Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Dec 1.
Published in final edited form as: Exp Physiol. 2020 Oct 22;105(12):2025–2032. doi: 10.1113/EP088919

Activation of 5-HT7 receptor but not NOS is necessary for chronic 5-HT-induced hypotension

Bridget M Seitz 1, Gregory D Fink 1, Stephanie W Watts 1
PMCID: PMC7902303  NIHMSID: NIHMS1638736  PMID: 33052620

Abstract

Low dose infusion of 5-hydroxytryptamine (5-HT) to rats causes both an acute and chronic fall in arterial blood pressure. The 5-HT7 receptor subtype plays a critical part in the observed hypotension. Acute (minutes to hours) 5-HT infusion shows no depressor role for NO, but 5-HT depressor responses under chronic conditions suggest that NO production may be critical. We test the hypothesis that NO contributes to the chronic, but not acute, depressor response to 5-HT. We compared the role of NO and 5-HT7 receptors in 5-HT induced hypotension under acute and chronic conditions in the same animal. Mean arterial pressure (MAP) and heart rate (HR) were measured via radiotelemetry in conscious rats during 5 days of saline or 5-HT (25 μg/kg/min; osmotic pump) infusion and for two days after infusion was stopped. To quantify the contributions of NO and the 5-HT7 receptor to 5-HT-induced hypotension, the nitric oxide synthase (NOS) inhibitor L-NAME or the selective 5-HT7 receptor antagonist SB267790 were given at 1, 3 and 5 days of chronic infusion, and 1 day after 5-HT infusion pumps were removed. L-NAME caused a pressor response of the same magnitude in the absence or presence of 5-HT infusion. Conversely, SB269970 did not affect MAP in the absence of 5-HT infusion and reversed the 5-HT-induced depressor response at each time point. Our findings demonstrate that acute and chronic 5-HT induced hypotension does not require NOS activation but does require continued activation of the 5-HT7 receptor.

Keywords: 5-HT, hypotension, nitric oxide synthase, 5-HT7 receptor

Subject area: Cardiovascular control

Introduction

5-HT was first identified in the cardiovascular system. One of the earliest studies of 5-HT. discovered that 5-HT lowered mean arterial pressure (MAP) when given acutely (< 1-hour duration) to the human (Page & McCubbin, 1956). Other studies validated that 5-HT caused a hypotension in multiple species including cat, dog and rodents (Centurion 2004; DeVries 1999, Page & McCubbin, 1956; Terron 1997; Villalon 2007). However, the importance of these collective findings supporting the hypotensive actions of 5-HT, given in the acute situation, was lost by decades of voluminous research that mainly supported 5-HT as a vasoconstrictor. 5-HT has thus been primarily thought of as a pressor hormone.

In 2008, we reported that a continuous low dose infusion of 5-HT (25 μg/kg/min) into normotensive conscious rats for a chronic time [one week (Diaz 2008) and up to one month (Davis 2012)] caused a sustained fall in MAP. This intervention was used to mimic the increased levels of 5-HT in circulating plasma observed in some chronic diseases that affect the cardiovascular system including carcinoid syndrome, inflammation, shock, systemic and pulmonary hypertension and obesity (Ayme-Dietrich 2017; Biondi 1986; Brenner 2007; Jones & Blackburn, 2002; Kim 2011; Shajib & Khan, 2015). This dose is considered low, as demonstrated by dose response studies in the male rat measuring blood pressure as an endpoint (12.5–100 μg/kg/min; Seitz 2019). This dose is also sufficient to elevate platelet free plasma levels of 5-HT from ~3 to 50 ng/ml as estimated by HPLC (Diaz 2008). The same chronic, low dose of 5-HT effectively lowered MAP, measured with radiotelemetry, in various rat models of hypertension: the spontaneously hypertensive rat (SHR), the Dahl S hypertensive rat and the deoxycorticosterone acetate salt (DOCA-salt) hypertensive rat [> 30–50 mmHg fall from baseline (Diaz 2008; Davis 2012; Watts 2012)]. Since acute hormonal effects on MAP can be modified under chronic conditions by well-known phenomena such as receptor down-regulation, receptor desensitization and physiological compensatory responses (e.g. baroreflexes), we also sought to identify the mechanisms responsible for the chronic hypotensive actions of 5-HT.

