Published Online
on April 7, 2008

A more recent version of this article appeared on May 1, 2008

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Submitted on October 2, 2007
Revised on October 17, 2007

Involvement of Tumor Necrosis Factor- in Angiotensin II–Mediated Effects on Salt Appetite, Hypertension, and Cardiac Hypertrophy

Srinivas Sriramula; Masudul Haque; Dewan S.A. Majid; and Joseph Francis^*

From the Comparative Biomedical Sciences (S.S., M.H., J.F.), School of Veterinary Medicine, Louisiana State University, Baton Rouge; the Department of Pharmacology (J.F.), Louisiana State University Health Sciences Center, New Orleans; and the Department of Physiology (D.S.A.M.), Tulane University Health Sciences Center, New Orleans, La.

^* To whom correspondence should be addressed. E-mail: jfrancis{at}lsu.edu.

Abstract—Hypertension is considered a low-grade inflammatory condition induced by various proinflammatory cytokines, including tumor necrosis factor (TNF)-. Recent studies have implicated an involvement of TNF- in the development of salt-sensitive hypertension induced by angiotensin II (Ang II). To understand further the relationship between TNF- and Ang II, we examined the responses to Ang II in TNF- knockout (TNF-^-/-) mice in the present study. A continuous infusion of Ang II (1 µg/kg per minute) for 2 weeks was given to both TNF-^-/- and wild-type (WT) mice with implanted osmotic minipumps. Daily measurement of water intake, salt intake, and urine output were performed using metabolic cages. Blood pressure was monitored continuously with implanted radiotelemetry. Ang II administration for 2 weeks caused increases in salt (0.2±0.07 to 5.6±0.95 mL/d) and water (5.4±0.34 to 11.5±1.2 mL/d) intake and in mean arterial pressure (115±1 to 151±3 mm Hg) in wild-type mice, but these responses were absent in TNF-^-/- mice (0.2±0.04 to 0.3±0.09 mL/d, 5.5±0.2 to 6.1±0.07 mL/d, and 113±2 to 123±3 mm Hg, respectively). Cardiac hypertrophy induced by Ang II was significantly attenuated in TNF-^-/- mice compared with wild-type mice. In a group of TNF-^-/- mice, when replacement therapy was made with recombinant TNF-, Ang II induced similar responses in salt appetite, mean arterial pressure, and cardiac hypertrophy, as observed in wild-type mice. These results suggest that TNF- plays a mechanistic role in mediating chronic Ang II–induced effects on salt appetite and blood pressure, as well as on cardiac hypertrophy.

Key words: angiotensin II • TNF- • salt appetite • cardiac hypertrophy • hypertension

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