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Am J Physiol Regul Integr Comp Physiol 296: R252-R256, 2009. First published August 27, 2008; doi:10.1152/ajpregu.90676.2008
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RECEPTORS AND SIGNALING PATHWAYS
HENRY PICKERING BOWDITCH AWARD LECTURE, 2008

The love of a lifetime: 5-HT in the cardiovascular system

Stephanie W. Watts

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

Submitted 11 August 2008 ; accepted in final form 20 August 2008


   ABSTRACT
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 ABSTRACT
REFERENCES
 
Serotonin [5-hydroxytryptamine (5-HT)] is an amine made from the essential amino acid tryptophan. 5-HT serves numerous functions in the body, including mood, satiety, and gastrointestinal function. Less understood is the role 5-HT plays in the cardiovascular system, although 5-HT receptors have been localized to every important cardiovascular organ and 5-HT-induced changes in physiological function attributed to activation of these receptors. This manuscript relates a few scientific stories that test the idea that 5-HT is important to the control of normal vascular tone, more so in the hypertensive condition. Currently, our laboratory is faced with two different lines of experimentation from which one could draw vastly different conclusions as to the ability of 5-HT to modify endogenous vascular tone and blood pressure. Studies point to 5-HT being important in maintaining high blood pressure, but other studies solidly support the ability of 5-HT to reduce elevated blood pressure. This work underscores that our knowledge of the functions of 5-HT in the cardiovascular system is significantly incomplete. As such, this field is an exciting one in which to be, because there are superb questions to be asked.

serotonin

HENRY PICKERING BOWDITCH was a man of many talents. A physiologist, photographer, kite builder, and singer (though tone deaf, according to his son Manfred). His dedication to physiology and scholarly activity is famous, and thus it was a true honor to give a lecture in his name. This paper will tell a story that is ongoing and has taken unexpected, exciting, and confusing turns. The focus of this story is a small molecule, serotonin [5-hydroxytryptamine (5-HT)].

5-HT has a long history in cardiovascular physiology. In 1868, scientists knew that the blood contained a substance(s) that caused blood vessels to contract. In the late 1930s, Vitorio Erspamer isolated a substance, enteramine, from gastric mucosa that also contracted blood vessels, and demonstrated this substance to be 5-HT (12). At the same time, Page and colleagues (26, 27, 29) also identified 5-HT in the blood. 5-HT is synthesized from the essential amino acid tryptophan in the enterochromaffin cells of the intestine, raphé nuclei of the brain, and other discrete sites. In these sites, 5-HT is best known as a neurotransmitter that can modify gastrointestinal motility and mood. 5-HT is released from the cells and acts on postsynaptic receptors. 5-HT can be taken back up into the neuron by the serotonin transporter (SERT), where it can be stored again, or metabolized into 5-hydroxyindole acetic acid (Fig. 1). The key piece of information here is that 5-HT exists both intracellularly and extracellularly, and thus has the potential of modifying function through both extracellular and intracellular mechanisms.


Figure 1
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  		Fig. 1. Synthetic schema for 5-HT. MAO, monoamine oxidase.

 
Since the discovery of 5-HT, researchers have been dedicated toward understanding its role in the cardiovascular system. This lecture is dedicated to the scientists who have invested time and energy into this complex area. There are so many to thank, but they include David Bohr, Don McGregor, Sir Horace Smirk, Paul Vanhoutte, and the special people, discussed below, who have helped me to become a scientist. Because this paper will not be comprehensive in its discussion of 5-HT in general or in the cardiovascular system, I direct you to some excellent resources here (2, 9, 11 15, 18, 20, 25, 34, 36).

