on August 28, 2006
Published online before print August 28, 2006, doi: 10.1161/01.HYP.0000239207.82326.29
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 6, 2006
From the Johannes Gutenberg University Hospital (M.O., A.D., P.W., U.H., E.S., H.M., A.L.K., A.M., T.M.), Division of Cardiology, Mainz, Germany; J.W. Goethe-University (R.P.B.), Institut für Kardiovaskuläre Physiologie, Frankfurt am Main, Germany; Institut für Pharmakologie (M.H., H.L., U.F.), Johannes Gutenberg-Universität Mainz, Mainz, Germany; and University Hospital Eppendorf (A.v.S.), Division of Cardiology, Hamburg, Germany. * To whom correspondence should be addressed. E-mail: tmuenzel{at}uni-mainz.de.
Abstract--Nebivolol is a
Revised on April 26, 2006
Nebivolol Inhibits Superoxide Formation by NADPH Oxidase and Endothelial Dysfunction in Angiotensin II-Treated Rats
Matthias Oelze;
1-receptor antagonist with vasodilator and antioxidant properties. Because the vascular NADPH oxidase is an important superoxide source, we studied the effect of nebivolol on endothelial function and NADPH oxidase activity and expression in the well-characterized model of angiotensin II-induced hypertension. Angiotensin II infusion (1 mg/kg per day for 7 days) caused endothelial dysfunction in male Wistar rats and increased vascular superoxide as detected by lucigenin-derived chemiluminescence, as well as dihydroethidine staining. Vascular NADPH oxidase activity, as well as expression at the mRNA and protein level, were markedly upregulated, as well as NOS III uncoupled, as evidenced by NO synthase III inhibitor experiments and dihydroethidine staining and by markedly decreased hemoglobin-NO concentrations. Treatment with the -receptor blocker nebivolol but not metoprolol (10 mg/kg per day for each drug) normalized endothelial function, reduced superoxide formation, increased NO bioavailability, and inhibited upregulation of the activity and expression of the vascular NADPH oxidase, as well as membrane association of NADPH oxidase subunits (Rac1 and p67phox). In addition, NOS III uncoupling was prevented. In vitro treatment with nebivolol but not atenolol or metoprolol induced a dissociation of p67phox and Rac1, as well as an inhibition of NADPH oxidase activity assessed in heart membranes from angiotensin II-infused animals, as well as in homogenates of Nox1 and cytosolic subunit-transfected and phorbol ester-stimulated HEK293 cells. These findings indicate that nebivolol interferes with the assembly of NADPH oxidase. Thus, inhibitory effects of this -blocker on vascular NADPH oxidase may explain, at least in part, its beneficial effect on endothelial function in angiotensin II-induced hypertension.
Key words: angiotensin II • nitric oxide synthase • endothelium • oxidative stress • vasodilation
This article has been cited by other articles:
 |
|
 |
|
  T. Munzel and T. Gori Nebivolol The Somewhat-Different beta-Adrenergic Receptor Blocker. J. Am. Coll. Cardiol., October 13, 2009; 54(16): 1491 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Balligand beta(3)-Adrenoceptor stimulation on top of beta(1)-adrenoceptor blockade "Stop or Encore?". J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1539 - 1542. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsumoto, N. Nakayama, K. Ishida, T. Kobayashi, and K. Kamata Eicosapentaenoic Acid Improves Imbalance between Vasodilator and Vasoconstrictor Actions of Endothelium-Derived Factors in Mesenteric Arteries from Rats at Chronic Stage of Type 2 Diabetes J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 324 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, M. Hortmann, A. Daiber, M. Oelze, M. A. Ostad, P. M. Schwarz, H. Xu, N. Xia, A. L. Kleschyov, C. Mang, et al. Cyclooxygenase 2-Selective and Nonselective Nonsteroidal Anti-Inflammatory Drugs Induce Oxidative Stress by Up-Regulating Vascular NADPH Oxidases J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 745 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsumoto, E. Noguchi, K. Ishida, T. Kobayashi, N. Yamada, and K. Kamata Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1165 - H1176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Welch Angiotensin II-Dependent Superoxide: Effects on Hypertension and Vascular Dysfunction Hypertension, July 1, 2008; 52(1): 51 - 56. [Full Text] [PDF]
|
|
|
|
|
|
A. Jabs, S. Gobel, P. Wenzel, A. L. Kleschyov, M. Hortmann, M. Oelze, A. Daiber, and T. Munzel Sirolimus-induced vascular dysfunction increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation. J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2130 - 2138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Baumhakel, N. Schlimmer, K. Buyukafsar, O. Arikan, and M. Bohm Nebivolol, but Not Metoprolol, Improves Endothelial Function of the Corpus Cavernosum in Apolipoprotein E-Knockout Mice J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 818 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Toprak, M. Cirit, M. Tanrisev, C. Yazici, O. Canoz, M. Sipahioglu, A. Uzum, R. Ersoy, and E. Y. Sozmen Preventive effect of nebivolol on contrast-induced nephropathy in rats Nephrol. Dial. Transplant., March 1, 2008; 23(3): 853 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, M. Kakami, E. Noguchi, T. Kobayashi, and K. Kamata Imbalance between endothelium-derived relaxing and contracting factors in mesenteric arteries from aged OLETF rats, a model of Type 2 diabetes Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1480 - H1490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Wenzel, U. Hink, M. Oelze, S. Schuppan, K. Schaeuble, S. Schildknecht, K. K. Ho, H. Weiner, M. Bachschmid, T. Munzel, et al. Role of Reduced Lipoic Acid in the Redox Regulation of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity: IMPLICATIONS FOR MITOCHONDRIAL OXIDATIVE STRESS AND NITRATE TOLERANCE J. Biol. Chem., January 5, 2007; 282(1): 792 - 799. [Abstract] [Full Text] [PDF]
|
|