title: Functional heterogeneity of NADPH oxidase-mediated contractions to endothelin with vascular aging.
abstract: OBJECTIVE
  Aging, a physiological process and main risk factor for cardiovascular and renal diseases, is associated with endothelial cell dysfunction partly resulting from NADPH oxidase-dependent oxidative stress. Because increased formation of endothelium-derived endothelin-1 (ET-1) may contribute to vascular aging, we studied the role of NADPH oxidase function in age-dependent contractions to ET-1.
  
  
  METHODS
  Renal arteries and abdominal aortas from young and old C57BL6 mice (4 and 24 months of age) were prepared for isometric force measurements. Contractions to ET-1 (0.1-100 nmol/L) were determined in the presence and absence of the NADPH oxidase-selective inhibitor gp91ds-tat (3 μmol/L). To exclude age-dependent differential effects of NO bioactivity between vascular beds, all experiments were conducted in the presence of the NO synthase inhibitor L-NAME (300 μmol/L).
  
  
  RESULTS
  In young animals, ET-1-induced contractions were 6-fold stronger in the renal artery than in the aorta (p<0.001); inhibition of NADPH oxidase by gp91ds-tat reduced the responses to ET-1 by 50% and 72% in the renal artery and aorta, respectively (p<0.05). Aging had no effect on NADPH oxidase-dependent and -independent contractions to ET-1 in the renal artery. In contrast, contractions to ET-1 were markedly reduced in the aged aorta (5-fold, p<0.01 vs. young) and no longer sensitive to gp91ds-tat.
  
  
  CONCLUSIONS
  The results suggest an age-dependent heterogeneity of NADPH oxidase-mediated vascular contractions to ET-1, demonstrating an inherent resistance to functional changes in the renal artery but not in the aorta with aging. Thus, local activity of NADPH oxidase differentially modulates responses to ET-1 with aging in distinct vascular beds.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Meyer
authors.affiliation: Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. Electronic address: eprossnitz@salud.unm.edu.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D012077:Renal Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D019255:NADPH Oxidases; D011188:Potassium
keywords: Age; Artery; Atherosclerosis; Endothelin-1 (PubChem CID: 16212950); Endothelium; Gp91ds-tat; Kidney; L-N(G)-nitroarginine methyl ester (PubChem CID: 39836); NADPH; Nox; Oxidative stress; Physiology; Renal; Superoxide; Vasoconstriction