Falling

I was introduced to 5-HT by my thesis mentor, Dr. Marlene Cohen. Dr. Cohen was an adjunct Professor of Pharmacology and Toxicology at Indiana University-Purdue University at Indianapolis, and a prominent Senior Research Fellow at Lilly Research Laboratories. She graciously opened her laboratory at Eli Lilly to me, and it felt like coming home. I discovered the powerful pharmacological/physiological technique of the isolated tissue bath. Smooth muscular tissue (and even atria!) from multiple species can be placed in this bath for measurement of isometric contractile force. I was impressed with the power that this system afforded the researcher and the versatility it allowed. I also discovered 5-HT, which had been a focus of Dr. Cohen's research for some time. Her laboratory had been dedicated to identifying the 5-HT receptor that mediated contraction of the isolated rat stomach fundus. Sir John Vane had introduced this tissue as a bioassay for 5-HT, as the stomach fundus is exquisitely sensitive to 5-HT. Dr. Cohen knew that a receptor mediated contraction to 5-HT in the stomach fundus, but the pharmacology and amino acid sequence of this receptor differed from anything that was known. Over time, she and her colleagues identified the fundal receptor as a new 5-HT receptor that was most closely related to the 5-HT2 receptors, and this receptor was called the 5-HT2B receptor (14, 19). This receptor is significant because of all vascular contractile 5-HT receptors (7 major subtypes exist, 15 subdivisions) (17), 5-HT has among the highest affinity for this receptor. One of the hallmarks of the 5-HT2B receptor is the significantly low affinity the 5-HT2 receptor antagonist ketanserin possesses for this receptor (17). Another important finding was that the tryptophan derivatives that include kynuramine can activate the 5-HT2B receptor, acting as partial agonists (28).

My thesis research was involved with a completely different 5-HT receptor, the guinea pig tracheal receptor. However, I paid attention to what Dr. Cohen was discovering in the fundus. I loved the serotonergic field, and my training with Dr. Cohen prepared me for a postdoctoral fellowship that would set the course for my career.

5-HT and Hypertension

I had the privilege of doing a postdoctoral fellowship with Dr. R. Clinton Webb, then Professor of Physiology at The University of Michigan. Dr. Webb and colleagues had demonstrated that arteries from hypertensive humans and animals were hyperresponsive to 5-HT (32, 38, 39). This followed important original work by Don McGregor and Sir Horace Smirk demonstrating the relatively selective hyperresponsiveness to 5-HT in the whole animal and isolated perfused mesentery (21). The hyperresponsiveness to 5-HT is intriguing. While arteries from hypertensive animals possess hyperresponsiveness to adrenergic receptor and calcium channel agonists, the increase in reactivity to 5-HT is one of the most profound (8, 32). This raises the question as to how hyperresponsiveness occurs, and whether the hyperresponsiveness to 5-HT plays a pathological role in hypertension. In the late 1970s and early 1980s, use of the 5-HT2 receptor antagonist ketanserin to reduce blood pressure looked promising, suggesting that the arterial responsiveness to 5-HT was important (33). However, it was discovered that ketanserin not only had affinity for what we now recognize as the 5-HT2A receptor, but for {alpha}1-adrenergic receptors (4, 5). Thus, the field was back to square one as to whether 5-HT was involved in blood pressure. During this time, other 5-HT2 receptor antagonists that lacked {alpha}-adrenergic receptor affinity (ritanserin, LY53857) were examined in hypertensive models, and a majority of studies suggested that 5-HT2 receptor blockade did not reduce blood pressure (36). What then does hyperresponsiveness to 5-HT mean?

The 5-HT2B Receptor

I have looked through a number of Bowditch lecture proceedings, and virtually every one contains the word "serendipity." How true it is that science and a scientific career can be blessed with serendipity. I had the good fortune to be in two different places that allowed me to put together two pieces of information that led to one of the first major hypotheses in my laboratory. While a graduate student with Dr. Cohen, I learned that the rat stomach fundus contracted to the metabolite kynuramine, defining kynuramine as a 5-HT2B receptor agonist. While I was a postdoctoral fellow, the Webb laboratory was using kynuramine and similar derivatives, demonstrating that arteries from hypertensive animals were hyperresponsive to these compounds (38). Could it be that the 5-HT2B receptor, which can be activated by kynuramine, is more active in arteries from hypertensive vs. normotensive models?

