Prejunctional 5-HT Receptors/Mechanisms and Modulation of Neurovascular Transmission: Comparison
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5-Hydroxytryptamine (5-HT), or serotonin, plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex, and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT1, 5-HT5) or activation (5-HT4, 5-HT6, 5-HT7) of adenylate cyclase, as well as activation (5-HT2) of phospholipase C; and (ii) ionotropic receptor (5-HT3), a ligand-gated Na+/K+ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured, depending on the type of prejunctional receptor involved.

  • 5-hydroxytryptamine
  • serotonin
  • CGRP
  • blood pressure
  • hypertension

1. A Summary on 5-HT Receptors

As summarized in Table 1, with the conjunction of structural, transductional, and operational (pharmacological) criteria, 5-HT receptors have been classified into seven receptor types (5-HT1-5-HT7) that can be grouped into: (i) six metabotropic (G-protein-coupled) receptors, namely: the 5-HT1 (further subdivided into the 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1e and 5-HT1F subtypes), 5-HT2 (further subdivided into the 5-HT2A, 5-HT2B and 5-HT2C subtypes), 5-HT4, 5-HT5 (further subdivided into the 5-HT5A and 5-ht5B subtypes), 5-HT6 and 5-HT7 receptor types; and (ii) one ligand-gated ion channel represented by the ionotropic 5-HT3 receptor type [1][2][3][4]. The corresponding subtypes of the 5-HT1, 5-HT2, and 5-HT5 receptor types share similar structural and transductional properties, but display very different pharmacological profiles.
Table 1. Classification of 5-HT receptors a.
5-HT

Receptor		 Receptor Subtype Agonists Antagonists Some Functions Canonical Transduction

System
5-HT1 5-HT1A 8-OH-DPAT WAY 100635 Central hypotension G-protein coupled receptor (Gi)

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5-HT1B Sumatriptan

CP-93,129 (rodents)		 SB224289 Vasoconstriction, sympatho-inhibition
5-HT1D PNU-109291

PNU-142633		 BRL15572 Autoreceptor, sympatho-inhibition
5-HT1e * 5-HT >> 5-CT LY334370 Methiothepin

(non-selective)		 Unknown
5-HTF LY344864, lasmiditan, LY334370 Methysergide

(non-selective)		 (−) Trigeminal system
5-HT5 5-HT5A 5-HT, ergotamine SB699551 Cardiac sympatho-inhibition in rats
5-HT5b * 5-CT (non-selective) Unknown Unknown
5-HT4 - Renzapride, BIMU8, ML10302, SC53116 GR 113808 SB204070 (+) Neuronal activity,

