Role of a cytokine-inducible nitric oxide synthase in the control of myocardial contractile state

Abstract

Nitric oxide (NO) is a nearly ubiquitous intercellular and intracellular chemical messenger produced by a family of enzymes collectively called NO synthases. Evidence from several laboratories documented the expression of the inducible NO synthase, or NOS2, within several cellular constituents of ventricular muscle, including cardiac myocytes, after exposure to inflammatory cytokines in vitro or in vivo. Cardiac microvascular endothelial cells, which are adjacent to myocytes in ventricular myocardium, also express NOS2 in response to cytokines, although NOS2 gene induction is differentially regulated between these two cell types through cell-specific second messenger pathways regulating transcriptional activators. Nitric oxide production in cardiac muscle is also regulated by other post-transcriptional and post-translational mechanisms. The autocrine or paracrine production of NO exerts important inotropic and lusitropic effects on cardiac contraction in several experimental preparations. In most cases, these functional effects are accompanied by NO-dependent increases in intracellular cyclic GMP, which may affect cardiac contraction through regulation of cyclic-AMP generation, L-type calcium current, or myofilament sensitivity to calcium in cardiac myocytes. Other cyclic-GMP-independent actions of NO may also mediate its contractile effects in the heart and may participate in the pathogenesis of the myocardial dysfunction accompanying local or systemic production of cytokines in sepsis, cardiac graft rejection, or heart failure.