Thus began a major push in my laboratory. In two different models of hypertension, we were able to demonstrate a dependence of the elevated blood pressure on 5-HT2B receptor activation (3, 31, 35, 37). In arteries, we showed upregulated expression of the 5-HT2B receptor mRNA and protein in hypertension. Importantly, this translated into increased function of the 5-HT2B receptor, supported by significant amounts of pharmacological studies in isolated arteries. Moreover, administration of the 5-HT2B receptor antagonist LY272015 reduced blood pressure of the hypertensive rat (7, 31, 37). One reason this hypothesis was and is so attractive is that 5-HT has such a high affinity for the 5-HT2B receptor compared with the normally expressed vascular 5-HT receptors (5-HT2A, 5-HT1B) and the 5-HT2B receptor is relatively insensitive to ketanserin. It could be argued that the circulating level of 5-HT was sufficient to activate expressed 5-HT2B receptors and, in fact, the free circulating levels of 5-HT (nonplatelet) are elevated in one of the models used, the DOCA salt hypertensive rat (10). This must occur, to some degree, to explain the ability of LY272015 to reduce blood pressure of hypertensive animals. Figure 2 depicts this hypothesis pictorially.


Figure 2
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  		Fig. 2. Depiction of hypothesis of upregulated 5-HT2B receptors in hypertension. 2A, 5-HT2A receptor; 2B, 5-HT2B receptor.

 
Where Does the 5-HT Come From?

While working on the 5-HT2B receptor hypothesis, we started thinking about from where the 5-HT that could activate the 5-HT2B receptor might come. Classical teachings suggest that the platelet is the primary source of circulating 5-HT, having taken up 5-HT from the enterochromaffin cells of the gastrointestinal system by means of a membrane SERT. Sympathetic neurons can also take up and store 5-HT, largely through actions of the norepinpehrine transporter. Could arteries take up 5-HT and release 5-HT? The ability of 5-HT to be released from peripheral tissues was discovered with use of the 5-HT-releasing substances fenfluramine/norfenfluramine (30). Used in the medical management of obesity, fenfluramine functions to release 5-HT in the central neuron to promote feelings of satiety. Unfortunately, it was discovered that the fluramines do this not only in the intended target neurons but also in pulmonary arterial cells and aortic valves. The end result of this stimulation is pulmonary hypertension and valvulopathy (1, 30). Thus, we embarked on a hypothesis that SERT existed in peripheral arteries.

Not only did we find that SERT was present and functional in systemic arteries but that a full serotonergic system existed (Fig. 3). Peripheral arteries, which included the aorta and superior mesenteric artery, can synthesize 5-HT, take up 5-HT, metabolize 5-HT, release 5-HT, and bind 5-HT intracellularly (22–24). Perhaps the most intriguing finding was that arteries could make their own 5-HT. While the quantity of this 5-HT paled compared with the 5-HT made by the intestine, it is an important finding because it draws attention to two points. First, the blood/blood platelet is not the only source of 5-HT for the artery. Second, the intra-arterial synthesis of 5-HT and retainment of 5-HT intracellularly begs the question of exactly what 5-HT is doing inside the cell. Could it be released to activate the upregulated 5-HT2B receptor in hypertension? It seemed at this point that we had identified two key lines of evidence that suggested 5-HT was pathogenic in hypertension. A local circuit of 5-HT release and activation of the 5-HT2B receptor would support endogenous activation of the receptor in support of elevated blood pressure.


Figure 3
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  		Fig. 3. Depiction of the serotonergic system within the arterial wall. TPH, tryptophan hydroxylase; AADC, amino acid decarboxylase. [From Ni W, et al. (22).]

 
Part of the reason for pursuing 5-HT as a pathogenic factor in hypertension is that plasma levels of 5-HT are elevated in hypertension subjects compared with subjects with normal blood pressure (5, 13). One could envision this higher level of 5-HT activating vascular receptors to promote increases in total peripheral resistance and blood pressure. To test this idea, we performed a series of experiments that radically changed how we think about 5-HT and blood pressure control.

What Does Elevated Plasma 5-HT Do to Systemic Blood Pressure?