vasodilatation,

tachycardiain pigs and humans		 Biomedicines 11 01864 i002

G-protein coupled receptor (Gs)
5-HT6 - 5-MeO-T ≥ 5-HT

SB357134 SB271046		 Ro 630563 Memory, not involved in

cardiovascular regulation
5-HT7 - 5-CT>>5-HT

AS-19		 SB269970 SB258719 Circadian rhythm, vasodila-

tation, tachycardia in cats
5-HT2 5-HT2A DOI, DOB

α-methyl-5-HT		 MDL100907

Ketanserin		 Vasoconstriction, plateletaggregation Biomedicines 11 01864 i003

G-protein coupled receptor (Gq)
5-HT2B DOI, BW723C86

α-methyl-5-HT		 SB204741

RS-127445		 Vasoconstriction, release of NO
5-HT2C DOI, Ro 60-0175

α-methyl-5-HT		 SB242084

RS-102221		 CSF production
5-HT3 Pentameric ion channel ** Phenylbiguanide

2-methyl-5-HT		 Tropisetron Granisetron

MDL-72222		 (+) Neuronal activity, reflex

bradycardia		 Ligand-gated ion channel

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Modified from Villalón [2]. AS-19, (2S)-(+)-5-(1,3,5-Trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin; CNS, central nervous system; CSF, cerebrospinal fluid; LSD, lysergic acid diethylamide; 5-MeOT, 5-methoxytryptamine; 5-CT, 5-carboxamidotryptamine; DOI, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; NO, nitric oxide; (−), inhibits; (+), stimulates. * Lowercase is used to denote a receptor with unknown functional roles in native cells or tissues. ** Five known subunits have been described (5-HT3A–5-HT3E) forming homomeric or heteromeric complexes. At least two subunits of 5-HT3A type are required to form a functional ion channel. a The pharmacological profile of each 5-HT receptor type is identified by applying inclusion and exclusion criteria.
Some agonists and antagonists employed to identify the pharmacological profile of each 5-HT receptor type are shown in Table 1. As previously established [1][2][3][4], the pharmacological identification of a specific 5-HT receptor type is based on the application of (i) inclusion criteria (i.e., selective agonists for this receptor mimic the effects of 5-HT, while selective antagonists for this receptor produce a blockade of the effects of 5-HT and the corresponding agonist); and (ii) exclusion criteria (i.e., agonists and antagonists for the other 5-HT receptors—and sometimes even for receptors unrelated to 5-HT—are inactive) (see Table 1). This knowledge (i) has helped to establish the role of 5-HT receptors in several diseases, including anxiety, depression, schizophrenia, drug addiction, cardiovascular pathologies (e.g., systemic, pulmonary and portal hypertension), cardiac disorders, migraine, etc.; and (ii) has led to the development of agonists and antagonists at 5-HT receptors for the therapeutic treatment of these—and other—diseases [1][2][3][4][5][6][7].

2. An Overview of the Effects of 5-HT on the Cardiovascular System

The cardiovascular effects of 5-HT are complex and include bradycardia/tachycardia, hypotension/hypertension, and vasodilatation/vasoconstriction. This complexity of effects is due to (i) the capability of 5-HT to interact at various levels, including the heart and blood vessels, as well as the central and peripheral (autonomic and sensory) nervous systems; and (ii) the involvement of serotonin 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5A, and 5-HT7 receptors, as well as a tyramine-like action or unidentified mechanisms, depending on the species and the experimental conditions [2][5][6][7][8]. Interestingly, the 5-HT6 receptor is not involved in the cardiovascular effects of 5-HT [2][7].

3. The Specific Interactions of 5-HT at Peripheral and Central Levels to Induce Cardiovascular Effects

3.1. Sensory Afferents

Overall, an intravenous (i.v.) bolus injection of 5-HT in anaesthetised animals results in a reflex bradycardia and hypotension by stimulating 5-HT3 receptors on vagal sensory afferents [2]. These neuronal 5-HT3 receptors were identified using selective agonists and antagonists (see Table 1).

3.2. Sympathetic Ganglia

It has been shown that i.v. 5-HT can stimulate and/or inhibit the sympathetic ganglia producing stimulation or inhibition of the sympathetic drive, and this results in changes in blood pressure and heart rate [2]. Moreover, the hyperpolarization of sympathetic ganglia produced by 5-HT is caused by the activation of 5-HT1A receptors in rats; these 5-HT1A receptors were identified by using selective agonists and antagonists (see Table 1).

3.3. Cardiac Effects of 5-HT

Central or i.v. administration of 5-HT may produce bradycardia and/or tachycardia, and the 5-HT receptors involved in these effects have been identified by using some of the agonists and antagonists shown in Table 1 [2][5]. Overall, two central 5-HT receptors regulate cardiovascular function: 5-HT1A receptors (generally inhibiting the sympathetic drive) and 5-HT2 receptors (largely stimulating the sympathetic drive) [2][9][10]; some of the agonists and antagonists used to identify these receptors are shown in Table 1. Admittedly, central administration of 5-HT elicits complex and contradictory cardiac effects which depend on, among other factors, the species, the exact site of central application, the drug used, and the dose employed [2][9][10]. In contrast, the bradycardia or tachycardia produced by i.v. administration of 5-HT is more controllable and consistent (see below) in view of the implied simplicity of the procedure.

3.3.1. Bradycardia

I.v. administration of 5-HT in intact animals results in a pronounced and transient bradycardia that is abolished after ganglion blockade, vagotomy, atropine, spinal section, or 5-HT3 receptor antagonists [2][5]. This response involves the Bezold–Jarisch reflex, originating from the depolarization of afferent cardiac sensory neurons via activation of 5-HT3 receptors [2][5]. Furthermore, 5-HT can also produce bradycardia by (i) a cardiac sympatho-inhibition via activation of prejunctional 5-HT1B, 5-HT1D and 5-HT5A receptors in pithed rats [2][11][12]; or (ii) a cardiac vagal stimulation via activation of 5-HT3 receptors on parasympathetic ganglia and postganglionic vagal nerves in rabbits [2][5] (see Table 1 for pharmacological tools).

