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      5-HT is a potent relaxant in rat superior mesenteric veins

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          Abstract

          Serotonin (5-HT, 5-hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5-HT does not directly relax isolated arteries, and microsphere experiments in 5-HT-infused rats suggested that 5-HT increased flow to the splanchnic bed. We hypothesized that 5-HT increased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real-time RT-PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5-HT 2B and 5-HT 7 receptor in the SMV. The SMV was mounted in tissue baths for measurement of isometric contraction. 5-HT caused a concentration-dependent relaxation of the endothelin-1 (ET-1)-contracted vein. The threshold of 5-HT-induced venous relaxation was significantly lower than for 5-HT-induced venous contraction (∼2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist-induced relaxation (receptor selectivity): 5-CT (5-HT 1/5-HT 7)>5-HT = LP-44 (5-HT 7)>PNU109291 (5-HT 1D) = BW723C86 (5-HT 2B). 8-OH-DPAT (5-HT 1A/7), CP93129 (5-HT 1B), mCPBG (5-HT 3/4), AS19 (5-HT 7) and TCB-2 (5-HT 2A) did not relax the isolated vein. Consistent with these findings, two different 5-HT 7 receptor antagonists SB 269970 and LY215840 but not the 5-HT 2B receptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5-CT-induced relaxation of the isolated SMV. 5-CT (1  μg kg −1 min −1, sc) also reduced blood pressure over 7 days. These findings suggest that 5-HT directly relaxes the SMV primarily through activation of the 5-HT 7 receptor.

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          Serotonin and blood pressure regulation.

          Anindya S. Barman, Stephanie W Watts, Tessa Davis … (2012)
          5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension.
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            Functional, molecular and pharmacological advances in 5-HT7 receptor research.

            Peter B. Hedlund, Lorna J. Sutcliffe (2004)
            The 5-HT7 receptor was among a group of 5-HT receptors that were discovered using targeted cloning strategies 12 years ago. This receptor is a seven-transmembrane-domain G-protein-coupled receptor that is positively linked to adenylyl cyclase. The distributions of 5-HT7 receptor mRNA, immunolabeling and radioligand binding exhibit strong similarities, with the highest receptor densities present in the thalamus and hypothalamus and significant densities present in the hippocampus and cortex. The recent availability of selective antagonists and knockout mice strains has dramatically increased our knowledge about this receptor. Together with unselective agonists, these new tools have helped to reveal the 5-HT7 receptor distribution in more detail. Important functional roles for the 5-HT7 receptor in thermoregulation, circadian rhythm, learning and memory, hippocampal signaling and sleep have also been established. Hypotheses driving current research indicate that this receptor might be involved in mood regulation, suggesting that the 5-HT7 receptor is a putative target in the treatment of depression.
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              Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist.

              Matthew Piper, Brian O. Smith, N Deeks … (2000)
              The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1)). Following a single dose (3 mg kg(-1)) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 5-CT (0.3 mg kg(-1) i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED(50) 2.96 mg kg(-1) i.p.) and the non-selective 5-HT(7) receptor antagonist metergoline (0.3 - 3 mg kg(-1) s.c.), suggesting a role for 5-HT(7) receptor stimulation in 5-CT induced hypothermia in guinea-pigs. SB-269970-A (30 mg kg(-1)) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3 h of EEG recording in conscious rats.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmacol Res Perspect
                Journal ID (iso-abbrev): Pharmacol Res Perspect
                Journal ID (publisher-id): prp2
                Title: Pharmacology Research & Perspectives
                Publisher: BlackWell Publishing Ltd (Oxford, UK )
                ISSN (Print): 2052-1707
                ISSN (Electronic): 2052-1707
                Publication date (Print): February 2015
                Publication date (Electronic): 05 January 2015
                Volume: 3
                Issue: 1
                Electronic Location Identifier: e00103
                Affiliations
                Department of Pharmacology and Toxicology, Michigan State University East Lansing, Michigan, 48824
                Author notes
                Correspondence Stephanie W. Watts, Department of, Pharmacology and Toxicology, Michigan, State University, 1355 Bogue Street Room, B445, East Lansing, 48824-1317 MI. Tel:, (517) 353-3724; Fax: (517)-353-8915; E-mail:, wattss@ 123456msu.edu

                Funding Information This work is supported by the National Institutes of Health HL107495.

                Article
                DOI: 10.1002/prp2.103
                PMC ID: 4317234
                PubMed ID: 25692021
                SO-VID: 55a62405-91df-44b0-9d29-de7bcedddec5
                Copyright © © 2015 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
                License:

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 19 June 2014
                Date revision received : 02 September 2014
                Date accepted : 15 September 2014
                Categories
                Subject: Original Articles

                Keywords: 5-ht,hypotension,venous circulation
                Data availability:
                Keywords: 5-ht, hypotension, venous circulation

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