We implanted miniosmotic pumps, filled with 5-HT or vehicle, subcutaneously in normal and mineralocorticoid hypertensive rats (DOCA-salt). The concentration of 5-HT chosen was based on studies by Gustafsson et al. (16) in which 5-HT, given over 90 days, caused valvulopathy. These studies suggested that rats could tolerate the constant exposure to elevated 5-HT. The pumps were implanted in animals with both normal and high blood pressure. Our hypothesis was that blood pressure may go up in the normal animal but would certainly become significantly elevated in the hypertensive rats. This hypothesis was based on the idea that the exogenous 5-HT would activate the more highly expressed 5-HT2B receptor in the hypertensive animal, thereby elevating total peripheral resistance and blood pressure. What we discovered was completely surprising. 5-HT, determined through HPLC to be elevated in the plasma, did not elevate blood pressure in the normal rat. Within 48 h of pump initiation, blood pressure had fallen ~20 mmHg in the normal rat. Moreover, 5-HT did not elevate blood pressure in the hypertensive rats but nearly normalized elevated blood pressure by dropping pressure by >50 mmHg (10). Clearly, we did not (and still don't) understand the totality of actions of 5-HT.

There is certainly a great deal of evidence that suggests 5-HT modifies the function of other organs/systems that modify blood pressure. 5-HT can change neuronal function, heart rate and strength, kidney perfusion pressure, and blood coagulation (36). Further studies suggested that 5-HT reduces sympathetic activity through ganglionic transmission (10), and this is consistent with the knowledge that sympathetic activity is elevated in many forms of hypertension. Moreover, blockade of nitric oxide synthase (NOS) abolished the hypotensive effect of 5-HT, indicating that 5-HT depended on NOS activity for its function. We are currently in the midst of understanding the multiplicity of actions of 5-HT in the cardiovascular system, and how 5-HT interacts with NOS.

Where Do We Go from Here?

The past 15 years of research have shown me that as much as I think I know about 5-HT, there is so much more to learn. The following are a few of the questions with which we wrestle.

These are the primary questions we are pursuing, and it is thrilling to have a chance to do so.

I can't express the privilege and gratefulness I feel for having the opportunity to work in science. How many people can say that they actually get paid for getting to think, create, and pass on a tradition? My world of science has been enormously influenced by many. Some of these individuals you met earlier in this paper. In particular, I owe a great deal of thanks to the students and fellows that have been a part of my laboratory. Their energy and ideas, willingness to try new things, and work as a team is one of the greatest things I will ever witness. These people include: Jennifer Florian, Amy Banes, Carolyn McKune, Zachary Hickner, Carrie Northcott, Amber Russell, Keshari Thakali, Wei Ni, Kevin Ogden, Theo Szasz, Jessica Diaz, Jessie Priestley, Nate Tykocki, Patrick Davis, and Elizabeth Linder. My colleagues at Michigan State University have also given me license to dream and have been true colleagues through the years. So, thanks to Sue Barman, Greg Fink, Jim Galligan, and JR Haywood. Thanks, too, to Ken Moore for giving me the chance to be a faculty member. Janice Thompson has been my right hand through the years, and science in the Watts lab wouldn't happen without her. A final thanks to scientists in this field for being persistent and willing to think differently about a fascinating molecule.


   ACKNOWLEDGMENTS
 
We acknowledge the British Journal of Pharmacology for allowing publication of Fig. 3 (23).


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. W. Watts, Dept. of Pharmacology and Toxicology, B445 Life Sciences Bldg., Michigan State Univ., East Lansing, MI 48824-1317 (e-mail: wattss{at}msu.edu)


