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

摘要

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-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. 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.