The acute and chronic 5-HT-induced hypotension are similar in that both require activation of the 5-HT7 receptor (Seitz 2017, 2019; Terron 1997). Where acute and chronic studies have disagreed is in the dependence of the 5-HT-induced hypotension on NOS activation. Specifically, the NOS inhibitor Nw-nitro-L-arginine (L-NNA, 10 days) prevented the chronic depressor action of 5-HT during a chronic, week-long infusion (Diaz 2008, Seitz 2014). By contrast, acute depressor responses to 5-HT7 receptor stimulation were not reduced by NOS inhibition (NG-nitro-L-arginine methyl ester (L-NAME; Terron 1997).

The conundrum in these contrasting findings lies in the fact that no studies support direct coupling of the 5-HT7 receptor to NOS. As a result of this knowledge, there are two explanations for the potentially contradicting findings described above. First, there could be a change over time in the dependency of 5-HT7 receptor dependent hypotension on NOS, moving from no dependence on NOS in the acute infusion to a dependence on NOS in the chronic infusion. Second, our interpretation of experiments in which NOS was inhibited chronically (not acutely) is incorrect.

Here we performed deliberate, rigorous time-course studies to compare the dependence of chronic 5-HT-induced hypotension on NOS activity. We test the hypothesis that NO contributes to the chronic, but not acute, depressor response to 5-HT. The rapid increase in blood pressure during acute blockade of NOS was used as an index of ongoing NO-related depressor activity. This time course was done in parallel with a similar time course of administration of the 5-HT7 receptor antagonist SB269970 to validate that activation of the 5-HT7 receptor was essential at the time points investigated. The outcome of this study is important for being able to continue winnowing possible physiological mechanisms by which 5-HT can lower blood pressure. If this is understood, then we can bring a more focused and intelligent approach to developing serotonergic agonists for therapeutic purposes.

Material and Methods

Ethical Approval

Animals: MSU Institutional Animal Care and Use Committee approved all protocols used in this study (PROTO201800191, approved 2/13/2019) and the principles of Grundy (2015) were followed. Ten Male Sprague –Dawley (SD) rats (275–300 g; Charles River Laboratories, Portage, MI, USA) were used for this study. Rats were housed in a temperature–controlled room (22°C) with 12-hour light/dark cycles and given standard chow and distilled water ad libitum. Males were used for this study because both male and female SD rats have shown similar time- and receptor-dependent responses to 5-HT infusion (Seitz 2019). Because of these findings, we achieved our scientific objective while reducing the number of animals used. At the end of the study, animals were euthanized by administration of pentobarbital sodium (360 mg/mL at 60–80 mg/kg, ip).

Radiotelemeter, femoral vein catheter and osmotic drug pump placement

Under isoflurane anesthesia (1.5% in oxygen), a radiotelemeter transmitter (HD-S10; Data Sciences International, MN, USA) was implanted subcutaneously through a 1–1.5 cm incision in the left inguinal area. The radiotelemeter catheter tip was introduced into the left femoral artery and advanced into the abdominal aorta below the renal artery. During the same surgery, an additional femoral catheter (polyethylene 50 tubing; Instech Laboratories, PA, USA) was implanted into the left femoral vein and externalized between the scapulae. During surgery, all animals received a dose of enrofloxacin (Baytril®, 2.5 mg/kg, im) and carprofen (Rimadyl®, 5 mg/kg, sc). To allow rats to move freely, they were placed in a tether jacket and the external portion of the vein catheter was advanced into a protective spring which was attached to a swivel cage top.

