Hypertension is a sustained elevation in blood pressure that represents a significant risk factor for common causes of morbidity and mortality including, heart disease, stroke, and end-stage renal disease. Despite research efforts, the exact mechanism underlying essential hypertension remains largely unknown, interestingly, several lines of evidence suggest an important association between hypertension and serotonin (5-hydroxytryptamine, 5-HT). Studies have demonstrated elevated levels of free plasma 5-HT in Doth human and animal models of hypertension compared to normotensive controls. Historically, these elevated levels were thought to contribute to essential hypertension. However, we have shown that elevated free plasma 5-HT has the ability to lower blood pressure in male deoxycorticosterone acetate (DOCA)-salt hypertensive and sham-normotensive rat. The mechanism underlying 5-HT-induced hypotension is not yet mown. We hypothesize that elevated levels of free plasma 5-HT lower blood pressure in a nitric oxide dependent manner by reducing total peripheral resistance. This may be the result of either a reduction in sympathetic nervous system (SNS) tone and/or stimulation of a vascular 5-HT receptor(s). An integrative approach will be used to elucidate the mechanism underlying 5-HT-induced hypotension. We will use several different techniques, including whole animal measures, SNS activity measures, and measures of vascular reactivity.
The aims for this study are as follows:
Specific aim 1 : will test the hypothesis that 5-HT-induced hypotension is mediated by a fall in total peripheral resistance in the DOCA-salt and sham rat.
Specific aim 2 : will test the hypothesis that chronic 5-HT infusion reduces sympathetic nerve activity or stimulates sensory afferent nerves.
Specific aim 3 : will test the hypothesis that 5-HT stimulates vascular receptors, leading to a release of nitric oxide, and vascular relaxation. This research will fill a gap in our understanding of how 5-HT functions in the cardiovascular system and explore the potentially beneficial role of 5-HT in hypertension. Additionally, this project may lead to discovery of novel therapeutic targets for the treatment of essential hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL099024-03
Application #
8209053
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2010-01-21
Project End
2013-07-20
Budget Start
2012-01-21
Budget End
2013-01-20
Support Year
3
Fiscal Year
2012
Total Cost
$39,561
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Osteopathic Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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
Watts, Stephanie W; Davis, Robert Patrick (2011) 5-hydroxtryptamine receptors in systemic hypertension: an arterial focus. Cardiovasc Ther 29:54-67
Linder, Aurea Elizabeth; Davis, Robert Patrick; Burnett, Robert et al. (2011) Comparison of the function of the serotonin transporter in the vasculature of male and female rats. Clin Exp Pharmacol Physiol 38:314-22
McDougal, Kathryn E; Fallin, M Daniele; Moller, David R et al. (2009) Variation in the lymphotoxin-alpha/tumor necrosis factor locus modifies risk of erythema nodosum in sarcoidosis. J Invest Dermatol 129:1921-6