Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment.
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.
Schulz
Eberhard
E
University Hospital Eppendorf, Division of Cardiology, Hamburg, Germany.
Tsilimingas
Nikolaus
N
Rinze
Ruth
R
Reiter
Beate
B
Wendt
Maria
M
Oelze
Mathias
M
Woelken-Weckmüller
Silke
S
Walter
Ulrich
U
Reichenspurner
Hermann
H
Meinertz
Thomas
T
Münzel
Thomas
T
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
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