Experimental protocols

The femoral vein catheter was flushed each day with heparinized saline (10 units/mL) and used for drug infusion of either SB-269970, a selective 5-HT7 receptor antagonist (SB269970 hydrochloride; Tocris Chemical Co, Minneapolis, MN, USA, catalog #1612; 33 μg/kg) for one group of rats (n=5) or N (ω)-nitro-L-arginine methyl ester; L-NAME, inhibitor of nitric oxide synthase (Sigma Chemical Co, St. Louis, MO USA; N5751; 3 mg/kg) in another group of rats (n=5). Compounds were dissolved in sterile saline, pH balanced to 6–7. Five days post-operation, baseline cardiovascular measurements were recorded for 5 days. Osmotic pumps (Model 2M L1; Alzet osmotic pumps CA, USA; dosing rate of 9.8 μL/hr) containing either sterile saline (with 1% ascorbate) or 5-HT (serotonin hydrochloride, Sigma Chemical Co, St Louis, MO, USA; catalog #H9523, 25 μg/kg in 1% ascorbate in sterile saline, pH balanced to pH 6–7) were then implanted subcutaneously caudal to the scapular area while under isoflurane anesthesia (1.5% in oxygen). After final day of infusion, pumps were removed from the rats (under isoflurane anesthesia) and cardiovascular parameters were monitored for one additional day (termed recovery). The weight of osmotic pumps was recorded before implantation and after removal to confirm saline or 5-HT delivery.

Time course and groups:

Rats were randomized into two groups. Group 1: rats (n=5) were challenged with an iv bolus of L-NAME (3 mg/kg). Group 2: a separate group of rats (n=5) were challenged with an iv bolus of SB-269970 (33 μg/kg). For both groups, the challenges occurred after 24 hours, 3 days and 5 days of 5-HT or saline infusion, and 24 hours after infusion pumps were removed. MAP and HR measurements were collected continuously for 5 minutes prior (baseline) to the administration of L-NAME or SB-269970 and 20 minutes after the administration of L-NAME or SB-269970.

Data and statistical analyses:

Quantitative data are reported as mean±SD for number of animals in parentheses. Quantitative data are also presented as a percent change from baseline (averaging daily MAP and HR from 5 days prior to the start of either saline or 5-HT administration). Statistical analyses were performed using repeated measures two-way ANOVA (GraphPad Prism 8) when comparing values from baseline, within groups, and between groups. A post-hoc test was performed at each time point using Bonferroni’s (between groups) and Dunnett’s (within groups) to correct for multiple comparisons. In all cases, a p value of <0.05 was considered statistically significant.

Results

MAP response to 5-HT7 receptor antagonist during one week of 5-HT infusion

No animals died or became sick before the reported experiments were concluded. Normotensive male rats with statistically similar baseline values for MAP and HR received a 5-HT or saline containing osmotic pump. There was minimal change in MAP during the 5 days of saline infusion compared to baseline; HR decreased slightly over time. In contrast, the 5-HT-treated rats had a significant reduction in MAP from day 1 to day 5. with the greatest depressor response occurred 24 hours after the start of 5-HT delivery. This was mirrored in time by an elevation in HR, significant for the first three days from the start of 5-HT infusion. Once the 5-HT drug pumps were removed, MAP returned to near baseline values and HR was significantly lower than baseline. The observed cardiovascular responses to one-week infusions of saline or 5-HT (25 μg/kg/min) in this study confirms what we have previously reported (Diaz 2008; Davis 2013).

To determine if 5-HT7 receptor activation was necessary for the duration of the 5-HT-induced hypotension over one week, the rats whose baseline values are shown in table 1 were challenged with an intravenous bolus of SB-269970, a selective 5-HT7 receptor antagonist, at 24 hours (figure 1A), 3 days (figure 1B), 5 days (figure 1C) or 24 hours after removal of drug pumps (figure 1D). In figure 1, the left column of graphs represents the conscious MAP recordings in minute averages; the right column of graphs represents the percent change from baseline for the MAP data over minute averages. It is important to note that the 5-HT-infused rats had a lower baseline MAP (table 1) at the start of each day, prior to the SB-269970 bolus, except at recovery (drug pump removed) when compared to their own baseline and to saline-infused rats.

Table 1.

