Role of the multidrug resistance protein-1 in hypertension and vascular dysfunction caused by angiotensin II

Julian D Widder, Tomasz J Guzik, Cornelius FH Mueller, Roza E Clempus, Harald Schmidt, Sergey Dikalov, Kathy K Griendling, Dean P Jones, David G Harrison

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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 (O-2(center dot-)) 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 O-2(center dot-) 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.
Original languageEnglish
Pages (from-to)762 - 768
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number4
Publication statusPublished - 2007

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