isopropyl)-adenosine (R-PIA), respectively. Allografts demonstrated evidence of histological rejection and a significantly impaired response to forskolin and isoproterenol on all days: [table: see text] (% increase in cAMP in response to forskolin or isoproterenol +/- standard error. All results P less than 0.03 except Day 4 forskolin and Day 5 isoproterenol.) No significant difference was noted between isografts and allografts stimulated with carbachol and R-PIA. These data suggest that a primary alteration in adenylyl cyclase activity may be a component of the molecular basis of reversible contractile dysfunction in cardiac allograft rejection.
Hanna
A K
AK
Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia 19104.
Louie
M
M
Miller
J
J
Hirsch
A
A
Liang
B T
BT
DiSesa
V J
VJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D006084:Graft Rejection; D006321:Heart / Q000503:physiopathology*; D016027:Heart Transplantation; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew
D000262:Adenylyl Cyclases