Trauma is the leading cause of death of young people in the U.S. (150,000/year). Most trauma deaths result either from insufficient tissue perfusion, due to excessive blood loss, or the development of inflammation, infection and end organ damage following resuscitation. Current treatment plans for hypovolemic shock rely on massive and rapid infusion of crystalloid fluids to raise cardiac output. It is now recognized that excessive volume resuscitation may increase blood loss and the reperfusion injury that contributes to the morbidity of hypovolemic shock. As such, the development of alternative strategies for the treatment of traumatic blood loss will be critical for the improvement of patient outcomes following hypovolemic shock; progressive hemorrhage produces a biphasic response. Increases in heart rate and sympathetic activity maintain blood pressure in the initial compensatory phase. These compensatory responses suddenly abate after significant blood loss (20-30%), resulting in hypotension, bradycardia and sympathoinhibition. We recently discovered that drugs that activate serotonin 5-HTIA receptors rapidly reverse the hypotensive and sympathoinhibitory responses to hemorrhage in conscious rats. Both central and systemic administration of 5-HTIA receptor agonists effectively raises blood pressure after either acute or sustained blood loss. These results indicate that 5-HTIA agonists could provide a promising therapy for hypovolemic shock. However, it is not known how 5-HTIA receptor activation increases arterial pressure or if the hemodynamic responses to agonist administration provide a beneficial effect on tissue perfusion. More importantly, it is not known if activation of 5-HTIA receptors can delay the transition from hypovolemic shock to circulatory collapse. Studies proposed in this project will determine the autonomic and hemodynamic effects of selective 5-HTIA agonists following sustained hypotensive hemorrhage to assess their impact on perfusion. Additional studies will assess the central nervous system mechanisms responsible for pressor effects of selective 5-HTIA agonists during hemorrhage. We will also assess the ability of clinically available 5-HT1A agonists to delay the transition from hypovolemic shock to circulatory collapse.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL076162-01
Application #
6754134
Study Section
Special Emphasis Panel (ZHL1-CSR-I (F1))
Program Officer
Lathrop, David A
Project Start
2004-02-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$293,600
Indirect Cost
Name
Loyola University Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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
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
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
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