Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome.
In this issue of the JCI, Stasch and colleagues suggest that a novel drug, BAY 58-2667, potently activates a pool of oxidized and heme-free soluble guanylyl cyclase (sGC; see the related article beginning on page 2552). The increased vasodilatory potency of BAY 58-2667 the authors found in a number of animal models of endothelial dysfunction and in human blood vessels from patients with diabetes suggests that there exists a subphenotype of endothelial dysfunction characterized by receptor-level NO resistance. Diseases associated with NO resistance would appear to be ideally suited for therapies directed at restoring redox homeostasis, sGC activity, and NO sensitivity.
Gladwin
Mark T
MT
Vascular Medicine Branch, National Heart, Lung, and Blood Institute, and Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. mgladwin@nih.gov
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D006152:Cyclic GMP / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D001565:Benzoates; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP