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Cytokine blockade attenuates sympathoexcitation in heart failure: Cross‐talk between nNOS, AT‐1R and cytokines in the hypothalamic paraventricular nucleus
Author(s) -
Guggilam Anuradha,
Patel Kaushik P.,
Haque Masudul,
Ebenezer Philip J.,
Kapusta Daniel R.,
Francis Joseph
Publication year - 2008
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1016/j.ejheart.2008.05.004
Subject(s) - medicine , endocrinology , heart failure , nitrotyrosine , cytokine , norepinephrine , angiotensin ii , nitric oxide synthase , baroreflex , sympathetic nervous system , nitric oxide , blood pressure , heart rate , dopamine
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‐α 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.