Cardiovascular responses to subseptic doses of endotoxin contribute to differential neuronal activation in rat brain

Abstract

The contribution of cardiovascular activity in the early central responses to systemic inflammation was assessed in rats following intravenous administration of subseptic doses of lipopolysaccharide (LPS). LPS at 12.5 μg/kg increased heart rate (HR) but did not alter mean arterial pressure (MAP), and induced interleukin-1β (IL-1β) gene expression at 1 h in circumventricular organs (CVOs), choroid plexus, meninges, blood vessels, and pituitary gland. IL-1β mRNA levels were attenuated at 2 h in most regions studied. LPS at 50 μg/kg caused a biphasic change in MAP, increased HR, increased levels of arginine vasopressin heteronuclear RNA in the hypothalamic paraventricular nucleus (PVN), and induced IL-1β gene expression in the nucleus of the solitary tract (NTS) at 1 h. LPS (both doses) induced Fos-like immunoreactivity (FLI) in the area postrema, organum vasculosum of the lamina terminalis, NTS, preoptic area, supraoptic nucleus, and PVN at 1 h. In the PVN, neurons with FLI were found primarily in the dorsal and dorsal medial parvocellular divisions after 12.5 μg/kg of LPS whereas neurons with FLI were found throughout the PVN after 50 μg/kg of LPS. After 2 h, FLI was widespread throughout the brain. Plasma ACTH levels were elevated at 1 and 2 h in response to both doses of LPS, and levels of CRF mRNA were increased after 2 h in the parvocellular PVN. Our results reveal that central responses to increasing doses of LPS show different patterns which are related to activation of distinct immune and viscerosensory pathways, and that cardiovascular responses contribute to early neuronal activation as LPS concentrations are increased.