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


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).


CONCLUSIONS
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.
Widder
Julian D
JD
Emory University, Division of Cardiology, Department of Medicine and the Atlanta Veterans Administration Hospital, Atlanta, GA 30322, USA.
Guzik
Tomasz J
TJ
Mueller
Cornelius F H
CF
Clempus
Roza E
RE
Schmidt
Harald H H W
HH
Dikalov
Sergey I
SI
Griendling
Kathy K
KK
Jones
Dean P
DP
Harrison
David G
DG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology*; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013481:Superoxides; D000804:Angiotensin II; D001708:Biopterins; D009569:Nitric Oxide; D019255:NADPH Oxidases; C003402:sapropterin; D019803:Glutathione Disulfide; D019331:NG-Nitroarginine Methyl Ester