title: Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment.
abstract: BACKGROUND
  In experimental animal models, long-term in vivo treatment with nitroglycerin (NTG) induces both endothelial dysfunction and tolerance to nitrates. However, it is still controversial whether nitrate tolerance in humans is associated with both endothelial dysfunction and impaired vascular response to nitrovasodilator-derived NO.
  
  
  RESULTS
  Patients undergoing elective bypass surgery were randomized to receive 48 hours of continuous NTG infusion (NTG group) or no nitrate therapy (control group). Segments of surgically removed arteria mammaria, vena saphena, and arteria radialis not required for the bypass procedure were used to examine (1) the vascular responsiveness to NTG and the endothelium-dependent vasodilator acetylcholine; (2) the expression of the NO target, the soluble guanylyl cyclase; (3) the expression of the soluble guanylyl cyclase/cGMP effector target, the cGMP-dependent protein kinase (cGK); and (4) the cGK activity as assessed by the phosphorylation state of its vascular substrate, the vasodilator-stimulated phosphoprotein at serine(239) (P-VASP). NTG treatment caused a marked degree of nitrate tolerance in all 3 vessel types studied and a significant cross-tolerance to the endothelium-dependent vasodilator acetylcholine in A. mammaria and A. radialis. Although soluble guanylyl cyclase, cGK-I, and VASP expression levels were not modified by NTG treatment, a marked decrease of P-VASP, a surrogate parameter for in-vivo cGK-I activity, was observed.
  
  
  CONCLUSIONS
  We conclude that long-term NTG treatment induces endothelial dysfunction and impaired vascular NO/cGMP signaling in humans, which can be monitored by measuring P-VASP levels.
authors.affiliation: University Hospital Eppendorf, Division of Cardiology, Hamburg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Tsilimingas
authors.forename: Ruth
authors.initials: R
authors.lastname: Rinze
authors.forename: Beate
authors.initials: B
authors.lastname: Reiter
authors.forename: Maria
authors.initials: M
authors.lastname: Wendt
authors.forename: Mathias
authors.initials: M
authors.lastname: Oelze
authors.forename: Silke
authors.initials: S
authors.lastname: Woelken-Weckmüller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000368:Aged; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology / Q000601:surgery; D006152:Cyclic GMP / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006162:Guanylate Cyclase; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008840:Microfilament Proteins; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000009:adverse effects / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017534:Radial Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects*; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin; D006152:Cyclic GMP