The starting MAP and HR values for male rats at baseline and after implantation with either saline or 5-HT (25 μg/kg/min) osmotic pump infused for 24 hour, 3 days, 5 days and recovery prior to SB-269970 administration. Values are means±SD for 5 rats per group. Baseline was determined by 5 days prior to saline or 5-HT drug pump implantation. Recovery is 24 hours after saline and 5-HT drug pump is removed.

Baseline 24 hours Day 3 Day 5 Recovery
Saline infused (n=5) MAP (mmHg) 109±1.6 106±3.8 105±7.9 105±6.2 103±6.2
HR (bpm) 374±8.5 340±27.5* 382±36.1* 352±41.1* 332±33.6*
5-HT infused (n=5) MAP (mmHg) 107±4.1 92±6.3*+ 96±8.9*+ 93±2.8*+ 114±6.9+
HR (bpm) 370±15.7 410±28.9*+ 389±16+ 356±11.3 344±13.0*
Open in a new tab
*:

p<0.05 between baseline and determined infusion day within groups;

+:

p< 0.05 differences between saline vs 5-HT for same day. BPM=beats per minute.

Figure 1.

Figure 1.

Open in a new tab

Effect of SB-269970 (33 mg/kg; iv bolus) on MAP over 20 minutes in normotensive male rats after infusion of either saline or 5-HT (25 μg/kg/min) for 24 hours (A), 3 days (B), 5 days (C) and recovery (D). Left side graphs represent raw data and right side graphs represent percent change from baseline. Baseline was determined by 5 minutes prior to SB-269970 bolus. Points represent means±SD for 5 rats per group per minute time. Recovery is determined by 24 hours after the osmotic pump (saline or 5-HT) was removed. *: p<0.05 5-HT-infused rats at baseline and after SB-269970 bolus for same day; and +: p< 0.05 differences between saline-infused vs 5-HT-infused for same day.

In saline-treated rats. there was no change in MAP compared to baseline when they were challenged with the 5-HT7 receptor antagonist at any time point (24 hours, 3 days, 5 days or recovery) (figure 1 A–D). In contrast, MAP was increased significantly by the 5-HT7 receptor antagonist in the 5-HT-treated rats (figure 1 A–C). After the 5-HT pump was removed, the antagonist did not alter MAP (figure 1 D). A similar magnitude of increase in MAP (~20% increase) was observed in 5-HT-infused rats at each time the 5-HT7 receptor antagonist was given, except during recovery (figure 1, right side graphs).

The MAP response to L-NAME during one-week infusion of 5-HT

A second group with similar baseline MAP and HR values received saline or 5-HT (table 2). This group had comparable baseline hemodynamic measurements to those used in the 5-HT7 receptor study (table 1). One exception is that by day 5, the 5-HT-infused rats in the L-NAME study showed a restoration of pre-infused MAP. Even with MAP restoration, a continued vasodepressor action of 5-HT likely was occurring at 5 days since termination of infusion led to a significant rebound increase in MAP.

Table 2.

The starting MAP and HR values for male rats at baseline and after implantation with either saline or 5-HT (25 μg/kg/min) osmotic pump infused for 24 hour, 3 days, 5 days and recovery prior to L-NAME administration. Values are means±SD for 5 rats per group. Baseline was determined by 5 days prior to saline or 5-HT drug pump implantation. Recovery is 24 hours after saline and 5-HT drug pump is removed.

Baseline 24 hours Day 3 Day 5 Recovery
Saline infused (n=5) MAP (mmHg) 107±4.0 100±4.5* 105±4.6 100±7.6 103±4.5
HR (bpm) 372±15.7 332±27.5 334±21.6 321±19.4 305±10.3
5-HT infused (n=5) MAP (mmHg) 104±2.7 85±2.2*+ 93±3*+ 101±7.6 110±5.6*
HR (bpm) 387±22.3 428±30.5 382±17+ 380±29 + 339±27
Open in a new tab
*:

p<0.05 between baseline and determined infusion day within groups;

+:

p< 0.05 differences between saline vs 5-HT for same day. BPM=beats per minute.

