Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins

1 Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine and Medical Service, 2 Veterans Administration Medical Center, Iowa City, Iowa 52242 In pathophysiological conditions, increased blood-borne TNF- induces a broad range of biological effects, including activation of the hypothalamic-pituitary-adrenal axis and sympathetic drive. In urethane-anesthetized adult Sprague-Dawley rats, we examined the mechanisms by which blood-borne TNF- activates neurons in paraventricular nucleus (PVN) of hypothalamus and rostral ventrolateral medulla (RVLM), two critical brain regions regulating sympathetic drive in normal and pathophysiological conditions. TNF- (0.5 µg/kg), administered intravenously or into ipsilateral carotid artery (ICA), activated PVN and RLVM neurons and increased sympathetic nerve activity, arterial pressure, and heart rate. Responses to intravenous TNF- were not affected by vagotomy but were reduced by mid-collicular decerebration. Responses to ICA TNF- were substantially reduced by injection of the cyclooxygenase inhibitor ketorolac (150 µg) into lateral ventricle. Injection of PGE 2 (50 ng) into lateral ventricle or directly into PVN increased PVN or RVLM activity, respectively, and sympathetic drive, with shorter onset latency than blood-borne TNF- . These findings suggest that blood-borne cytokines stimulate cardiovascular and renal sympathetic responses via a prostaglandin-dependent mechanism operating at the hypothalamic level. cytokines; paraventricular nucleus of hypothalamus; rostral ventrolateral medulla; renal sympathetic nerve activity; prostaglandin E 2