Mild hemorrhage produces autonomic and endocrine compensatory responses that are able to greatly minimize hypotension. These well- known responses are mostly caused by unloading of arterial barorceptors and include withdrawal of cardiovagal tone and a vigorous activation of the sympathetic outflow. If hemorrhage is more severe the autonomic compensatory mechanisms are paradoxically reversed. This second or ~ decompensatory~ phase of hemorrhage is characterized by bradycardia and a sharp decrease of sympathetic activity ( hemorrhage-induced sympathoinhibiton. HiSI) that produce further cardiovascular deterioration. Initiation of the decompensatory phase has been attributed to the activation of vagal afferent from the cardiopulmonary region however the central pathways of HiSI are not known. Nevertheless several studies have suggested that CNS opiod peptides may play a key role in genesis of this phenomenon. The objective of the proposed work is to investigate the CNS portion of the circuitry involved in hemorrhage induced sympathoinhibition and bradyardia. The study will be divided into five parts.
Aim 1 : using an established anestheized rat model, we will determine whether HiSI can be explained by a reduction in the discharge rate of the vasomotor neurons of the rostral ventrolateral medulla.
Aim 2 : we will determine whether hypotensive hemorrhage activates CVLM GABAergic neurons that arborize in RVLM. We will also determine whether the CVLM region is necessary for HiSI to occur.
Aim 3 : we will determine whether hypotensive hemorrhage reduces central respiratory drive and whether this effect contributes to HiSI Aim 4: we will determine whether the release of opioid peptides in RVLM contributes to hiSl Aim 5: we will determine which CNS neurons are activated by hypotensive hemorrhage in conscious rats and whether they are opiodergic or GABAergic. Understanding the neurophysiological mechanisms triggered by hypotensive hemorrhage should lead to improved ability to manage this all too frequent clinical problem.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL060003-01A1
Application #
2824158
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1999-04-01
Project End
2004-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Hur, Elizabeth E; Zaborszky, Laszlo (2005) Vglut2 afferents to the medial prefrontal and primary somatosensory cortices: a combined retrograde tracing in situ hybridization study [corrected] J Comp Neurol 483:351-73
Stornetta, Ruth L; Sevigny, Charles P; Guyenet, Patrice G (2003) Inspiratory augmenting bulbospinal neurons express both glutamatergic and enkephalinergic phenotypes. J Comp Neurol 455:113-24
Stornetta, Ruth L; Rosin, Diane L; Wang, Hong et al. (2003) A group of glutamatergic interneurons expressing high levels of both neurokinin-1 receptors and somatostatin identifies the region of the pre-Botzinger complex. J Comp Neurol 455:499-512
Weston, Matthew; Wang, Hong; Stornetta, Ruth L et al. (2003) Fos expression by glutamatergic neurons of the solitary tract nucleus after phenylephrine-induced hypertension in rats. J Comp Neurol 460:525-41
Rosin, Diane L; Hettinger, Barbara D; Lee, Amy et al. (2003) Anatomy of adenosine A2A receptors in brain: morphological substrates for integration of striatal function. Neurology 61:S12-8
Guyenet, Patrice G; Stornetta, Ruth L; Schreihofer, Ann M et al. (2002) Opioid signalling in the rat rostral ventrolateral medulla. Clin Exp Pharmacol Physiol 29:238-42
Wang, Hong; Germanson, Teresa P; Guyenet, Patrice G (2002) Depressor and tachypneic responses to chemical stimulation of the ventral respiratory group are reduced by ablation of neurokinin-1 receptor-expressing neurons. J Neurosci 22:3755-64
Guyenet, Patrice G; Sevigny, Charles P; Weston, Matthew C et al. (2002) Neurokinin-1 receptor-expressing cells of the ventral respiratory group are functionally heterogeneous and predominantly glutamatergic. J Neurosci 22:3806-16
Llewellyn-Smith, I J; Schreihofer, A M; Guyenet, P G (2001) Distribution and amino acid content of enkephalin-immunoreactive inputs onto juxtacellularly labelled bulbospinal barosensitive neurons in rat rostral ventrolateral medulla. Neuroscience 108:307-22
Stornetta, R L; Schreihofer, A M; Pelaez, N M et al. (2001) Preproenkephalin mRNA is expressed by C1 and non-C1 barosensitive bulbospinal neurons in the rostral ventrolateral medulla of the rat. J Comp Neurol 435:111-26

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