on February 1, 2007
Published online before print February 1, 2007, doi: 10.1161/01.ATV.0000259298.11129.a2
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 23, 2006
Accepted on January 5, 2007
Role of the Multidrug Resistance Protein-1 in Hypertension and Vascular Dysfunction Caused by Angiotensin II
Julian D. Widder ;
From the Emory University Division of Cardiology, Department of Medicine and the Atlanta Veterans Administration Hospital (J.D.W., T.J.G., C.F.H.M., R.E.C., S.I.D., K.K.G., D.P.J., D.G.H.), Ga; and Monash University, Department of Pharmacology & Centre for Vascular Health (H.H.H.W.S.), Melbourne, Australia.
* To whom correspondence should be addressed. E-mail: dharr02{at}emory.edu.
Objective--Human endothelial cells use the multidrug resistance protein-1 (MRP1) to export glutathione disulfide (GSSG). This can promotes thiol loss during states of increased glutathione oxidation. We investigated how MRP1 modulates blood pressure and vascular function during angiotensin II-induced hypertension.
Methods and Results--Angiotensin II-induced hypertension altered vascular glutathione flux by increasing GSSG export and decreasing vascular levels of glutathione in wild-type (FVB) but not in MRP1-/- mice. Aortic endothelium-dependent vasodilatation was reduced in FVB after angiotensin II infusion, but unchanged in MRP1-/- mice. Aortic superoxide (O2·-) production and expression of several NADPH oxidase subunits were increased by angiotensin II in FVB. These effects were markedly blunted in MRP1-/- vessels. The increase in O2·- production in FVB vessels caused by angiotensin II was largely inhibited by L-NAME, suggesting eNOS uncoupling. Accordingly, aortic tetrahydrobiopterin and levels of NO were decreased by angiotensin II in FVB but were unchanged in MRP1-/-. Finally, the hypertension caused by angiotensin II was markedly blunted in MRP1-/- mice (137±4 versus 158±6 mm Hg).
Conclusion--MRP1 plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension and its presence is essential for the hypertensive response to angiotensin II.
Key words: endothelial function • glutathione • hypertension • MRP1 • oxidative stress
This article has been cited by other articles:
 |
|
 |
|
  C. F.H. Mueller, K. Wassmann, J. D. Widder, S. Wassmann, C. H. Chen, B. Keuler, A. Kudin, W. S. Kunz, and G. Nickenig Multidrug Resistance Protein-1 Affects Oxidative Stress, Endothelial Dysfunction, and Atherogenesis via Leukotriene C4 Export Circulation, June 3, 2008; 117(22): 2912 - 2918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Paravicini and R. M. Touyz NADPH Oxidases, Reactive Oxygen Species, and Hypertension: Clinical implications and therapeutic possibilities Diabetes Care, February 1, 2008; 31(Supplement_2): S170 - S180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Guzik, N. E. Hoch, K. A. Brown, L. A. McCann, A. Rahman, S. Dikalov, J. Goronzy, C. Weyand, and D. G. Harrison Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction J. Exp. Med., October 1, 2007; 204(10): 2449 - 2460. [Abstract] [Full Text] [PDF]
|
|