   REFERENCES
TOP
 ABSTRACT
 REFERENCES
 

  1. Abenhaim L, Moride Y, Brenot F, Rich S, Benichous J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of pulmonary hypertension. N Engl J Med 335: 609–616, 1996.[Abstract/Free Full Text]
  2. Azmitia EC. Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation and apoptosis. Brain Res Bull 56: 413–424, 2001.[CrossRef][Web of Science][Medline]
  3. Banes AB, Watts SW. Upregulation of arterial serotonin 1B and 2B receptors in deoxycorticosterone acetate-salt hypertension. Hypertension 39: 394–398, 2002.[Abstract/Free Full Text]
  4. Blauw GJ, van Brummelen P, Doorenbos CJ, van der Velde EA, van Zwieten PA. The acute and chronic antihypertensive effects of ketanserin cannot be explained by blockade of vascular serotonin, type 2, receptors or {alpha}1-adrenergic receptors. Clin Pharmacol Ther 49: 377–384, 1991.[Medline]
  5. Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL, Kilic F. Plasma serotonin levels and the platelet serotonin transporter. J Neurochem 102: 206–215, 2007.[CrossRef][Web of Science][Medline]
  6. Cohen ML, Fuller RW, Kurz KD. Evidence that blood pressure reduction by serotonin antagonists is related to {alpha}-receptor blockade in spontaneously hypertensive rats. Hypertension 5: 676–681, 1983.[Abstract/Free Full Text]
  7. Cohen ML, Schenck KW, Mabry TE, Nelson DL, Audia JE. LY272015, a potent, selective and orally active 5-HT2B receptor antagonist. J Serotonin Res 3: 131–144, 1996.
  8. Collis MG, Vanhoutte PM. Vascular reactivity of isolated perfused kidneys from male and female spontaneously hypertensive rats. Circ Res 41: 759–767, 1977.[Free Full Text]
  9. Cote F, Fligney C, Fromes Y, Mallet J, Vodjdani G. Recent advances in understanding serotonin regulation of cardiovascular function. Trends Mol Med 10: 232–238, 2004.[CrossRef][Web of Science][Medline]
  10. Diaz J, Ni W, King A, Fink GD, Watts SW. 5-hydroxytryptamine lowers blood pressure in normotensive and hypertensive rats. J Pharmacol Exp Ther 325: 1031–1038, 2008.[Abstract/Free Full Text]
  11. Doggrell SA. The role of 5-HT on the cardiovascular and renal systems and the clinical potential of 5-HT modulation. Expert Opin Investig Drugs 12: 805–823, 2003.[Medline]
  12. Erspamer V, Asero B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 169: 800–801, 1952.[Medline]
  13. Fetkovska N, Amstein R, Ferracin F, Regenass M, Buhler FR, Pletscher A. 5-Hydroxytryptamine kinetics and activation of blood platelets in patients with essential hypertension. Hypertension 15: 267–273, 1990.[Abstract/Free Full Text]
  14. Foguet M, Hoyer D, Ardo LA, Parekh A, Kluxen FW, Kalkman HO, Stuhmer W, Lubbert H. Cloning and functional characterization of the rat stomach fundus serotonin receptor. EMBO J 11: 3481–3487, 1992.[Medline]
  15. Green RA. Neuropharmacology of 5-hydroxytryptamine. Br J Pharmacol 146: 306–312, 2006.
  16. Gustafsson BI, Tommeras K, Nordrum I, Loennechen JP, Brunsvik A, Solligard E, Fossmark R, Bakke I, Syversen U, Waldum H. Long -term serotonin administration induces heart valve disease in rats. Circulation 111: 1517–1522, 2005.[Abstract/Free Full Text]
  17. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71: 533–554, 2002.[CrossRef][Web of Science][Medline]
  18. Kaumann AJ, Levy FO. 5-Hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther 111: 67–76, 2006.
  19. Kursar JD, Nelson DL, Wainscott DB, Cohen ML, Baez M. Molecular cloning, functional expression and pharmacological characterization of a novel serotonin receptor (5-hydroxytryptamine2F) from the rat stomach fundus. Mol Pharmacol 42: 549–557, 1992.[Abstract]
  20. MacLean MR, Herve P, Eddahibi S, Adnot S. 5-Hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension. Br J Pharmacol 131: 161–168, 2000.[CrossRef][Web of Science][Medline]
