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Enhanced Contractility of Renal Afferent Arterioles From Angiotensin-Infused Rabbits

Roles of Oxidative Stress, Thromboxane Prostanoid Receptors, and Endothelium

From Division of Nephrology and Hypertension and the Cardiovascular-Kidney Institute, Georgetown University, Washington, DC.

Correspondence to Dr Christopher S. Wilcox, Chief, Division of Nephrology and Hypertension, Georgetown University Medical Center, 3800 Reservoir Road, NW, PHC Suite F6003, Washington, DC 20007-2197. E-mail wilcoxch{at}georgetown.edu

We tested the hypothesis that cyclooxygenase (COX), thromboxane A₂ synthase (TxA₂-S), thromboxane prostanoid receptors (TP-Rs), or superoxide anion (O₂^–) mediates enhanced contractions of renal afferent arterioles (Aff) of angiotensin II (Ang II)-infused rabbits. Rabbits were infused with vehicle (sham), Ang II 60 ng·kg^–1·min^–1 (Ang II 60) or 200 ng·kg^–1·min^–1 (Ang II 200). There was a selective enhanced vasoconstriction of Affs from Ang II 60 rabbits to Ang II (diameter–78±8% versus –43±9%; P<0.01) that was normalized by a TP-R antagonist but not by a superoxide dismutase (SOD) mimetic. Affs from Ang II 200 rabbits had increased (P<0.01) mRNA for COX-2 and enhanced vasoconstriction to Ang II, U-46 619 (TP-R mimetic), and endothelin-1 that was normalized by ifetroban plus tempol together. Endothelium removal enhanced Ang II responses of Affs from sham rabbits but blunted responses from Ang II 200 rabbits and abolished responses to ifetroban. Affs from Ang II 200 rabbits had an endothelium-dependent contraction factor (EDCF) response to that was blunted (P<0.001) by a SOD mimetic or antagonists of COX-1 or TxA₂-S but normalized by antagonists of COX-2 or TP-R. Thus, enhanced Ang II responses in Affs from rabbits infused with slow pressor Ang II are mediated independently by O₂^– in the vascular smooth muscle cells and by an EDCF that is principally a vasoconstrictor prostaglandin generated by COX-2 >–1 activating TP-Rs, whereas enhanced responses in rabbits infused with a lower Ang II dose are dependent on TP-R but not O₂^–.

Key Words: thromboxane A₂ • nitric oxide • cyclooxygenase • superoxide anion • tempol • reactive oxygen species • endothelium-derived contraction factor • endothelium-derived relaxation factor

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