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.
|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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