Interpreting the serotonin blood pressure paradox: An updated integrative framework for hypertension

McEvoy JW, McCarthy CP, Bruno RM, Brouwers S, Canavan MD, Ceconi C, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Eur Heart J. 2024;45(38):3912–4018. doi:10.1093/eurheartj/ehae178.
Open DOI Search in Google Scholar Back to article
Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16(4):223–237. doi:10.1038/s41581-019-0244-2.
Open DOI Search in Google Scholar Back to article
Watts SW, Morrison SF, Davis RP, Barman SM. Serotonin and blood pressure regulation. Pharmacol Rev. 2012;64(2):359–388. doi:10.1124/pr.111.004697.
Open DOI Search in Google Scholar Back to article
Vanhoutte PM. Serotonin and the blood-vessel wall. J Hypertens Suppl. 1986;4(5):S112–S115.
Search in Google Scholar Back to article
Frishman WH, Grewall P. Serotonin and the heart. Ann Med. 2000;32(3):195–209. doi:10.3109/07853890008998827.
Open DOI Search in Google Scholar Back to article
Soslau G. Cardiovascular serotonergic system: evolution, receptors, transporter, and function. J Exp Zool A Ecol Integr Physiol. 2022;337(2):115–127. doi:10.1002/jez.2554.
Open DOI Search in Google Scholar Back to article
Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264–276. doi:10.1016/j.cell.2015.02.047.
Open DOI Search in Google Scholar Back to article
Bader M. Serotonylation: serotonin signaling and epigenetics. Front Mol Neurosci. 2019;12:288. doi:10.3389/fnmol.2019.00288.
Open DOI Search in Google Scholar Back to article
Williams RB, Bishop GD, Haberstick BC, Smolen A, Brummett BH, Siegler IC, et al. Population differences in associations of serotonin transporter promoter polymorphism (5HTTLPR) di- and triallelic genotypes with blood pressure and hypertension prevalence. Am Heart J. 2017;185:110–122. doi:10.1016/j.ahj.2016.12.013.
Open DOI Search in Google Scholar Back to article
Zhang Y, Wang N, Zhang L, Zhuang Y, Xin Q, Gu X, et al. Serotonin (5-hydroxytryptamine): metabolism, signaling, biological functions, diseases, and emerging therapeutic opportunities. MedComm. 2025;6(9):e70383. doi:10.1002/mco2.70383.
Open DOI Search in Google Scholar Back to article
Mercado CP, Kilic F. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mol Interv. 2010;10(4):231–241. doi:10.1124/mi.10.4.6.
Open DOI Search in Google Scholar Back to article
Kubo T, Taguchi K, Ozaki S, Amano M, Ishizuka T. 8-OH-DPAT-induced hypotensive action and sympathoexcitatory neurons in the rostral ventrolateral medulla of the rat. Brain Res Bull. 1995;36(4):405–411. doi:10.1016/0361-9230(94)00221-L.
Open DOI Search in Google Scholar Back to article
Comet MA, Bernard JF, Hamon M, Laguzzi R, Sevoz-Couche C. Activation of nucleus tractus solitarius 5-HT2A but not other 5-HT2 receptor subtypes inhibits the sympathetic activity in rats. Eur J Neurosci. 2007;26(2):345–354. doi:10.1111/j.1460-9568.2007.05673.x.
Open DOI Search in Google Scholar Back to article
Merahi N, Orer HS, Laporte AM, Gozlan H, Hamon M, Laguzzi R. Baroreceptor reflex inhibition induced by the stimulation of serotonin3 receptors in the nucleus tractus solitarius of the rat. Neuroscience. 1992;46(1):91–100. doi:10.1016/0306-4522(92)90011-P.
Open DOI Search in Google Scholar Back to article
Spinieli RL, Cornelius-Green J, Cummings KJ. A serotonin-deficient rat model of neurogenic hypertension: influence of sex and sympathetic vascular tone. J Neurophysiol. 2022;128(5):1199–1206. doi:10.1152/jn.00358.2022.
Open DOI Search in Google Scholar Back to article
Mandal AK, Kellar KJ, Friedman E, Pineo SV, Hamosh P, Gillis RA. Importance of central nervous system serotonin-1A receptors for mediating the hypotensive effect of urapidil. J Pharmacol Exp Ther. 1989;251(2):563–570. doi:10.1016/S0022-3565(25)20845-X.
Open DOI Search in Google Scholar Back to article
Bielen E, Fagard R, Staessen J, Lijnen P, Van Hoof R, Amery A. Urapidil-induced hemodynamic changes in humans. Am J Cardiol. 1989;64(7):16D–21D. doi:10.1016/0002-9149(89)90690-5.
Open DOI Search in Google Scholar Back to article
Tanaka N, Nakamura E, Ohkura M, Kuwabara M, Yamashita A, Onitsuka T, et al. Both 5-hydroxytryptamine 5-HT2A and 5-HT1B receptors are involved in the vasoconstrictor response to 5-HT in the human isolated internal thoracic artery. Clin Exp Pharmacol Physiol. 2008;35(7):836–840. doi:10.1111/j.1440-1681.2008.04933.x.
Open DOI Search in Google Scholar Back to article
Li N, Wallen NH, Ladjevardi M, Hjemdahl P. Effects of serotonin on platelet activation in whole blood. Blood Coagul Fibrinolysis. 1997;8(8):517–523. doi:10.1097/00001721-199711000-00006.
Open DOI Search in Google Scholar Back to article
Bruning TA, van Zwieten PA, Blauw GJ, Chang PC. No functional involvement of 5-hydroxytryptamine1A receptors in nitric oxide-dependent dilatation caused by serotonin in the human forearm vascular bed. J Cardiovasc Pharmacol. 1994;24(3):454–461. doi:10.1097/00005344-199409000-00014.
Open DOI Search in Google Scholar Back to article
Gonzalez-Pons R, McRae K, Thompson JM, Watts SW. 5-HT7 receptor restrains 5-HT-induced 5-HT2A mediated contraction in the isolated abdominal vena cava. J Cardiovasc Pharmacol. 2021;78(2):319–327. doi:10.1097/FJC.0000000000001057.
Open DOI Search in Google Scholar Back to article
Cameron HA, Waller PC, Ramsay LE. Ketanserin in essential hypertension: use as monotherapy and in combination with a diuretic or beta-adrenoceptor antagonist. Br J Clin Pharmacol. 1987;24(6):705–711. doi:10.1111/j.1365-2125.1987.tb03235.x.
Open DOI Search in Google Scholar Back to article
Donnelly R, Elliott HL, Meredith PA, Reid JL. Acute and chronic ketanserin in essential hypertension: antihypertensive mechanisms and pharmacokinetics. Br J Clin Pharmacol. 1987;24(5):599–606. doi:10.1111/j.1365-2125.1987.tb03218.x.
Open DOI Search in Google Scholar Back to article
Hosie J, Stott DJ, Robertson JI, Ball SG. Does acute serotonergic type-2 antagonism reduce blood pressure? Comparative effects of single doses of ritanserin and ketanserin in essential hypertension. J Cardiovasc Pharmacol. 1987;10(Suppl 3):S86–S88. doi:10.1097/00005344-198700103-00022.
Open DOI Search in Google Scholar Back to article
Reigstad CS, Salmonson CE, Rainey JF 3rd, Szurszewski JH, Linden DR, Sonnenburg JL, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 2015;29(4):1395–1403. doi:10.1096/fj.14-259598.
Open DOI Search in Google Scholar Back to article
Yang T, Maki KA, Marques FZ, Cai J, Joe B, Pepine CJ, et al. Hypertension and the gut microbiome: a Science Advisory From the American Heart Association. Hypertension. 2025;82(9):e160–e170. doi:10.1161/HYP.0000000000000247.
Open DOI Search in Google Scholar Back to article
Welathanthree M, Keating DJ, Macefield VG, Carnevale D, Marques FZ, Muralitharan RR. Cross-talk between microbiota-gut-brain axis and blood pressure regulation. Clin Sci (Lond). 2025;139(9):431–447. doi:10.1042/CS20240787.
Open DOI Search in Google Scholar Back to article
Sree Kumar H, Zubcevic J. Host-microbiota interactions regulate gut serotonergic signaling: implications for hypertension. Am J Physiol Cell Physiol. 2025;329(6):C1742–C1751. doi:10.1152/ajpcell.00608.2025.
Open DOI Search in Google Scholar Back to article
Rieder M, Gauchel N, Bode C, Duerschmied D. Serotonin: a platelet hormone modulating cardiovascular disease. J Thromb Thrombolysis. 2021;52(1):42–47. doi:10.1007/s11239-020-02331-0.
Open DOI Search in Google Scholar Back to article
Brand T, Anderson GM. The measurement of platelet-poor plasma serotonin: a systematic review of prior reports and recommendations for improved analysis. Clin Chem. 2011;57(10):1376–1386. doi:10.1373/clinchem.2011.163824.
Open DOI Search in Google Scholar Back to article
von Volkmann HL, Brønstad I, Fiskerstrand T, Gudbrandsen OA. Comparison of pre-analytical conditions for quantification of serotonin in platelet-poor plasma. Pract Lab Med. 2019;17:e00136. doi:10.1016/j.plabm.2019.e00136.
Open DOI Search in Google Scholar Back to article
Pillalamarri S, Anderson GM. The continued mismeasurement of plasma serotonin: a systematic review. Biomed Chromatogr. 2025;39(3):e70016. doi:10.1002/bmc.70016.
Open DOI Search in Google Scholar Back to article
