Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus.
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.


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-alpha and IL-1beta 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.


CONCLUSIONS
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.
Guggilam
Anuradha
A
Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA-70803, United States.
Patel
Kaushik P
KP
Haque
Masudul
M
Ebenezer
Philip J
PJ
Kapusta
Daniel R
DR
Francis
Joseph
J
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism*; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D010431:Pentoxifylline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*
D016207:Cytokines; D044140:Receptor, Angiotensin, Type 1; D052248:Nitric Oxide Synthase Type I; D010431:Pentoxifylline