Humans have elevations in circulating free serotonin (5-hydroxytryptamine, 5-HT) in several important clinical, chronic situations. These include anaphylactic shock, cardiopulmonary bypass, carcinoid cancer and hemodialysis, all of which presents with a fall in blood pressure. Additionally, millions of individuals use medications that increase plasma 5-HT concentration, and changes in blood pressure are a side effect of these medications. Finally, the committed substrate for 5-HT synthesis, 5-hydroxytryptophan (5-HTP), is taken as an aide for sleep, mood disorders, menopause and many other conditions and causes a fall in blood pressure. We were the first to demonstrate that, in the rat, a long-term administration of 5-HT (1 week) directly reduced the blood pressure of the conscious, healthy rat through reduction of total peripheral resistance (TPR). The 5- HT-induced chronic fall in blood pressure is dependent on the activity of nitric oxide synthase (NOS) because the NOS inhibitor N-nitro-L-arginine (LNNA) abolished 5-HT-induced chronic fall in blood pressure in multiple situations. At no time has our understanding of the mechanisms of 5-HT been more important, and ours is the first to address this clinically relevant issue. The overall goal of thi project and long-term goal of our laboratory is to identify the mechanism(s) by which 5-HT elicits a fall in blood pressure in normotensive animals. Our central hypothesis is that 5-HT reduces TPR through 1) direct vascular;and 2) indirect vascular effects through removal of sympathetic tone mediated either centrally or peripherally. Preliminary experiments support the ability of 5-HT to increase flow in cutaneous and splanchnic circulations so we will focus on these two beds. An integrative approach and team with significant expertise will be used to address three specific aims. Sprague-Dawley rats will be the primary model, but we will also use the novel serotonin transporter (SERT) knockout rat. We employ a powerful technique for repeated measures of blood pressure using combined radiotelemetry and the programmable iPrecio(R) pump for drug delivery in conscious rats, as well as neural measures in anesthetized rats.
Aim 1 directly addresses the controversial issue of whether 5-HT enters the central nervous system (CNS).
Aim 2 will dissect whether 5-HT causes direct vascular relaxation and/or reduces sympathetic nerve activity to decrease blood pressure.
Aims 1 and 2 will determine whether and where the effects of 5-HT are NOS-dependent.
Aim 3 closes this proposal powerfully by testing whether activation of the 5-HT receptor implicated in Aims 1 and 2 causes a NOS- and 5-HT- receptor dependent fall in blood pressure, and whether 5-HTP-infusion reduces blood pressure chronically in a NOS- and 5-HT-receptor dependent manner. The impact and promise of this work lies in 1) addressing controversies head-on (5-HT enter the CNS? 5-HT in vitro vs 5-HT in vivo?) and 2) in discovering mechanisms of 5-HT action that may be beneficial to human regulation of blood pressure, given that chronic 5-HT nearly normalized elevated blood pressure of the conscious mineralocorticoid and spontaneously hypertensive rat.

Public Health Relevance

A substantial number of medications (antidepressants, for example) and the over the counter supplement 5- hydroxytryptophan are taken with the intent to increase extracellular concentration of the hormone 5- hydroxytryptamine (5-HT) and improve mood, sleep and satiety. Elevations in circulating 5-HT also occur in anaphylactic shock, cardiopulmonary bypass, carcinoid cancer and hemodialysis and a decrease in blood pressure is associated with all these events. Our work investigates the mechanisms of 5-HT-induced fall in blood pressure and whether 5-HT-like compounds might be useful in controlling blood pressure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Maric-Bilkan, Christine
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Michigan State University
Schools of Osteopathic Medicine
East Lansing
United States
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Seitz, Bridget M; Orer, Hakan S; Krieger-Burke, Teresa et al. (2017) 5-HT causes splanchnic venodilation. Am J Physiol Heart Circ Physiol 313:H676-H686
Watts, Stephanie W (2016) Oh, the places you'll go! My many colored serotonin (apologies to Dr. Seuss). Am J Physiol Heart Circ Physiol 311:H1225-H1233
Seitz, Bridget M; Krieger-Burke, Teresa; Fink, Gregory D et al. (2016) Serial Measurements of Splanchnic Vein Diameters in Rats Using High-Frequency Ultrasound. Front Pharmacol 7:116
Petersen-Jones, Humphrey G; Johnson, Kyle B; Hitomi, Kiyotaka et al. (2015) Transglutaminase activity is decreased in large arteries from hypertensive rats compared with normotensive controls. Am J Physiol Heart Circ Physiol 308:H592-602
Darios, Emma S; Barman, Susan M; Orer, Hakan S et al. (2015) 5-Hydroxytryptamine does not reduce sympathetic nerve activity or neuroeffector function in the splanchnic circulation. Eur J Pharmacol 754:140-7
Young, Lindsey W; Darios, Emma S; Watts, Stephanie W (2015) An immunohistochemical analysis of SERT in the blood-brain barrier of the male rat brain. Histochem Cell Biol 144:321-9
Watts, Stephanie W; Darios, Emma S; Seitz, Bridget M et al. (2015) 5-HT is a potent relaxant in rat superior mesenteric veins. Pharmacol Res Perspect 3:e00103
Watts, Stephanie W (2014) Serotonin and sensory nerves: meeting in the cardiovascular system. Vascul Pharmacol 63:1-3
Davis, Robert Patrick; Szasz, Theodora; Garver, Hannah et al. (2013) One-month serotonin infusion results in a prolonged fall in blood pressure in the deoxycorticosterone acetate (DOCA) salt hypertensive rat. ACS Chem Neurosci 4:141-8
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

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