Kamal LA, Le Quan-Bui KH, Meyer P. Decreased uptake of 3H-serotonin and endogenous content of serotonin in blood platelets in hypertensive patients. Hypertension. 1984;6(4):568–573. doi:10.1161/01.HYP.6.4.568.
Open DOI Search in Google Scholar Back to article
Biondi ML, Agostoni A, Marasini B. Serotonin levels in hypertension. J Hypertens Suppl. 1986;4(1):S39–S41.
Search in Google Scholar Back to article
Nityanand S, Tekwani BL, Chandra M, Shanker K, Singh BN. Kinetics of serotonin in platelets in essential hypertension. Life Sci. 1990;46(5):367–372. doi:10.1016/0024-3205(90)90016-K.
Open DOI Search in Google Scholar Back to article
Fetkovska N, Pletscher A, Ferracin F, Amstein R, Buhler FR. Impaired uptake of 5-hydroxytryptamine platelet in essential hypertension: clinical relevance. Cardiovasc Drugs Ther. 1990;4(Suppl 1):105–109. doi:10.1007/BF00053439.
Open DOI Search in Google Scholar Back to article
Jafri SM, Chandra N, Dhawan S, Soni D, Chandra M, Shanker K. Factors influencing platelet serotonin uptake in essential hypertension. Int J Cardiol. 1992;34(3):327–333. doi:10.1016/0167-5273(92)90031-W.
Open DOI Search in Google Scholar Back to article
Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL, et al. Plasma serotonin levels and the platelet serotonin transporter. J Neurochem. 2007;102(1):206–215. doi:10.1111/j.1471-4159.2007.04542.x.
Open DOI Search in Google Scholar Back to article
Tomoda F, Takata M, Oh-Hashi S, Ueno H, Yasumoto K, Iida H, et al. Altered renal response to enhanced endogenous 5-hydroxytryptamine after tryptophan administration in essential hypertension. Clin Sci (Lond). 1992;82(5):551–557. doi:10.1042/cs0820551.
Open DOI Search in Google Scholar Back to article
Hirose M, Tomoda F, Koike T, Yamazaki H, Ohara M, Liu H, et al. Imbalance of renal production between 5-hydroxytryptamine and dopamine in patients with essential hypertension complicated by microalbuminuria. Am J Hypertens. 2013;26(2):227–233. doi:10.1093/ajh/hps008.
Open DOI Search in Google Scholar Back to article
Choi JR, Jeon M, Koh SB. Association between serotonin 2A receptor (HTR2A) genetic variations and risk of hypertension in a community-based cohort study. BMC Med Genet. 2020;21(1):5. doi:10.1186/s12881-019-0927-3.
Open DOI Search in Google Scholar Back to article
Liolitsa D, Powell JF, Prince M, Lovestone S. Association study of the 5-HT2A receptor gene polymorphism, T102C and essential hypertension. J Hum Hypertens. 2001;15(5):335–339. doi:10.1038/sj.jhh.1001177.
Open DOI Search in Google Scholar Back to article
Calvi A, Fischetti I, Verzicco I, Belvederi Murri M, Zanetidou S, Volpi R, et al. Antidepressant drugs effects on blood pressure. Front Cardiovasc Med. 2021;8:704281. doi:10.3389/fcvm.2021.704281.
Open DOI Search in Google Scholar Back to article
Zhong Z, Wang L, Wen X, Liu Y, Fan Y, Liu Z. A meta-analysis of effects of selective serotonin reuptake inhibitors on blood pressure in depression treatment: outcomes from placebo and serotonin and noradrenaline reuptake inhibitor controlled trials. Neuropsychiatr Dis Treat. 2017;13:2781–2796. doi:10.2147/NDT.S141832.
Open DOI Search in Google Scholar Back to article
Zhang L, Li G, Liu M. A meta-analysis on the association between SSRIs and blood pressure in patients with CVD and depression. J Affect Disord. 2023;340:181–188. doi:10.1016/j.jad.2023.08.032.
Open DOI Search in Google Scholar Back to article
Pillinger T, Arumuham A, McCutcheon RA, D'Ambrosio E, Basdanis G, Branco M, et al. The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis. Lancet. 2025;406(10515):2063–2077. doi:10.1016/S0140-6736(25)01293-0.
Open DOI Search in Google Scholar Back to article
Walther DJ, Peter JU, Winter S, Holtje M, Paulmann N, Grohmann M, et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell. 2003;115(7):851–862. doi:10.1016/S0092-8674(03)01014-6.
Open DOI Search in Google Scholar Back to article
Watts SW, Priestley JRC, Thompson JM. Serotonylation of vascular proteins important to contraction. PLoS One. 2009;4(5):e5682. doi:10.1371/journal.pone.0005682.
Open DOI Search in Google Scholar Back to article
