(Circulation. 2001;103:2188.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Effects of In Vivo Nitroglycerin Treatment on Activity and Expression of the Guanylyl Cyclase and cGMP-Dependent Protein Kinase and Their Downstream Target Vasodilator-Stimulated Phosphoprotein in Aorta
From University Hospital Eppendorf, Division of Cardiology, Hamburg (M.O., H.M., A.W., U.H., T. Meinertz, T. Münzel); Institute of Cardiovascular Physiology, J.W. Goethe-University Clinics, Frankfurt/Main (A.M., S.K., A.T.); Bayer AG, Wuppertal (J.-P.S.); and Institut für Klinische Biochemie und Pathobiochemie (A.S., U.W.), Würzburg, Germany.
Correspondence to Thomas Münzel, MD, Universitätskrankenhaus Eppendorf, Abteilung für Kardiologie, Martinistraße 52, 20246 Hamburg, Germany. E-mail muenzel{at}uke.uni-hamburg.de
Background—Chronic in vivo treatment with nitroglycerin (NTG) induces tolerance to nitrates and cross-tolerance to nitrovasodilators and endothelium-derived nitric oxide (NO). We previously identified increased vascular superoxide formation and reduced NO bioavailability as one causal mechanism. It is still controversial whether intracellular downstream signaling to nitrovasodilator-derived NO is affected as well.
Methods and Results—We
therefore studied the effects of 3-day NTG treatment of rats and
rabbits on activity and expression of the immediate NO target soluble
guanylyl cyclase (sGC) and on the cGMP-activated protein kinase
I (cGK-I). Tolerance was induced either by chronic NTG infusion via
osmotic minipumps (rats) or by NTG patches (rabbits). Western blot
analysis, semiquantitative reverse transcription–polymerase
chain reaction, and Northern blot analysis revealed significant
and comparable increases in the expression of sGC
1 and ß1 subunit
protein and mRNA. Studies with the oxidative fluorescent dye
hydroethidine revealed an increase in superoxide in the
endothelium and smooth muscle. Stimulation with NADH
increased superoxide signals in both layers. Although cGK-I expression
in response to low-dose NTG was not changed, a strong reduction in
vasodilator-stimulated phosphoprotein (VASP) serine239
phosphorylation (specific substrate of cGK-I) was
observed in tolerant tissue from rats and rabbits. Concomitant in vivo
and in vitro treatment with vitamin C improved tolerance, reduced
oxidative stress, and improved P-VASP.
Conclusions—We therefore conclude that increased expression of sGC in the setting of tolerance reflects a chronic inhibition rather than an induction of the sGC–cGK-I pathway and may be mediated at least in part by increased vascular superoxide.
Key Words: protein kinases • vasodilator-stimulated phosphoprotein • nitrate tolerance • hydroethidine • superoxide production
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