Animals (table 2) were challenged with a bolus of the inhibitor of L-NAME (3 mg/kg) at 24 hours (figure 2A), 3 days (figure 2B), 5 days (figure 2C) or 24 hours after removal of the 5-HT or saline osmotic drug pumps (figure 2D). The 5-HT-treated group had a lower baseline MAP after 24-hours of infusion compared to saline-infused animals, as expected. However, both the saline-infused and 5-HT-infused rats showed a similar increase in MAP to L-NAME (figure 2A). At 3 days of infusion (saline or 5-HT), the 5-HT-treated rats showed somewhat of a greater increase in MAP response to L-NAME compared to the saline-treated animals. At 5 days of infusion and at recovery, both the saline-treated and 5-HT-treated animals had similar baseline MAP values and nearly similar MAP response to the L-NAME bolus.

Figure 2.

Figure 2.

Open in a new tab

Effect of LNAME [(3 mg/kg; iv bolus)] on MAP over 20 minutes in normotensive male rats after infusion of either saline or 5-HT (25 μg/kg/ min) for 24 hours (A), 3 days (B), 5 days (C) and recovery (D). Left side graphs represent raw data and right side graphs represent percent change from baseline. Baseline is determined by 5 minutes prior to LNAME bolus. Points represent means±SD for 5 rats per group per minute time. Recovery is determined by 24 hours after the osmotic pump (saline or 5-HT) was removed. #: p<0.05 saline-infused rats at baseline and after LNAME bolus for same day; *: p<0.05 5-HT-infused rats at baseline and after LNAME bolus for same day; and +: p< 0.05 saline-infused vs 5-HT-infused for same day.

Discussion

The importance of this work is predicated on findings that a low dose infusion of 5-HT can significantly lower arterial pressure in human and other species (Page 1956; Villalon 2007; Diaz 2008; Cade 1992; Kaumann 2006). Understanding the mechanisms of 5-HT-induced hypotension would help determine if such a mechanism could be taken advantage of therapeutically. With this study, we solved the conundrum of studies that both supported (chronic) and refuted (acute) the necessity of NOS activity in 5-HT-induced hypotension. Presently, we show that low dose 5-HT infusion is independent of NOS activation throughout all time points of chronic infusion, and we confirm the importance of 5-HT7 receptor activation throughout this same infusion.

Role of the 5-HT7 receptor in low dose 5-HT-induced depressor response

The blood pressure outcome of 5-HT infusion depends on the concentration of 5-HT infused, the site of infusion, and the specific 5-HT receptor subtypes that are activated by this dose and within the sites reached through administration. When given through a mini osmotic pump (sc), MAP was decreased from day 1 to day 5 (figure 1) with a low dose 5-HT (25 μg/kg/min). The 5-HT7 receptor antagonist SB269970 fully reversed the fall in MAP at all time points. SB269970 possesses an affinity (Ki) for the 5-HT7 receptor that is 50–1,000 times greater than any other serotonergic receptor (pdsp.unc.edu/databases). We are therefore confident the low dose of 5-HT infused in our protocol primarily lowers blood pressure by activating the 5-HT7 receptor. This is important to acknowledge because 5-HT can also cause a depressor response mediated through activation of 5-HT1B/1D or 5-HT2B receptors, as well as 5-HT7 receptors (Kaumann 2006; Berger 2009). The 5-HT2B receptor is of particular interest because, unlike the 5-HT7 receptor, it is NOS-coupled (Watts 2012). The low dose of 5-HT infused presently produces a concentration of free circulating 5-HT in the plasma (Diaz 2008) that is adequate to activate the 5-HT7 receptor (affinity; Ki ~7nM) (pdsp.unc.edu/databases). The 5-HT1B/1D or 5-HT2B likely make minimal contributions to the depressor response to infused 5-HT. Two studies support this idea. First, the selective 5-HT2B receptor agonist (BW723C86) caused a dose-dependent vasopressor (rather than vasodepressor) response (Centurion 2004). Second, sumatriptan, a selective 5-HT1B/1D agonist, evoked contraction, not relaxation, in the saphenous vein of a dog, suggestive of a pressor response to the agonist (Villalon 2007). Thus, we can exclude the involvement of the 5-HT1B/1D or 5-HT2B receptors in the response presently studied.