Guilluy C, Rolli-Derkinderen M, Tharaux PL, Melino G, Pacaud P, Loirand G. Transglutaminase-dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem. 2007;282(5):2918–2928. doi:10.1074/jbc.M604195200.
Open DOI Search in Google Scholar Back to article
Liu Y, Wei L, Laskin DL, Fanburg BL. Role of protein transamidation in serotonin-induced proliferation and migration of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2011;44(4):548–555. doi:10.1165/rcmb.2010-0078OC.
Open DOI Search in Google Scholar Back to article
Guilluy C, Eddahibi S, Agard C, Guignabert C, Izikki M, Tu L, et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med. 2009;179(12):1151–1158. doi:10.1164/rccm.200805-691OC.
Open DOI Search in Google Scholar Back to article
Stier CT Jr, McKendall G, Itskovitz HD. Serotonin formation in nonblood-perfused rat kidneys. J Pharmacol Exp Ther. 1984;228(1):53–56. doi:10.1016/S0022-3565(25)21590-7.
Open DOI Search in Google Scholar Back to article
Stier CT Jr, Itskovitz HD. Formation of serotonin by rat kidneys in vivo. Proc Soc Exp Biol Med. 1985;180(3):550–557. doi:10.3181/00379727-180-42216.
Open DOI Search in Google Scholar Back to article
Takahashi T, Hisa H, Satoh S. Serotonin-induced renin release in the dog kidney. Eur J Pharmacol. 1991;193(3):315–320. doi:10.1016/0014-2999(91)90145-G.
Open DOI Search in Google Scholar Back to article
Oleshchuk OM, Chornomydz AV. Endothelial dysfunction: problematic issues of definition and classification. Achiev Clin Exp Med. 2025;3:170–179. doi:10.11603/1811-2471.2025.v.i3.15567.
Open DOI Search in Google Scholar Back to article
Vrints CJ, Bult H, Bosmans J, Herman AG, Snoeck JP. Paradoxical vasoconstriction as result of acetylcholine and serotonin in diseased human coronary arteries. Eur Heart J. 1992;13(6):824–831. doi:10.1093/oxfordjournals.eurheartj.a060264.
Open DOI Search in Google Scholar Back to article
Forstermann U, Mugge A, Bode SM, Frolich JC. Response of human coronary arteries to aggregating platelets: importance of endothelium-derived relaxing factor and prostanoids. Circ Res. 1988;63(2):306–312. doi:10.1161/01.RES.63.2.306.
Open DOI Search in Google Scholar Back to article
Watanabe T, Pakala R, Katagiri T, Benedict CR. Angiotensin II and serotonin potentiate endothelin-1-induced vascular smooth muscle cell proliferation. J Hypertens. 2001;19(4):731–739. doi:10.1097/00004872-200104000-00010.
Open DOI Search in Google Scholar Back to article
Dzau VJ, Hodgkinson CP. Precision hypertension. Hypertension. 2024;81(4):702–708. doi:10.1161/HYPERTENSIONAHA.123.21710.
Open DOI Search in Google Scholar Back to article
Cseh D, Yasmin, McDonnell BJ, Maki-Petaja KM, Simonian T, Cockcroft JR, et al. Phenotypes of hypertension: impact of age and sex on hemodynamic mechanisms. J Am Heart Assoc. 2025;14(17):e042096. doi:10.1161/JAHA.125.042096.
Open DOI Search in Google Scholar Back to article
Rauseo E, Salih AM, Cooper J, Abdulkareem M, Banerji CRS, Chadalavada S, et al. Clinical phenotypes in hypertension: a data-driven approach to risk stratification. Hypertension. 2026;83(6):e25187. doi:10.1161/HYPERTENSIONAHA.125.25187.
Open DOI Search in Google Scholar Back to article
Xu X, Khunsriraksakul C, Eales JM, Rubin S, Scannali D, Saluja S, et al. Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets. Nat Commun. 2024;15(1):2359. doi:10.1038/s41467-024-46132-y.
Open DOI Search in Google Scholar Back to article

Authors

Metrics

Articles in this issue

DOI: https://doi.org/10.2478/rjc-2026-0032 | Journal eISSN: 2734-6382 | Journal ISSN: 1220-658X

Journal RSS Feed

Language: English

Published on: Nov 6, 2026

Published by: Romanian Society of Cardiology

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

serotonin,

hypertension,

blood pressure,

serotonin transporter,

endothelial dysfunctio

Related subjects:

Pediatrics and juvenile medicine,

Paediatric cardiology,

Surgery,

Cardiac surgery

© 2026 Oleksandra Oleshchuk, Yurii Chornomydz, Andrii Chornomydz, published by Romanian Society of Cardiology
This work is licensed under the Creative Commons Attribution 4.0 License.

AHEAD OF PRINT