Following a critical amount of blood loss, compensatory neural responses that normally help maintain blood pressure suddenly fail, causing vasodilation, profound bradycardia and life-threatening hypotension. The central nervous system mechanisms that mediate this sympatholytic response are unknown. A more comprehensive understanding of such mechanisms could lead to novel treatments for circulatory shock and other disorders with aberrant activation of sympatholytic reflexes such as myocardial infarct of the inferoposterior wall of the heart, exertional syncope associated with aortic stenosis or neurogenic syncope. In vivo models devised to examine these responses have been limited due to the effects of anesthesia on autonomic function. The objective of this proposal is to elucidate the role of hindbrain serotonergic cellular- and receptor mediated mechanisms in the sudden loss of sympathetic activity that accompanies severe blood loss in the conscious rat. Specifically, studies have been designed to identify the source of serotonin and the receptor populations that mediate sympathetic withdrawal during hemorrhage. The proposed experiments involve novel uses of classic physiological models to study the role of discrete hindbrain neuronal and receptor populations in the regulation of sympathetic function in unanesthetized rats. Anatomical studies that combine neuronal tract tracing with immunhistochemical markers of neuronal phenotype and function will be used to determine the source and projection site of serotonin involved in sympathetic reflexes. The novel techniques outlined in this proposal will help to determine hindbrain serotonergic cellular and receptor function on sympathetic regulation in general and on hemorrhage responses in particular, a goal which has, until now, been hampered by the confounding influence of anesthesia on hemorrhage responses and serotonergic function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072354-04
Application #
7073307
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Barouch, Winifred
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$216,783
Indirect Cost
Name
Loyola University Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Vantrease, Jaime E; Dudek, Nichole; DonCarlos, Lydia L et al. (2015) 5-HT1A receptors of the nucleus tractus solitarii facilitate sympathetic recovery following hypotensive hemorrhage in rats. Am J Physiol Heart Circ Physiol 309:H335-44
Tiniakov, Ruslan; Pahan, Kalipada; Scrogin, Karie E (2012) Sympathetic innervation of the splanchnic region mediates the beneficial hemodynamic effects of 8-OH-DPAT in hemorrhagic shock. Am J Physiol Regul Integr Comp Physiol 303:R527-38
Davis, Robert Patrick; Pattison, Jill; Thompson, Janice M et al. (2012) 5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved. BMC Pharmacol 12:4
Kung, Ling-Hsuan; Scrogin, Karie E (2011) Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation. Am J Physiol Regul Integr Comp Physiol 301:R1367-79
Kung, Ling-Hsuan; Glasgow, Jaimee; Ruszaj, Anna et al. (2010) Serotonin neurons of the caudal raphe nuclei contribute to sympathetic recovery following hypotensive hemorrhage. Am J Physiol Regul Integr Comp Physiol 298:R939-53
Marvin, Eric; Scrogin, Karie; Dudas, Bertalan (2010) Morphology and distribution of neurons expressing serotonin 5-HT1A receptors in the rat hypothalamus and the surrounding diencephalic and telencephalic areas. J Chem Neuroanat 39:235-41
Tiniakov, Ruslan; Scrogin, Karie E (2009) The spleen is required for 5-HT1A receptor agonist-mediated increases in mean circulatory filling pressure during hemorrhagic shock in the rat. Am J Physiol Regul Integr Comp Physiol 296:R1392-401
Tiniakov, Ruslan; Osei-Owusu, Patrick; Scrogin, Karie E (2007) The 5-hydroxytryptamine1A receptor agonist, (+)-8-hydroxy-2-(di-n-propylamino)-tetralin, increases cardiac output and renal perfusion in rats subjected to hypovolemic shock. J Pharmacol Exp Ther 320:811-8
Tiniakov, Ruslan; Scrogin, Karie E (2006) The serotonin 5-Hydroxytryptaphan1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, stimulates sympathetic-dependent increases in venous tone during hypovolemic shock. J Pharmacol Exp Ther 319:776-82
Osei-Owusu, Patrick; Scrogin, Karie (2006) Role of the arterial baroreflex in 5-HT1A receptor agonist-mediated sympathoexcitation following hypotensive hemorrhage. Am J Physiol Regul Integr Comp Physiol 290:R1337-44

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