Blocking the 5-HT7 receptor had no influence on arterial pressure in the absence of 5-HT infusion (figure 2). SB269970 had no effect unless 5-HT was co-administered in other studies (Albayrak 2013). Thus, the concentration of free 5-HT in the plasma (platelet poor) in the basal state is likely insufficient to stimulate 5-HT7 receptors. However, when 5-HT was chronically co-administered with a 5-HT7 receptor antagonist, MAP was higher than it was in rats receiving only the 5-HT7 receptor antagonist. This pressor response or rebounding of blood pressure could occur because lowering MAP chronically by 5-HT infusion engages counter-regulatory pressure mechanisms whose effects are observed after the 5-HT7 receptor is blocked. Likely mediators for rebounded blood pressure include baroreflex unloading leading to sympathetic activation and vagal withdrawal (hence the increases in HR that has been observed). Other likely possibilities include increased renin-angiotensin system activity and body fluid retention due to reduced pressure natriuresis.

NOS activity is not necessary for the 5-HT7 receptor mediated depressor response

Currently, there is no evidence that the 5-HT7 receptor (a G-protein coupled receptor) is directly coupled to NOS. However, blockade of NOS completely prevented the chronic depressor action of 5-HT (Diaz 2008; Seitz 2014). We concluded that chronic 5-HT-induced hypotension was dependent on activation of NOS, although this was not consistent with our understanding of 5-HT7 receptor signaling. In those experiments, L-NNA was administered for 7–10 days prior to 5-HT infusion. This created the classic model of experimental L-NNA hypertension, with chronic blockade of NOS resulting in endothelial dysfunction and vascular wall remodeling.

Presently, we reasoned that if chronic 5-HT infusion lowers MAP at least in part by activating NOS, NOS inhibition should cause a larger pressor response during chronic 5-HT infusion vs vehicle infusion. However, animals receiving 5-HT or saline infusion had similar increases in MAP to NOS blockade throughout the duration of the experiment. Stimulation of NOS does not appear to contribute to 5-HT-induced hypotension at any time point. Because of the modest elevation in blood pressure caused by inhibition of NOS on day 3, the role for NOS in the early stages of the depressor response to 5-HT cannot be ruled out by our results. On the whole, these results are consistent with L-NAME having no effect on the hypotensive response observed during acute 5-HT infusions (Alsip 1992; Terron 1997).

There are explanations as to why our previous studies produced apparently misleading results. Physiological changes (e.g. vascular remodeling) that occur during lengthy administration of L-NNA (7–10 days; Kung 1995) could have interfered with the chronic depressor actions of 5-HT. The present experiments examined the involvement of NOS at select time points during one week of 5-HT-induced hypotension. Over this shorter exposure to the NOS inhibitor, the vascular remodeling and other long-term consequences of blocking NO would not be expected (Paulis 2008).

Limitations and future directions

We recognize limitations of this study. Fist, chronic 5-HT infusion probably does not fully mimic situations in vivo where excess 5-HT is released into the circulation. Second, our study did not explore possible engagement of other endogenous vasodilators such as adenosine, prostacyclin, and activation of ATP-sensitive K+ channel-mediated hyperpolarization in the chronic depressor effect of 5-HT7 receptor activation (Brayden 2003; Triggle 2012). ATP-dependent K+ channels may mediate acute 5-HT7 mediated vasodilation, as glibenclamide abolished 5-HT7 agonist induced renal vasodilation in vitro (Garcia Pedraza 2016).

Conclusion

This study demonstrates the independence of 5-HT7 receptor mediated, 5-HT-induced hypotension from NOS in conscious rats during all time points during a chronic infusion. This knowledge allows us to proceed with a more focused approach (e.g. exclusion of NOS) into the physiological mechanisms by which 5-HT lowers blood pressure. Ultimately, this work will allow for the development of new therapies that take advantage of this hypotensive mechanism and could be used to treat diseases such as hypertension.

