Serotonin and blood pressure regulation

Abstract

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.

Fig. 1.

Chemical schematic of the synthesis and metabolism of 5-HT.

Fig. 2.

Response of the vasculature to 5-HT, as depicted by using the rat vasculature as a model. Both constriction (C) and relaxation (R) may be listed for the same species if both responses were observed. Species name is listed, and the subtype of the receptor mediating the response is listed second (1B, 2A). UK, unknown receptor mechanism. Data were collected from the following references: Lemberger et al., 1984; Miller et al., 1984; Feniuk et al., 1985; Nyborg and Mikkelsen, 1985; Cohen, 1986; Leff et al., 1987; Hamel et al., 1989, ; Parsons et al., 1989, ; Bodelsson et al., 1990; Borton et al., 1990; Chester et al., 1990; Gaw et al., 1990; Mylecharane, 1990; Toda and Okamura, 1990; van Heuven-Nolsen et al., 1990; Asher et al., 1991; Lai et al., 1991; Parsons, 1991; Sumner, 1991; Cushing and Cohen, 1992a,, ; Dorigo et al., 1992; Eglen et al., 1992; Weiner et al., 1992; Bax et al., 1993; Glusa and Müller-Schweinitzer, 1993; Jansen et al., 1993; Cushing et al., 1994, ; Yildiz and Tuncer, 1994; Fujiwara and Chiba, 1995; Miranda et al., 1995; Schmuck et al., 1996; Terrón, 1996; Valentin et al., 1996; Verheggen et al., 1996, , , ; Zwaveling et al., 1996; Ellwood and Curtis, 1997; Parsons et al., 1998; Nilsson et al., 1999; Roon et al., 1999; Terrón and Falcón-Neri, 1999; Bouchelet et al., 2000; Galzin et al., 2000; Geerts et al., 2000; Ishida et al., 2001; Lamping and Faraci, 2001; McKune and Watts, 2001; Schöning et al., 2001; Razzaque et al., 2002; Teng et al., 2002; van den Broek et al., 2002; Froldi et al., 2003, ; Edvinsson et al., 2005; Nagai et al., 2007; Zerpa et al., 2007; Masu et al., 2008; Linder et al., 2010; Radenkoviä et al., 2010.

Fig. 3.

Distribution of 5-HT in organs when infused with vehicle or 5-HT at a dose of 25 μg · kg⁻¹ · min⁻¹ in the rat for one week. Vehicle animals receive saline. Bars represent means ± S.E.M. for n = 6. Boxes highlight organs that are of cardiovascular interest. [Adapted from Linder AE, Beggs KM, Burnett RJ, and Watts SW (2009) Body distribution of infused serotonin in rats. Clin Exp Pharmacol Physiol 36:599–601 Copyright © 2009 John Wiley & Sons, Inc. Used with permission.

Fig. 4.

Schematic of the potential sites at which 5-HT could interact to lower blood pressure within the context of the sympathetic nervous system. Small geometric shapes represent individual classes of 5-HT receptors; semicircular red arrow indicates inhibition.

Fig. 5.

Central autonomic circuits and potential central sites of action of systemically administered serotonin. The excitatory (+), inhibitory (−), or mixed (±) connections shown between the various autonomic nuclei are based on data described by Barman and Gebber (2000), Guyenet (2006), and Morrison (2004). The solid pentagon symbols show locations of 5-HT receptors. BAT, brown adipose tissue; CVLM, caudal ventrolateral medulla; DMH, dorsomedial hypothalamus; LTF, lateral tegmental field; NA, nucleus ambiguus; NTS, nucleus of the tractus solitarius.

Fig. 6.

A, classic triphasic (1, 2, 3) effect of 5-HT (75 μg/kg bolus) on blood pressure in the anesthetized rat. Time base below traces is 1 s/division. Total time base is 75 s. B, effect of 5-HT (25 μg · kg⁻¹ · min⁻¹, subcutaneous pump) on blood pressure (top) and heart rate (bottom) in the conscious rat over the course of 30 h. Dashed vertical line indicates implantation of pump. Points represent means ± S.E.M. for the number of animals in parentheses.

Fig. 7.

Top, ability of 5-HT (25 μg · kg⁻¹ · min⁻¹, subcutaneous pump) to lower blood pressure of a male SHR. Bottom, concomitant heart rate measures. Dashed vertical line indicates implantation of the pump. Points are means ± S.E.M. for the number of animals in parentheses. *, p < 0.05, significantly different from vehicle time point.

Fig. 8.

Correlation between platelet poor plasma (x-axis, left) and rich plasma (right) with mean arterial blood pressure (telemetric) taken from conscious rats at the end of a 1-week infusion of 5-HT.