EXPRESSION, ACTIVITY AND FUNCTIONAL-SIGNIFICANCE OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN THE FAILING HUMAN HEART

Objectives. The study was designed to evaluate the functional impact o f nitric oxide (NO) generation within the myocardium on cardiac contra ction in the failing human heart. Background. Heart failure is associa ted with activation of cytokines and expression of inducible nitric ox ide synthase (NOS II), which generates NO from L-arginine. Nitric oxid e has been shown to modulate myocardial performance, raising the possi bility that cardiac generation of NO by NOS II modulates cardiac contr action in the failing human heart. Methods. Left ventricular (LV) tiss ue of 24 patients with end-stage heart failure was obtained during car diac transplantation. Gene expression of NOS II and endothelial NO-syn thase (NOS III) was quantified by competitive reverse transcription-po lymerase chain reaction and compared to tissues of five non-failing do nor hearts. Nitric oxide synthase II activity was determined by citrul line assay and related to changes in force of contraction induced by t he beta-adrenergic agonist isoproterenol, NO-donors and/or N-mono-meth yl-L-arginine (L-NMMA), an inhibitor of NOS. Results. While NOS III mR NA was reduced in failing hearts, NOS II mRNA was increased in failing LV tissue and correlated with NOS II activity. High NOS II activity w as associated with early relaxation and impaired responsiveness to bet a-adrenergic stimulation, that is, the inotropic response to isoproter enol in failing hearts was inversely related to NOS II activity (r = 0 .61, p < 0.005). Nitric oxide donors or L-NMMA did not affect myocardi al performance in failing hearts at baseline. However, L-NMMA enhanced the positive inotropic response to beta-adrenergic stimulation in fai ling hearts with high NOS II activity. Nitric oxide donors attenuated the isoproterenol-induced increase in force of contraction of failing hearts. Conclusions. Cardiac production of NO by NOS II attenuates the positive inotropic effects of beta-adrenergic stimulation and hastens relaxation in failing human hearts. (C) 1998 by the American College of Cardiology.