Brain p44/42 mitogen‐activated protein kinase contributes to the sympathetic response to blood‐borne TNF‐α in rats

Abstract

Blood‐borne pro‐inflammatory cytokines act upon the central nervous system to increase sympathetic drive in normal and pathophysiological conditions including heart failure. The underlying signaling pathways are still poor understood. We tested the hypothesis that brain p44/42 mitogen‐activated protein kinase (MAPK) mediates tissue necrosis factor ‐ alpha (TNF‐α) induced sympatho‐excitatory responses. In urethane‐anesthetized rats, a centrally directed intracarotid artery (ICA) injection of TNF‐α elicited significant (p<0.05) increases in renal sympathetic nerve activity (RSNA), mean blood pressure (MBP) and heart rate (HR), and in hypothalamic phosphorylated p44/42 MAPK expression (Western blot and immunofluorescence). Intracerebroventricular (ICV) pretreatment (4 days before) with small interfering RNA (siRNA) using SMART pool siRNA targeting p44/42 MAPK significantly reduced the increases in RSNA, MBP and HR induced by ICA TNF‐α, but pretreatment with vehicle or control siRNA had no effect. TNF‐α induced increases in RSNA, MBP and HR were similarly diminished by a continuous ICV infusion of the p44/42 MAPK inhibitor PD98059. These data suggest that blood‐borne TNF‐α activates the brain p44/42 MAPK pathway to elicit sympatho‐excitatory responses. Supported by a VA Merit Review Award and NIH RO1 HL073986.