5-HT as a mediator of blood pressure regulation

It’s been a long road, but a good one. Science doesn’t always happen fast. Consistent application of time, experimentation, analysis, back tracking and doing it all over again has moved this project from something we didn’t understand but was so surprised by in 2008 to one in 2024 that may provide a new drug.

5-HT was discovered in blood and is best known as a vasoconstrictor of isolated blood vessels.  Circulating levels of 5-HT are elevated in hypertension, and thus we hypothesized several years ago infused 5-HT would elevate blood pressure.  So had the field as a whole!  To our surprise, 5-HT reduced blood pressure and our laboratory has been dedicated to understanding the mechanisms by which it occurs (first reported in Diaz et al, 2008).  Our important contributions to this field were recognized with an invited review by Pharmacological Reviews (b) on this very subject.  We are looked to as a leader in this particular field with the hope of developing a novel serotonergic therapy for lowering blood pressure.  The papers here support our expertise in serotonergic pharmacology and specifically venous serotonergic mechanisms (c). 

Technically, this work is outstanding in utilizing existing techniques and making them work in the rat.  We use novel dual pressure telemeters to measure blood pressures in the arterial and venous circulation simultaneously, and have recently validated use of ultrasound to measure venous diameter (d).

In 2017, we created the worlds first 5-HT7 receptor knockout (KO) rat and have just published on the creation of these rats in 2019 (e, f). F is particularly important as it reports that the 5-HT7 receptor is absolutely essential for the 5-HT-induced fall in blood pressure. Gifford Biosciences was the company that really helped us prove this was so - an important pharmacological technique of autoradiography came to our rescue! In 2020, we received an R01 from NIH to study this very project with the goal have having a firm grasp on how stimulation of the 5-HT7 receptor results in a fall in blood pressure. This is done in collaboration with Dr. Gregory D Fink, also a faculty member of the PHM/TOX department, and also Dr. Bill Jackson (PHM/TOX).

•In 2024, we are investigating HOW the 5-HT7 receptor is stimulated to cause a hypotension, with activation of either Gs or beta-arrestin pathways contributing. This brings this project into state of the art pharmacology by recognizing agonists of a receptor can be biased. Our ultimate goal is to develop a drug that is not only selective for the 5-HT7 receptor but also specific for the pathway most effective in lowering blood pressure.

a.  Diaz, J., Ni, W., King, A., Fink, G. D. and Watts, S. W.: 5-hydroxytryptamine lowers blood pressure in normotensive and hypertensive rats.  J Pharmacol Exp Ther, 325:1031-1038, 2008. PMID 18305011.

b. Invited Review: Watts, S. W., Morrison S. M and Barman SM:  Serotonin and Blood Pressure Regulation, Pharmacol. Rev., 64:359-388, 2012.  PMCID:PMC3310484.

c. Watts, S. W., Darios, E., Seitz, B. M., Burnett, R and Thompson, J. M.: 5-HT is a potent relaxant in rat superior mesenteric veins.  Pharmacology Research and Perspectives, e00103.doi:10.1102/prp2.103, 2015.  PMID: 25692021

d. Seitz, B. M., Krieger-Burke Teresa, Fink, G. D. and Watts, S. W.: Serial measurements of splanchnic vein diameters in rats using high frequency ultrasound, Frontiers in Pharmacology; experimental Pharmacology and Drug Discovery, http://dx.doi.org/10.3389/fphar.2016.00116 03 May 2016.

E. Demireva EY, Xie H, Flood ED, Thompson JM, Seitz BM and Watts SW: Creation of the 5-hydroxytryptamine receptor knockout (5-HT7 KO) rat as a tool for cardiovascular research, accepted, Physiological Genomics, 2019.   

F. Seitz, B. M., Demireva, E. Y., Xie, H., Fink, G. D., Krieger-Burke, T., Burke, W M. and Watts, S.W.:  5-HT does not lower blood pressure in the 5-HT7 knockout rat, accepted Physiological Genomics, 2019.