Fellowship/Adams: Modulation of Rostral Ventrolateral Medulla Neuronal Activity during Phase II of a Severe Homorrhage

In mammals, there are two distinct phases in the hemodynamic and neurohumoral response to acute blood loss or hemorrhage. In Phase I, arterial blood pressure (ASP) is maintained by a baroreceptor-mediated increase in sympathetic vasoconstrictor drive (14, 43). Phase II occurs once the loss in blood volume becomes severe (>25%) and is characterized by an abrupt decrease in vascular resistance, ASP, and heart rate (14, 43). The precipitous drop in ASP is primarily due to a withdrawal or inhibition of sympathetic nerve activity (SNA) and the resultant decrease in vascular resistance. A number of studies have demonstrated that this sympathoinhibition is mediated by cardiac vagal afferent nerves (3, 12, 58, 64). Several studies suggest that reflexive changes in SNA during arterial baroreceptor and vagal afferent activation are mediated by sympathetic-regulatory neurons of the rostral ventrolateral medulla (RVLM; 9, 16). It is well established that basal sympathetic outflow is maintained by the tonic drive of neurons in the RVLM to sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord (9,16). These RVLM cells are barosensitive as changes in RVLM neuronal activity directly correlate with changes in SNA during manipulations in ASP (2, 15, 36). In addition, activation of unmyelinated vagal afferents decreases RVLM cell discharge, SNA, and ASP via GASA subtype-A receptor activation (55, 60, 61). Given these data, the central hypothesis of this proposal is that decompensated hemorrhage results from activation of unmyelinated cardiac vagal afferents which increases GABAergic-mediated inhibition of RVLM neurons. This decrease in RVLM unit activity removes excitatory drive to sympathetic preganglionic neurons in the spinal cord and thereby reduces SNA, vascular resistance, and ABP. The specific aims of this proposal are to determine 1.) whether a severe hemorrhage decreases the activity of RVLM sympathetic-regulatory neurons and whether this decrease in discharge correlates with the inhibition of renal SNA; 2.) whether vagal afferents contribute to the inhibition of RVLM neuronal discharge during a severe hemorrhage; and 3.) what brainstem neurons are activated by a severe hemorrhage and project to the RVLM and whether these neurons are GABAergic.