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 of nitric oxide (NO) generation within the myocardium on cardiac contraction in the failing human heart. Background. Heart failure is associated with activation of cytokines and expression of inducible nitric oxide synthase (NOS II), which generates NO from L-arginine. Nitric oxide has been shown to modulate myocardial performance, raising the possibility that cardiac generation of NO by NOS II modulates cardiac contraction in the failing human heart. Methods. Left ventricular (LV) tissue of 24 patients with end-stage heart failure was obtained during cardiac transplantation. Gene expression of NOS II and endothelial NO-synthase (NOS III) was quantified by competitive reverse transcription-polymerase chain reaction and compared to tissues of five nonfailing donor hearts. Nitric oxide synthase II activity was determined by citrulline assay and related to changes in force of contraction induced by the β-adrenergic agonist isoproterenol, NO-donors and/or N-mono-methyl-L-arginine (L-NMMA), an inhibitor of NOS. Results. While NOS III mRN was reduced in failing hearts, NOS II mRN was increased in failing LV tissue and correlated with NOS II activity. High NOS II activity was associated with early relaxation and impaired responsiveness to β-adrenergic stimulation, that is, the inotropic response to isoproterenol in failing hearts was inversely related to NOS II activity (r = 0.61, p < 0.005). Nitric oxide donors or L-NMM did not affect myocardial performance in failing hearts at baseline. However, L-NMM enhanced the positive inotropic response to β-adrenergic stimulation in failing 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 β-adrenergic stimulation and hastens relaxation in failing human hearts.