New Findings.

  • What is the central question of this study? What mechanisms account for the hypotension observed during chronic elevations in circulating 5-hydroxytryptamine in rats?

  • What is the main finding and its importance? Chronic 5-hydroxytryptamine induced hypotension requires continued activation of the 5-HT7 receptor subtype but does not require NO, an outcome that resolves previous conflicting results. Therapeutic interruption of the hypotensive actions of 5-HT under pathophysiological conditions can only be achieved through blockade of the 5-HT7 receptor.

Funding:

NIH grant HL151413 to SWW and GDF, and AHA fellowship (18PRE34000041) to BMS.

Footnotes

Conflict of Interest: None to declare

Data Availability: Made upon request.

References

  1. Albayrak A, Halici Z, Cadirci E, Polat B, Karakus E, Bayir Y,…. Dogrul A (2013). Inflammation and peripheral 5-HT7 receptors: The role of 5-HT7 receptors in carrageenan induced inflammation in rats. European Journal of Pharmacology, 715, 270–279. [DOI] [PubMed] [Google Scholar]
  2. Alsip NL & Harris PD (1992). Serotonin-induced dilation of small arterioles is not mediated via endothelium-derived relaxing factor in skeletal muscle. European Journal of Pharmacology, 229,117–124. [DOI] [PubMed] [Google Scholar]
  3. Ayme-Dietrich E, Aubertin-Kirch G, Maroteaux L & Monassier L (2017). Cardiovascular remodeling and the peripheral serotonergic system. Archives of Cardiovascular Disease, 110:51–59. [DOI] [PubMed] [Google Scholar]
  4. Berger M, Gray JA & Roth BL (2009). The expanded biology of serotonin. Annual Review of Medicine, 60, 355–366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Biondi ML, Agostoni A & Marasini B (1986). Serotonin levels in hypertension. Journal of Hypertension, 4:S39–S41 [PubMed] [Google Scholar]
  6. Brayden JE (2002). Functional roles of KATP channels in vascular smooth muscle, Clinical and Experimental Pharmacology and Physiology, 29, 312–316. [DOI] [PubMed] [Google Scholar]
  7. Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL & Kilic F (2007). Plasma serotonin levels and the platelet serotonin transporter. Journal of Neurochemistry, 102:206–215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cade JR, Fregly MJ & Privette M (1992). Effect of tryptophan and 5-hydroxytryptophan on the blood pressure of patients with mild to moderate hypertension. Amino Acids, 2, 133–140. [DOI] [PubMed] [Google Scholar]
  9. Centurión D, Glusa E, Sánchez-López A, Valdivia LF, Saxena PR & Villalón CM (2004). 5-HT7, but not 5-HT2B, receptors mediate hypotension in vagosympathectomized rats. European Journal of Pharmacology, 502, 239–242. [DOI] [PubMed] [Google Scholar]
  10. Davis RP, Pattison J, Thompson JM, Tiniakov R, Scrogin KE & Watts SW. (2012) 5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved. BMC Pharmacology, 12:4 doi: 10.11186/1471-2210-12-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Davis RP, Szasz T, Garver H, Burnett R, Tykocki NR & Watts SW (2013). One-month serotonin infusion results in a prolonged fall in blood pressure in the deoxycorticosterone acetate (DOCA) salt hypertensive rat. ACS Chemical Neurosci. 4, 141–148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. De Vries P, De Visser PA, Heiligers JPC, Villalón CM & Saxena PR (1999). Changes in systemic and regional haemodynamics during 5-HT7 receptor mediated depressor responses in rats. Naunyn-Schmiedeberg’s Archives Pharmacology, 359, 331–338. [DOI] [PubMed] [Google Scholar]
  13. Diaz J, Ni W, King A, Fink GD & Watts SW. (2008). 5-hydroxytryptamine lowers blood pressure in normotensive and hypertensive rats. Journal of Pharmacology and Experimental Therapeutics, 325, 1031–1038. [DOI] [PubMed] [Google Scholar]
