Reversible contractile dysfunction in reversible experimental cardiac allograft rejection: alterations in the beta-receptor-stimulated adenylylcyclase pathway.

Alterations in the beta-adrenergic receptor adenylylcyclase (AC) pathway are well known in heart failure. Previous studies by our group have demonstrated impaired function of the AC pathway and contractile reserve when stimulated with isoproterenol (ISO) or forskolin (F) in cardiac allografts with moderate or severe rejection. To determine if recovery of the AC pathway occurs when rejection is reversed, we used a rat heterotopic heart transplant model. Lewis (L) rats received either isografts or Lewis-Brown Norway (LBN) allografts (ALLO). The hearts were explanted on Day 4 and reimplanted into a recipient syngeneic with the original donor (L to L, LBN to LBN). Grafts were harvested 2 days later and analyzed. Receptor-mediated modulation of AC activity was investigated using ISO, F, and the metabolic inhibitor of AC, R-N6-(2-phenylisopropyl)-adenosine (R-PIA). ISO- and F-mediated stimulation of AC were significantly impaired in ALLO (see Table). CARB and R-PIA remained unchanged. [table: see text] Reimplanted hearts had no histologic evidence of rejection and had normal cAMP production in response to ISO and F. In conclusion, AC alterations are concordant with histologic changes in this reversible model of heart failure. Such alterations may be a component in the contractile dysfunction associated with rejection.