Grants and Contracts Details
The neurohumoral and hemodynamic responses to a severe hemorrhage occur in two phases. Initially, arterial blood pressure (ASP) is maintained by an arterial baroreceptor-mediated increase in sympathetic nerve activity (SNA) and vascular resistance. Once the loss in intravascular volume becomes severe (>25%), animals including humans display a vasovagal syncope reaction characterized by a precipitous drop in ASP and marked bradycardia. The drop in ASP is largely mediated by a decrease in vascular resistance due to a withdrawal of SNA or sympathoinhibition. Several lines of evidence suggest this decompensatory phase is triggered by cardiac vagal afferent nerves. A loss of consciousness and fainting follows and death may ensue if cardiac output and ASP (and SNA) is not restored. Sasal sympathetic outflow arises from the tonic drive of vasomotor neurons in the rostral ventrolateral medulla (RVLM) to sympathetic preganglionic neurons in the thoracic and lumbar spinal cord. A myriad of studies indicates that the reflexive changes in ASP and SNA during activation of arterial baroreceptor and vagal afferent nerves is mediated by RVLM neurons. More importantly, electrical or chemical activation of unmyelinated vagal afferents decreases RVLM unit discharge and SNA through activation of GABA(A) receptors in the RVLM. In this proposal, the overall hypothesis is that a severe hemorrhage activates cardiac vagal afferents to decrease SNA through a GABAergic-mediated inhibition of RVLM sympathetic-regulatory neurons. The specific aims are: (1) a severe hemorrhage decreases the activity of RVLM neurons and this depends upon vagal afferent nerves, (2) the inhibition of RVLM neurons and SNA during a severe hemorrhage is mediated by activation of GABA(A) receptors within the RVLM, and (3) a severe hemorrhage synaptically influences GABAergic neurons in the medulla that project to the RVLM. In these experiments, a variety of approaches will be employed including in vivo extracellular single-unit recordings of spinally-projecting RVLM neurons in anesthetized rats. The proposed studies will represent an important step toward the development of centrally-acting drugs that effectively reverse the sympathoinhibitory response and stabilize ABP during a severe hemorrhage.
|Effective start/end date||1/1/06 → 12/31/07|
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