Pentose phosphate pathway coordinates multiple redox-controlled relaxing mechanisms in bovine coronary arteries

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 285; no. 6; pp. H2316 - H2326
• Main Authors: Gupte, Sachin A, Arshad, Muhammad, Viola, Steven, Kaminski, Pawel M, Ungvari, Zoltan, Rabbani, Golam, Koller, Akos, Wolin, Michael S
• Format: Journal Article
• Language: English
• Published: United States 01.12.2003
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; 6-Aminonicotinamide - pharmacology; Adenylyl Cyclase Inhibitors; Androsterone - pharmacology; Animals; Arteries - metabolism; Calcium - metabolism; Calcium - pharmacology; Calcium-Transporting ATPases - antagonists & inhibitors; Cattle; Coronary Vessels - metabolism; Dithiothreitol - pharmacology; Free Radical Scavengers - pharmacology; Fura-2; Glutathione - metabolism; Glutathione Disulfide - metabolism; Guanylate Cyclase; Hydrogen Peroxide - metabolism; NADP - metabolism; Pentose Phosphate Pathway - drug effects; Pentose Phosphate Pathway - physiology; Potassium Channel Blockers - pharmacology; Potassium Chloride - pharmacology; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Serotonin - pharmacology; Soluble Guanylyl Cyclase; Superoxides - metabolism; Teratogens - pharmacology; Tetraethylammonium - pharmacology; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00229.2003

Department of Physiology, New York Medical College, Valhalla, New York 10595 Submitted 20 March 2003 ; accepted in final form 31 July 2003 Pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN) and epiandrosterone (Epi), were employed to examine whether changes in NADP(H) redox regulates contractile force in endothelium-removed bovine coronary arteries (BCAs). 6-AN (0.01–5 mM) or Epi (1–500 µM) elicited dose-dependent relaxation in BCAs contracted with 30 mM KCl, 0.1 µM U-44619, and endothelin-1 but not with phorbol 12,13-dibutyrate, a protein kinase C activator that causes Ca 2+ -independent contraction. Relaxation to PPP inhibition was associated with oxidation of NADPH and glutathione (GSH). Relaxation to 6-AN was not mediated by H 2 O 2 , because it was not altered by hypoxia or the peroxide scavenger ebselen (100 µM). The thiol reductant DTT (3 mM) attenuated the relaxation to 6-AN and Epi by 30–40%. Inhibition of glycolysis or mitochondrial electron transport did not elicit relaxation in BCAs contracted with 30 mM KCl, suggesting these pathways may not be involved in relaxation elicited by PPP inhibition. High doses of K + channel blockers [e.g., TEA (10 mM) and 4-aminopyridine (10 mM)] only partially inhibited the relaxation to 6-AN. On the basis of changes in the fura-2 fluorescence ratio, 6-AN and Epi appeared to markedly reduce intracellular Ca 2+ . Thus PPP inhibition oxidizes NADPH and GSH and appears to activate a novel coordination of redox-controlled relaxing mechanisms in BCAs mediated primarily through decreasing intracellular Ca 2+ . calcium; redox signaling; vasodilator mechanisms Address for reprint requests and other correspondence: M. S. Wolin, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (E-mail: mike_wolin{at}nymc.edu ).