  21. McGregor DD, Smirk FH. Vascular reactivity to 5-hydroxytryptamine and hypertension in the rat. Naunyn Schmiedebergs Arch Pharmacol 272: 101–116, 1970.
  22. Ni W, Geddes TJ, Priestley JRC, Szasz T, Kuhn DM, Watts SW. The existence of a local serotonergic system in peripheral arteries. Br J Pharmacol 154: 663–674, 2008.[CrossRef][Web of Science][Medline]
  23. Ni W, Li MW, Thakali K, Fink GD, Watts SW. The fenfluramine metabolite (+)-norfenfluramine is vasoactive. J Pharmacol Exp Ther 309: 845–852, 2004.[Abstract/Free Full Text]
  24. Ni W, Thompson JM, Northcott CA, Lookingland K, Watts SW. The serotonin transporter is present and functional in peripheral arterial smooth muscle. J Cardiovasc Pharmacol 43: 770–781, 2004.[CrossRef][Web of Science][Medline]
  25. Ni W, Watts SW. 5-Hydroxytryptamine in the cardiovascular system: focus on the serotonin transporter (SERT). Clin Exp Pharmacol Physiol 33: 575–583, 2006.[CrossRef][Web of Science][Medline]
  26. Page IH, McCubbin JW. Modification of vascular responses to serotonin by drugs. Am J Physiol 174: 436–440, 1953a.[Free Full Text]
  27. Page IH, McCubbin JW. The variable arterial pressure response to serotonin in laboratory animals and man. Circ Res 1: 354–362, 1953b.[Abstract/Free Full Text]
  28. Pomfret DW, Schenck KW, Fludzinski P, Cohen ML. Interaction of 5-hydroxykynurenamine, L-kynurenine and kynuramine with multiple serotonin receptors in smooth muscle. J Pharmacol Exp Ther 241: 465–471, 1987.[Abstract/Free Full Text]
  29. Rapport MM, Green AA, Page IH. Serum vasoconstrictor (serotonin) IV. Isolation and characterization. J Biol Chem 176: 1243–1251, 1948.[Free Full Text]
  30. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102: 2836–2841, 2000.[Abstract/Free Full Text]
  31. Russell A, Banes A, Berlin H, Fink GD, Watts SW. 5-Hydroxytryptamine2B receptor function is enhanced in the N{omega}-nitro-L-arginine hypertensive rat. J Pharmacol Exp Ther 303: 179–187, 2002.[Abstract/Free Full Text]
  32. Turla MD, Webb RC. Vascular Responsiveness to 5-hydroxytryptamine in experimental hypertension. In: The Peripheral Actions of 5-Hydroxytryptamine, edited by Fozard JR. Oxford, UK: Oxford University Press, 1989, p. 327–353.
  33. Vanhoutte P, Amery A, Birkenhager W, Breckenridge A, Buhler F, Distler A, Dormandy J, Doyle A, Frohlich E, Hansooon L, Hedner T, Hollenberg N, Jensen HE, Lund-Johansen P, Meyer PL, Opie L, Robertson I, Safar M, Schalekamp M, Symoens J, Trap-Jensen J, Zanchetti A. Serotoninergic mechanisms in hypertension. Focus on the effects of ketanserin. Hypertension 11: 111–133, 1988.[Abstract/Free Full Text]
  34. Villalon CM, Centurion D. Cardiovascular responses produced by 5-hydroxytryptamine: a pharmacological update on receptors/mechanisms involved and therapeutic implications. Naunyn Schmiedebergs Arch Pharmacol 376: 45–63, 2007.[CrossRef][Medline]
  35. Watts SW. The 5-HT2B receptor antagonist LY272015 inhibits 5-HT-induced contraction in the aorta of mineralocorticoid-salt hypertensive rats. J Serotonin Res 4: 197–206, 1997.
  36. Watts SW. 5-HT in systemic hypertension: foe, friend or fantasy? Clin Sci (Lond) 108: 399–412, 2005.[Medline]
  37. Watts SW, Fink GD. 5-HT2B-receptor antagonist LY272015 is antihypertensive in DOCA-salt-hypertensive rats. Am J Physiol Heart Circ Physiol 276: H944–H952, 1999.[Abstract/Free Full Text]
  38. Watts SW, Gilbert L, Webb RC. 5-HT2B receptor mediates contraction to 5-HT in the mesenteric artery of DOCA-salt hypertensive rats. Hypertension 26: 1056–1059, 1995.[Abstract/Free Full Text]
  39. Webb RC. Increased vascular sensitivity to serotonin and methysergide in hypertension in rats. Clin Sci 63: 73s–75s, 1982.




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