We have previously reported that inhibition of Cu/Zn superoxide dismutase (SOD) in endothelium-removed bovine pulmonary arteries (BPA) attenuates nitrovasodilator-elicited relaxation and that a NADH oxidase linked to the redox status of cytosolic NADH is the major detectable source of superoxide (O₂) production in this tissue. In the present study, we investigated whether NADH oxidase-derived O₂ participated in inhibition of nitrovasodilator-elicited relaxation and soluble guanylate cyclase (sGC) stimulation. Lactate (10 mM) and pyruvate (10 mM) were employed to increase and decrease, respectively, NADH-dependent O₂ production in the BPA presumably by modulating cytosolic NAD(H) through the lactate dehydrogenase reaction. A 30-min pretreatment with 10 mM diethyldithiocarbamate (DETCA) was used to inhibit Cu/Zn SOD, and S-nitroso-N-acetylpenicillamine (SNAP) was employed as a source of nitric oxide (NO). Lactate or pyruvate did not alter relaxation to NO. However, when the response to NO was inhibited by DETCA, lactate potentiated and pyruvate reduced the inhibitory effects of DETCA. SOD attenuated the inhibitory effects of DETCA plus lactate. In the presence of 10 µM SNAP, the activity of sGC in a BPA homogenate preparation (which was reconcentrated to approximate tissue conditions) was not altered by SOD. However, NADH (0.1 mM) decreased sGC activity by 70%, and this effect of NADH was attenuated in the presence of SOD. Thus cytosolic NADH redox and Cu/Zn SOD activity have important roles in controlling the inhibitory effects of O₂ derived from NADH oxidase on sGC activity and cGMP-mediated relaxation to nitrovasodilators in BPA.

nitric oxide; redox; superoxide anion; superoxide dismutase; reduced nicotinamide adenine dinucleotide

This article has been cited by other articles:

				W. J. Pearce, J. M. Williams, C. R. White, and T. M. Lincoln Effects of chronic hypoxia on soluble guanylate cyclase activity in fetal and adult ovine cerebral arteries J Appl Physiol, July 1, 2009; 107(1): 192 - 199. [Abstract] [Full Text] [PDF]

				T. N. Milovanova, V. M. Bhopale, E. M. Sorokina, J. S. Moore, T. K. Hunt, M. Hauer-Jensen, O. C. Velazquez, and S. R. Thom Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo J Appl Physiol, February 1, 2009; 106(2): 711 - 728. [Abstract] [Full Text] [PDF]

				T. N. Milovanova, V. M. Bhopale, E. M. Sorokina, J. S. Moore, T. K. Hunt, M. Hauer-Jensen, O. C. Velazquez, and S. R. Thom Lactate Stimulates Vasculogenic Stem Cells via the Thioredoxin System and Engages an Autocrine Activation Loop Involving Hypoxia-Inducible Factor 1 Mol. Cell. Biol., October 15, 2008; 28(20): 6248 - 6261. [Abstract] [Full Text] [PDF]

				T. Yada, H. Shimokawa, K. Morikawa, A. Takaki, Y. Shinozaki, H. Mori, M. Goto, Y. Ogasawara, and F. Kajiya Role of Cu,Zn-SOD in the synthesis of endogenous vasodilator hydrogen peroxide during reactive hyperemia in mouse mesenteric microcirculation in vivo Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H441 - H448. [Abstract] [Full Text] [PDF]

				E. Toth, A. Racz, J. Toth, P. M. Kaminski, M. S. Wolin, Z. Bagi, and A. Koller Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH2/TXA2 mediation Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3096 - H3104. [Abstract] [Full Text] [PDF]

				R. A. Oeckler, E. Arcuino, M. Ahmad, S. C. Olson, and M. S. Wolin Cytosolic NADH redox and thiol oxidation regulate pulmonary arterial force through ERK MAP kinase Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1017 - L1025. [Abstract] [Full Text] [PDF]

				S. A. Gupte, P. M. Kaminski, B. Floyd, R. Agarwal, N. Ali, M. Ahmad, J. Edwards, and M. S. Wolin Cytosolic NADPH may regulate differences in basal Nox oxidase-derived superoxide generation in bovine coronary and pulmonary arteries Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H13 - H21. [Abstract] [Full Text] [PDF]

				S. A. Gupte, M. Arshad, S. Viola, P. M. Kaminski, Z. Ungvari, G. Rabbani, A. Koller, and M. S. Wolin Pentose phosphate pathway coordinates multiple redox-controlled relaxing mechanisms in bovine coronary arteries Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2316 - H2326. [Abstract] [Full Text] [PDF]

				T. J. Bivalacqua, J. S. Armstrong, J. Biggerstaff, A. B. Abdel-Mageed, P. J. Kadowitz, W. J. G. Hellstrom, and H. C. Champion Gene transfer of extracellular SOD to the penis reduces O2−{middle dot} and improves erectile function in aged rats Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1408 - H1421. [Abstract] [Full Text] [PDF]

				S. A. Gupte, K.-X. Li, T. Okada, K. Sato, and M. Oka Inhibitors of Pentose Phosphate Pathway Cause Vasodilation: Involvement of Voltage-Gated Potassium Channels J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 299 - 305. [Abstract] [Full Text] [PDF]

				P. Sinnaeve, J.-D. Chiche, Z. Nong, O. Varenne, N. Van Pelt, H. Gillijns, D. Collen, K. D. Bloch, and S. Janssens Soluble Guanylate Cyclase {{alpha}}1 and {beta}1 Gene Transfer Increases NO Responsiveness and Reduces Neointima Formation After Balloon Injury in Rats via Antiproliferative and Antimigratory Effects Circ. Res., January 19, 2001; 88(1): 103 - 109. [Abstract] [Full Text] [PDF]

				S. A. Gupte, T. Rupawalla, D. Phillibert Jr., and M. S. Wolin NADPH and heme redox modulate pulmonary artery relaxation and guanylate cyclase activation by NO Am J Physiol Lung Cell Mol Physiol, December 1, 1999; 277(6): L1124 - L1132. [Abstract] [Full Text] [PDF]

				T. Iesaki, S. A. Gupte, and M. S. Wolin A Flavoprotein Mechanism Appears to Prevent an Oxygen-Dependent Inhibition of cGMP-Associated Nitric Oxide-Elicited Relaxation of Bovine Coronary Arteries Circ. Res., November 26, 1999; 85(11): 1027 - 1031. [Abstract] [Full Text] [PDF]

				J. R. Kersten and D. C. Warltier Modulation of the adaptive response to myocardial ischemia by coexisting disease Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2268 - H2270. [Full Text] [PDF]