During periods of acute rejection, transplanted hearts have increased nitric oxide (NO) production and depressed contractile function. Myocytes isolated from rejecting hearts exhibit parallel increases in NO production and reduced shortening, indicating that the contractile dysfunction of the transplanted heart is intrinsic to the myocytes. We tested the hypothesis that the contractile dysfunction of the rejecting heart is due to an NO-mediated inhibition of the L-type calcium current. Ventricular myocytes isolated from rejecting rat hearts (allografts) expressed inducible nitric oxide synthase (iNOS) and produced substantially more NO than did myocytes isolated from non-rejecting rat hearts (isografts). Aminoguanidine, an inhibitor of iNOS, reduced NO production by allograft myocytes, but was without effect on NO production by isograft myocytes. In the absence of exogenous l -arginine (the precursor of NO), the calcium current was identical in allograft and isograft myocytes. In the presence of l -arginine, the calcium current was reduced in allograft myocytes compared to isograft myocytes. Superfusion of the myocytes with either aminoguanidine or KT5823 (an inhibitor of the cyclic GMP-dependent protein kinase) reversed the depression of the calcium current in allograft myocytes, but neither inhibitor had an effect on calcium current in isograft myocytes. These results indicate that increased production of NO by myocytes isolated from rejecting hearts leads to a reduction in the calcium current. This mechanism may contribute substantially to the contractile dysfunction of rejecting transplanted hearts.
Copyright 2001 Academic Press.