Heterogeneous expression and activity of endothelial and inducible nitric oxide synthases in end-stage human heart failure: their relation to lesion site and beta-adrenergic receptor therapy.

Background: Recent reports have suggested that excessive amounts of endogenous NO may contribute to the myocardial dysfunction and injury in heart failure. In the present report, we investigate the cellular expression and activity of endothelial (eNOS) and inducible (iNOS) NO synthase in failing human hearts with special reference to the underlying lesion and drug therapy.

Methods And Results: Myocardial tissues were obtained from 28 failing human hearts with various pathogeneses and 4 nonfailing hearts as controls. Only weak or focal expression of both eNOS and iNOS was seen in ventricles of nonfailing hearts. In failing hearts, immunoreactivity and hybridization signals for eNOS were increased only in cardiac myocytes of subendocardial areas. Signals for iNOS in cardiac myocytes were consistently seen in heart failure of various pathogeneses and were apparent in both infarcted and noninfarcted regions of ischemic cardiomyopathy. Apparent signals for iNOS were also seen in infiltrating macrophages in infarcted regions of ischemic cardiomyopathy, myocarditis, and septic hearts. The expression of eNOS but not iNOS in the myocytes was intimately associated with beta-adrenergic therapy before the operation, being more abundant in patients on beta-blockers compared with diminished presence in patients on beta-agonists. In contrast to immunohistochemical data, iNOS activity was more variable than constitutive NOS activity and correlated significantly with the density of infiltrating macrophages.

Conclusions: These results suggest that whereas increased eNOS and/or iNOS expression in failing cardiac myocytes may in general contribute to myocardial dysfunction, myocyte injury or death associated with inflammatory lesions may be caused in part by abundant iNOS expression within infiltrating macrophages rather than cardiac myocytes.