© 2008 European Society of Cardiology
Cytokine blockade attenuates sympathoexcitation in heart failure: Cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus
a Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University Baton Rouge, LA-70803, United States
b Department of Pharmacology, LSU Health Sciences Center New Orleans, LA-70119, United States
c Department of Cellular and Integrative Physiology, University of Nebraska Medical Center Omaha, NE-68198, United States
* Corresponding author. Louisiana State University, School of Veterinary Medicine, Comparative Biomedical Sciences, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, United States. Tel.: +1 225 578 9752; fax: +1 225 578 9895. E-mail address: jfrancis{at}lsu.edu (J. Francis).
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Abstract |
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Objective: To investigate evidence for the interplay between cytokines, angiotensin II and nNOS in the paraventricular nucleus (PVN), for regulating sympathetic outflow in a rat model of CHF.
Methods and results: Heart failure was induced in Sprague–Dawley rats by coronary artery ligation. One group of rats was treated with pentoxifylline (PTX, 30 mg/kg IP), a cytokine blocker, or vehicle, for 5 weeks. Another group of rats was pre-treated with PTX before coronary ligation to study prior cytokine blocking effect on survival. Both groups were combined in the analysis. Echocardiography demonstrated an increase in LV end-diastolic pressure and Tei index after 5 weeks in CHF rats. ELISA revealed a significant increase in plasma TNF-
and IL-1β in CHF rats. Inducible NOS (iNOS) and angiotensin receptor-type 1 (AT-1R) mRNA expressions were increased, while neuronal NOS (nNOS) was decreased in the PVN of CHF rats; these changes were reversed by PTX. PTX treatment also decreased plasma norepinephrine and epinephrine levels and improved baroreflex control of renal sympathoexcitation in CHF rats. Immunohistochemistry revealed elevated 3-nitrotyrosine formation in the heart and the PVN of CHF rats, but not in PTX treated rats.
Conclusion: PTX decreased both peripheral and central cytokine expression, alleviated nitric oxide dysregulation, and inhibited the formation of peroxynitrite in the PVN resulting in decreased sympathoexcitation in CHF rats.
Key Words: Congestive heart failure • Cytokines • Sympathoexcitation • Neuronal nitric oxide synthase • AT-1 receptor • Peroxynitrite
Received January 4, 2008; Revised April 6, 2008; Accepted May 6, 2008
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