Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin II of afferent arterioles from rabbits infused with angiotensin II.
The hypothesis that O(2)(.-) enhances angiotensin II (AngII)-induced vasoconstriction and impairs acetylcholine-induced vasodilation of afferent arterioles (Aff) in AngII-induced hypertension was investigated. Rabbits (n = 6 per group) received 12 to 14 d of 0.154 M NaCl (Sham), subpressor AngII (60 ng/kg per min; AngII 60) or slow pressor AngII (200 ng/kg per min; AngII 200). Individual Aff were perfused in vitro at 60 mmHg. AngII 200 increased mean arterial pressure (mean +/- SD; 103 +/- 9 versus 73 +/- 6 mmHg; P < 0.01), plasma lipid peroxides (2.6 +/- 0.3 versus 2.0 +/- 0.3 nM; P < 0.05), renal cortical NADPH- and NADH-dependent O(2)(.-) generation, and Aff mRNA for p22(phox) 5-fold (P < 0.001) but decreased that for AT(1)-receptor 2.4-fold (P < 0.01). AngII 60 increased only NADH-dependent O(2)(.-) generation by renal cortex. Aff from AngII 200 rabbits had diminished acetylcholine relaxations (+50 +/- 4 versus +85 +/- 6%; P < 0.001), but these became similar in the presence of nitro-L-arginine (10(-4) M). Aff from AngII 60 and AngII 200 rabbits had unchanged norepinephrine contractions (10(-7) M) but significantly (P < 0.05) enhanced AngII contractions (10(-8) M: Sham -52 +/- 5 versus AngII 60 to 77 +/- 5 versus AngII 200 to 110 +/- 10%). The superoxide dismutase mimetic tempol (10(-4) M) moderated the AngII responses of Aff from AngII 200 rabbits to levels of AngII 60 rabbits (-64 +/- 7%). The AngII slow pressor response enhances renal cortical O(2)(.-) and p22(phox) expression. Increased O(2)(.-) generation in Aff mediates an impaired nitric oxide synthase-dependent endothelium-derived relaxing factor response and paradoxically enhances contractions to AngII despite downregulation of the mRNA for AT(1) receptors. A subpressor dose of AngII enhances Aff responses to AngII independent of O(2)(.-).
Division of Nephrology and Hypertension and Center for Hypertension and Renal Disease Research, Georgetown University, Washington, DC 20007, USA.
Dan
D
Wang
Yifan
Y
Chen
Tina
T
Chabrashvili
Shakil
S
Aslam
Lillian J
LJ
Borrego Conde
Jason G
JG
Umans
Christopher S
CS
Wilcox
D000344:Afferent Pathways / Q000098:blood supply / Q000187:drug effects; D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D007263:Infusions, Parenteral; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D018384:Oxidative Stress / Q000502:physiology*; D011817:Rabbits; D011930:Reaction Time / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*
D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II