title: 5-HT1A receptors of the nucleus tractus solitarii facilitate sympathetic recovery following hypotensive hemorrhage in rats.
abstract: The role of serotonin in the hemodynamic response to blood loss remains controversial. Caudal raphe serotonin neurons are activated during hypotensive hemorrhage, and their destruction attenuates sympathetic increases following blood loss in unanesthetized rats. Caudal raphe neurons provide serotonin-positive projections to the nucleus tractus solitarii (NTS), and disruption of serotonin-positive nerve terminals in the NTS attenuates sympathetic recovery following hemorrhage. Administration of 5-HT1A-receptor agonists following hemorrhage augments sympathetic-mediated increases in venous tone and tissue hypoxia. These findings led us to hypothesize that severe blood loss promotes activation of 5-HT1A receptors in the NTS, which facilitates sympathetic recovery and peripheral tissue perfusion. Here, we developed an adeno-associated viral vector encoding an efficacious small hairpin RNA sequence targeting the rat 5-HT1A receptor. Unanesthetized rats subjected to NTS injection of the anti-rat 5-HT1A small hairpin RNA-encoding vector 4 wk prior showed normal blood pressure recovery, but an attenuated recovery of renal sympathetic nerve activity (-6.4 ± 12.9 vs. 42.6 ± 15.6% baseline, P < 0.05) 50 min after 21% estimated blood volume withdrawal. The same rats developed increased tissue hypoxia after hemorrhage, as indicated by prolonged elevations in lactate (2.77 ± 0.5 vs. 1.34 ± 0.2 mmol/l, 60 min after start of hemorrhage, P < 0.05). 5-HT1A mRNA levels in the commissural NTS were directly correlated with renal sympathetic nerve activity (P < 0.01) and inversely correlated with lactate (P < 0.05) 60 min after start of hemorrhage. The data suggest that 5-HT1A receptors in the commissural NTS facilitate tissue perfusion after blood loss likely by increasing sympathetic-mediated venous return.
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois;
authors.forename: Jaime E
authors.initials: JE
authors.lastname: Vantrease
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois;
authors.forename: Nichole
authors.initials: N
authors.lastname: Dudek
authors.affiliation: Department of Cellular and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; and Neuroscience Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.
authors.forename: Lydia L
authors.initials: LL
authors.lastname: DonCarlos
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; Department of Cellular and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; and Neuroscience Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois kscrogi@luc.edu.
authors.forename: Karie E
authors.initials: KE
authors.lastname: Scrogin
mesh_terms: D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure; D001810:Blood Volume; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007022:Hypotension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000294:innervation*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D019344:Lactic Acid
keywords: adeno-associated virus; blood pressure; lactate; serotonin; shRNA