6533b839fe1ef96bd12a59b2

RESEARCH PRODUCT

Targeting Heme-Oxidized Soluble Guanylate Cyclase

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Increased peripheral vascular resistance is a hallmark of advanced chronic congestive heart failure (CHF) and contributes to the phenomenon of increased afterload that complicates that condition. Multiple factors have been proposed to contribute to this phenomenon, such as increased sodium water content of the vasculature, increased activation of neurohormonal vasoconstrictor forces, and intrinsic abnormalities of the vasculature. During the past decade, it has also been shown that CHF is associated with a severe degree of endothelial dysfunction in experimental animals, as well as in humans. Given that the endothelium, as well as endothelium-dependent vasodilation, plays a crucial role in the control of systemic hemodynamics, this phenomenon is probably an important reason for increased vascular resistance and afterload in heart failure. Because the NO–cGMP–cGMP-dependent kinase-1 relaxation pathway is predominantly responsible for the regulation of vascular tone (Figure), numerous studies have examined abnormalities of this pathway in heart failure. Experimental and clinical studies revealed that NO production is decreased because of decreased expression of endothelial NO synthase and diminished endothelial NO synthase–mediated NO production. A further related mechanism related to this is increased production of vascular superoxide anions, which may react with NO in a diffusion-limited reaction to form the highly reactive intermediate peroxynitrite (Figure). Increased superoxide production, however, is clearly not limited to the endothelium, because more recent experimental studies revealed increased oxidative stress throughout the vasculature, including the media and adventitia.1 Oxidative stress within the media reacts with NO formed as it diffuses from the endothelium and also inhibits NO signaling, thereby causing a state of vascular NO resistance. Theoretically, the decrease in vascular NO bioavailability may be used as an argument to initiate …