THE SYNERGISTIC EFFECTS OF PROINFLAMMATORY CYTOKINES ON CARDIOVASCULAR FUNCTION AND SYMPATHETIC OUTFLOW IN RAT

Abstract

Objective: Inflammation has been implicated in the pathophysiology of cardiovascular dysfunction and neurohumoral activation in cardiovascular diseases. Our previous work has demonstrated that proinflammatory cytokines (PICs) in cardiovascular/autonomic brain regions contribute significantly to the sympathetic excitation and cardiac dysfunction in heart failure and hypertension. Notably, the chronic inflammatory conditions in these disease settings are caused by numerous inflammatory cytokines and chemokines. Given that the elevated levels of a single effector cytokine in the pathophysiological condition are insufficient to cause a significant change in hemodynamic and sympathetic responses, how PIC-driven neuroinflammation promotes sympathetic activation remains unclear. This work sought to determine whether PICs in the brain have a synergistic action to exaggerate their inflammatory effects on hemodynamic and sympathetic responses in rats. Design and method: Blood pressure (BP, mmHg), heart rate (HR, beats/min) and renal sympathetic nerve activity (RSNA, % change) were continuously recorded for 4-5 hours in urethane anesthetized male Sprague Dawley rats. The inflammatory cytokines tumor necrosis factor-↑ (TNF-↑), interleukin (IL)-1↓, IL-6 and vehicle were injected intracerebroventricularly (ICV). Results: We found that while ICV injection of TNF-↑, IL-1↓ or IL-6 alone at a low dose (10 ng, respectively) did not induce significant changes in BP, HR and RSNA, the combined injection of all three cytokines at the same dose (10 ng) elicited a substantial (*p<0.05) increase in BP (18.2 ± 2.1*), HR (62 ± 7*) and RSNA (94.5 ± 5.2 %*), that began within 15-20 mins. These responses peaked at 2-3 hours after ICV injection and remained elevated for the rest of the recording period. Additionally, ICV injection of TNF-↑, IL-1↓ or IL-6 alone at a high dose (50 ng, respectively), produced a dramatic and long-lasting increase in BP, HR and RSNA, that closely resembles the time course and response pattern induced by ICV injection of all three cytokines concurrently at the low dose (10 ng). Conclusions: These data suggest a synergistically excitatory action of PICs in the brain on sympathetic outflow. Interventions that simultaneously target multiple cytokines may have an extended anti-inflammatory effect of reducing sympathetic excitation in hypertension and heart failure.