  14. Garcia-Pedraza JA, Garcia M, Martin ML, Rodriguez-Barbero A & Moran A (2016). 5-HT2 receptor blockade exhibits 5-HT vasodilator effects via nitric-oxide, prostacyclin and ATP-sensitive potassium channels in rat renal vasculature. Vascular Pharmacology, 79, 51–59. [DOI] [PubMed] [Google Scholar]
  15. Grundy D (2015) Principles and standards for reporting animal experiments in The Journal of Physiology and Experimental Physiology. Experimental Physiology, 1007, 755–758. [DOI] [PubMed] [Google Scholar]
  16. Jones BJ & Blackburn TP (2002). The medical benefit of 5-HT research. Pharmacology, Biochemistry and Behavior, 71:555–568. [DOI] [PubMed] [Google Scholar]
  17. Kaumann AJ & Levy FO (2006). 5-Hydroxytryptamine receptors in the human cardiovascular system. Pharmacology & Therapeutics, 111, 674–706. [DOI] [PubMed] [Google Scholar]
  18. Kim H-J, Kim JH, Noh S, Hur HJ, Sung MJ, Hwang J-T, Park JH, Yang HJ, Kim M-S, Kwon DY & Yoon SH (2011). Metabolic analysis of livers and serum from high-fat diet induced obese mice. Journal of Proteome Research, 10:722–731. [DOI] [PubMed] [Google Scholar]
  19. Kung CF, Moreau P, Takase H & Luscher TF (1995). L-NAME hypertension alters endothelial and smooth muscle function in rat aorta. Hypertension, 26, 744–751. [DOI] [PubMed] [Google Scholar]
  20. Page IH & McCubbin JW (1956) Arterial pressure response to infused serotonin in normotensive dogs, cats, hypertensive dogs and man. American Journal of Physiology, 184:265–270. [DOI] [PubMed] [Google Scholar]
  21. Paulis L, Zicha J, Kunes J, Hojna S, Behuliak M, Celec P, …Simko F (2008). Regression of L-NAME-induced hypertension: The role of nitric oxide and endothelium-derived constricting factor. Hypertension Research, 31, 793–803. [DOI] [PubMed] [Google Scholar]
  22. Seitz BM, Demireva EY, Xie H, Fink GD, Krieger-Burke T, Burke WM & Watts SW (2019) 5-HT does not lower blood pressure in the 5-HT7 knock-out rat. Physiologic Genomics, doi: 10.1152/physiolgenomics.00031.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Seitz BM, Orer HS, Krieger-Burke T, Darios ES, Thompson J, Fink GD & Watts SW (2017). 5 -HT causes splanchnic venodilation. American Journal of Physiology Heart and Circulatory Physiology, 313, H676–H686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Seitz BM & Watts SW (2014). Serotonin-induced hypotension is mediated by a decrease in intestinal vascular resistance. Pharmacologia, 5(2), 50–54. [Google Scholar]
  25. Shajib MS & Khan WI (2015). The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiologica (Oxf), 213(3):561–74. [DOI] [PubMed] [Google Scholar]
  26. Terrón JA (1997). Role of 5-ht7 receptors in the long-lasting hypotensive response induced by 5-hydroxytryptamine in the rat. British Journal of Pharmacology, 121, 563–571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Triggle CR, Samuel SM, Ravishankar S, Marei I, Arunachalam G & Ding H (2012). The endothelium: influencing vascular smooth muscle in many ways. Canadian Journal of Physiology and Pharmacology, 90, 713–738. [DOI] [PubMed] [Google Scholar]
  28. Villalon CM& Centurion D (2007). Cardiovascular response produced by 5-hydroxytriptamine: a pharmacological update on the receptors/mechanisms involved and therapeutic implications. Naunyn-Schmiedeberg’s Archives of Pharmacology, 376, 45–63. [DOI] [PubMed] [Google Scholar]
  29. Watts SW, Morrison SF, Davis RP & Barman SM (2012). Serotonin and blood pressure regulation. Pharmacological Reviews, 64, 359–388. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES