This project will help to characterize the central nervous system mechanisms that regulate autonomic and respiratory compensation following hypovolemic hypotension and circulatory shock. Experiments will be conducted to test the hypothesis that caudal hindbrain serotonergic neurons activated by acidosis, stimulate 5-HT1A receptors to promote sympathetic-mediated venoconstriction of the splanchnic vascular bed during hypovolemia. It is further proposed that the preferential constriction of the venous vasculature induced by 5-HT1A receptor activation will produce less reperfusion injury during resuscitation from hypovolemic shock than clinically used vasoconstrictor agents which tend to constrict arterial vascular beds.
Aim 1 will determine whether caudal hindbrain serotonin is critical for maintenance or recovery of sympathetic-mediated whole body venous tone and venous return following severe blood loss.
Aim 2 will determine whether the acidemia associated with hypovolemia or respiratory and metabolic acidosis per se contribute to activation of caudal hindbrain serotonin neural activation and subsequent respiratory and autonomic responses. Further studies will assess with acidosis contributes to the maintenance of blood pressure through a preferential venoconstriction.
Aim 3 will determine whether serotonin acts on 5-HT1A receptors to mediate compensatory responses to hypovolemia and whether this endogenous pathway can be exploited to produce a more favorable hemodynamic response during resuscitation from hypovolemic shock. These studies will rely heavily on a carefully developed in vivo rat and mouse models of hypotensive hemorrhage and hypovolemic shock. State of the art techniques for continuous monitoring of hemodynamic parameters, sympathetic nerve activity and central respiratory drive in unanesthetized animals will be used to assess cardiovascular parameters after pharmacological and molecular manipulation of serotonin and serotonin receptor levels. In addition, newly developed techniques for the recording of sympathetic activity in the unanesthetized mouse will enable use of genetically altered mice for investigation of the receptors involved in the compensatory responses to blood loss. Furthermore, novel molecular techniques to more acutely alter serotonin levels in discrete brain regions will be utilized to dissect regions important in the neural control of the circulatory responses to blood loss. Finally, pre-clinical, translational studies will address the potential utility of using 5-HT1A receptor agonists as adjuvants in resuscitation from circulatory shock.

Public Health Relevance

Despite recent advances in emergency medicine, traumatic blood loss is currently one of the leading causes of death of individuals under 40 in the US. Patients typically succumb to severe blood loss either because of too little tissue perfusion or because of tissue injury incurred during the resuscitation process. Our studies will attempt to validate a new, promising therapy that may help patients recover from circulatory shock without further injuring tissue during the resuscitation process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072354-08
Application #
8197458
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2002-09-01
Project End
2014-03-31
Budget Start
2011-12-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$259,875
Indirect Cost
$84,875
Name
Loyola University Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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
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
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; James, Amy; Crane, James et al. (2005) 5-Hydroxytryptamine 1A receptors in the paraventricular nucleus of the hypothalamus mediate oxytocin and adrenocorticotropin hormone release and some behavioral components of the serotonin syndrome. J Pharmacol Exp Ther 313:1324-30