Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment
Standard
Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. / Schulz, Eberhard; Tsilimingas, Nikolaus; Rinze, Ruth; Reiter, Beate; Wendt, Maria; Oelze, Mathias; Woelken-Weckmüller, Silke; Walter, Ulrich; Reichenspurner, Hermann; Meinertz, Thomas; Münzel, Thomas.
in: CIRCULATION, Jahrgang 105, Nr. 10, 12.03.2002, S. 1170-1175.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment
AU - Schulz, Eberhard
AU - Tsilimingas, Nikolaus
AU - Rinze, Ruth
AU - Reiter, Beate
AU - Wendt, Maria
AU - Oelze, Mathias
AU - Woelken-Weckmüller, Silke
AU - Walter, Ulrich
AU - Reichenspurner, Hermann
AU - Meinertz, Thomas
AU - Münzel, Thomas
PY - 2002/3/12
Y1 - 2002/3/12
N2 - 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.METHODS AND 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.
AB - 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.METHODS AND 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.
KW - Aged
KW - Blood Vessels/drug effects
KW - Cell Adhesion Molecules/metabolism
KW - Coronary Artery Bypass
KW - Coronary Disease/drug therapy
KW - Cyclic GMP/metabolism
KW - Cyclic GMP-Dependent Protein Kinase Type I
KW - Cyclic GMP-Dependent Protein Kinases/metabolism
KW - Dose-Response Relationship, Drug
KW - Drug Tolerance
KW - Endothelium, Vascular/drug effects
KW - Female
KW - Guanylate Cyclase
KW - Humans
KW - Immunohistochemistry
KW - In Vitro Techniques
KW - Male
KW - Mammary Arteries/drug effects
KW - Microfilament Proteins
KW - Middle Aged
KW - Nitric Oxide/metabolism
KW - Nitroglycerin/adverse effects
KW - Phosphoproteins/metabolism
KW - Phosphorylation/drug effects
KW - Radial Artery/drug effects
KW - Receptors, Cytoplasmic and Nuclear/metabolism
KW - Saphenous Vein/drug effects
KW - Signal Transduction/drug effects
KW - Soluble Guanylyl Cyclase
KW - Vasodilation/drug effects
KW - Vasodilator Agents/adverse effects
U2 - 10.1161/hc1002.105186
DO - 10.1161/hc1002.105186
M3 - SCORING: Journal article
C2 - 11889009
VL - 105
SP - 1170
EP - 1175
JO - CIRCULATION
JF - CIRCULATION
SN - 0009-7322
IS - 10
ER -
