Effects of a novel soluble guanylyl cyclase mhtbrtor, lH-[1,2,4]oxadtazolo [4,3-a]qumoxal~n-l-one (ODQ), were characterized on guanylyl cyclase activity m cytosohc fraction of COS-7 cells overexpressmg the (Y, and PI subunits of the rat soluble enzyme ODQ was a noncompetmve mhtbttor of soluble guanylyl cyclase with respect to Mn'+ or Mn'+-GTP and was a mixed competrttve/noncompetltlve mhrbltor wtth respect to mtnc oxide (NO) donation ODQ (10 pmol/L) reduced deta nonoatestimulated cGMP productron m COS-7 cells overexpressmg soluble guanylyl cyclase and m rat aorttc vascular smooth muscle cells ODQ did not mhrbtt parttculate forms of the enzyme rat guanylyl cyclase-A, -B, or -C, did not block NO synthase, and did not auto-oxrdtze deta nonoate-donated NO m the presence of cells at physrologrcal pH Therefore, ODQ IS a selective mhrbttor of soluble guanylyl cyclase Using ODQ m isolated aorttc rmg preparations, we tested the hypothesis that soluble guanylyl cyclase mediates vasorelaxant acttvtty associated with NO Phenylephrme (100 nmol/L)-precontracted, isolated rat aortas were relaxed m a concentratton-dependent manner by deta nonoate (001 to 100 pmol/L) and mtroglycerm (001 to 300 hmol/L) ODQ (10 pmol/L) attenuated deta nonoate-and mtroglycermmediated relaxatron of contracted aortas ODQ had no effect on natrmrettc peptrde-, S-bromo-cGMP-, rsoproterenol-, or brmakahm-mediated aorttc relaxation These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant acttvtty associated with mtnc oxide (Hypertension. 1997;29 [part 2]:254-261.)Key Words l cychc GMP l endothelmm-dertved relaxing factor l guanylyl cyclase l mtrtc oxide l mtrtc oxtde synthase l natrmrettc peptrdes l vasodrlatatton N 'itrtc oxide is now known to be the maJor endothehum-dertved relaxmg factor I* Several vasodilators, mcludmg bradykmm, acetylcholme, and serotonm, are thought to have activity by virtue of then effects to strmulate endothelial cell NOS. 12 Several studies over the years have suggested that the vasodilatory actions of NO are mediated by increases m cGMP'-3 NO and several precursors of the radical activated soluble forms of guanylyl cyclase,l-4 and membrane permeable analogs of cGMP vasodilated blood vessels 1 5 In addltron, m most studies NO-stimulated production of cGMP correlates with the NO-mediated vasodilation However, NO-induced smooth muscle relaxation has been drssociated from increases m cGMP in some studies.4.6.7 Potential explanations for the latter observation are that NO also stimulates guanylyl cyclase activity in cell types other than vascular smooth muscle (ie, adventrtia, fibroblasts, autonomic nerves, and/or endothelmm), that current assays for vascular contractile responses are significantly more sensitive than the measurement of cGMP concentrations wnhm cellular compartments associated with vasoactivny, and that NO may mediate vascular effects independent of guanylyl cyclase stimulation Several groups have used either methylene blue or LY83583 as sGC mhibitors to focus on the latter ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.