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

Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2316-26. doi: 10.1152/ajpheart.00229.2003. Epub 2003 Aug 21.

Abstract

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 microM) elicited dose-dependent relaxation in BCAs contracted with 30 mM KCl, 0.1 microM U-44619, and endothelin-1 but not with phorbol 12,13-dibutyrate, a protein kinase C activator that causes Ca2+-independent contraction. Relaxation to PPP inhibition was associated with oxidation of NADPH and glutathione (GSH). Relaxation to 6-AN was not mediated by H2O2, because it was not altered by hypoxia or the peroxide scavenger ebselen (100 microM). 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 Ca2+. 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 Ca2+.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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*

Substances

  • Adenylyl Cyclase Inhibitors
  • Free Radical Scavengers
  • Potassium Channel Blockers
  • Receptors, Cytoplasmic and Nuclear
  • Teratogens
  • Vasoconstrictor Agents
  • Superoxides
  • 6-Aminonicotinamide
  • Serotonin
  • NADP
  • Tetraethylammonium
  • Potassium Chloride
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Hydrogen Peroxide
  • Androsterone
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Calcium-Transporting ATPases
  • Glutathione
  • Calcium
  • Dithiothreitol
  • Fura-2
  • Glutathione Disulfide