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

Widder JD, Guzik TJ, Mueller CF, Clempus RE, Schmidt HH, Dikalov SI, Griendling KK, Jones DP, Harrison DG
Arterioscler Thromb Vasc Biol. 2007 27 (4): 762-8

PMID: 17272743 · DOI:10.1161/01.ATV.0000259298.11129.a2

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.

MeSH Terms (20)

Angiotensin II Animals Aorta ATP Binding Cassette Transporter, Subfamily B, Member 1 Biopterin Blood Pressure Endothelium, Vascular Enzyme Inhibitors Glutathione Disulfide Hypertension Isoenzymes Male Mice Mice, Inbred Strains Mice, Knockout NADPH Oxidases NG-Nitroarginine Methyl Ester Nitric Oxide Superoxides Vasodilation

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