3.3.2. Tachycardia

I.v. administration of 5-HT in vagotomised animals induces a tachycardic effect that may be mediated by a wide variety of receptors/mechanisms, depending on the species and the experimental conditions [2][5]. These receptors/mechanisms include: (i) a tyramine-like action in spinal guinea pigs; (ii) direct stimulation of 5-HT2A receptors on the cardiac pacemaker in reserpinized pithed rats; (iii) activation of 5-HT3 receptors on cardiac sympathetic neurons in the perfused heart of a rabbit, resulting in noradrenaline release and cardiac stimulation; (iv) activation of 5-HT3 receptors on a calcitonin gene-related peptide (CGRP)-containing sensory neurons in an isolated guinea pig atrium, resulting in CGRP release and cardiac stimulation; (v) direct stimulation of 5-HT3 receptors on a cardiac pacemaker in conscious dogs; (vi) direct stimulation of 5-HT4 receptors on a cardiac pacemaker in healthy anaesthetized pigs (which is also involved in the positive inotropic effects of 5-HT in isolated human atria and in rats with chronic heart failure); (vii) direct stimulation of 5-HT7 receptors on a cardiac pacemaker in spinal cats; and (viii) unidentified mechanisms in the isolated hearts of certain lamellibranch and gastropod species (including Mercenaria mercenaria, Patella vulgata, Tapes watlingi, Helix aspersa, Aplysia, etc.). These receptors were pharmacologically identified using selective agonists and antagonists for each type (see Table 1).

3.4. Vascular and Blood Pressure Effects of 5-HT

As explained in other reviews [2][6][7], i.v. administration of 5-HT results in a triphasic effect on arterial blood pressure, consisting of an initial transient vasodepressor effect followed by a vasopressor effect, and then a late long-lasting vasodepressor effect.

3.4.1. Initial Transient Vasodepressor Effect

This response results from an abrupt bradycardia (and the consequent decrease in cardiac output) following stimulation of 5-HT3 receptors on afferent cardiac vagal afferents (i.e., the Bezold–Jarisch reflex; see above and Table 1).

3.4.2. Vasopressor Effect

This effect (which varies quantitatively, depending on the species and the experimental conditions) involves the activation of vascular 5-HT2 receptors in resistance blood vessels (resulting in peripheral vasoconstriction). It is worth noting that a release of catecholamines by activation of 5-HT2 receptors in the adrenal medulla also plays a role in dogs, whereas activation of 5-HT1B receptors produces vasoconstriction in cranial and carotid arteries in humans, pigs and dogs [2]. Interestingly, 5-HT1B and 5-HT2 receptors elicit vasoconstriction in the internal carotid bed of anaesthetised dogs, while 5-HT directly activates, in vitro, α-adrenoceptors in rabbit ears and external carotid arteries [2]. Some of the agonists and antagonists used to identify these receptors are shown in Table 1.

3.4.3. Late Long-Lasting Vasodepressor Effect

This effect predominantly involves the activation of musculotropic 5-HT7 receptors [2][6][7], although several receptors/mechanisms may play a role, depending on the experimental conditions. These receptors/mechanisms may include: (i) Direct vasodilatation. The direct vasodilatation to 5-HT involves 5-HT7 receptors in a wide variety of blood vessels under different experimental conditions [2][5][6][7]. Some of the agonists and antagonists used to identify these receptors (applying the aforementioned inclusion and exclusion criteria) are shown in Table 1. Moreover, in the blood vessels where 5-HT7 receptors produce vasodilatation and 5-HT2/5-HT1B receptors produce vasoconstriction, the final effect of 5-HT would depend on the pre-existing vascular tone, the dose employed, and the proportions in which these receptors are distributed [2]. (ii) Prejunctional inhibition of perivascular sympathetic neurons. The prejunctional inhibition induced by 5-HT and related agonists on perivascular sympathetic neurons has been confirmed in vitro and in vivo in many blood vessels [2]. This vascular sympatho-inhibition, generally mediated by 5-HT1 receptors, may involve the 5-HT1A, 5-HT1B and/or 5-HT1D receptor subtypes, depending on the vascular bed under study, the species, and the experimental conditions [2]. Interestingly, sympatho-inhibitory 5-HT7 receptors could also be involved when rats are chronically pretreated with the 5-HT2 receptor antagonist sarpogrelate [2][13]. These receptors were pharmacologically identified by applying the inclusion and exclusion criteria (see Table 1 and Figure 1).
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Figure 1. Prejunctional 5-HT receptors are involved in the inhibition of postganglionic autonomic and sensory CGRPergic function at the vascular level. Generally, 5-HT can inhibit the release of noradrenaline, acetylcholine, and CGRP via activation of the 5-HT1 receptor family (coupled to Gi/o proteins; this figure shows the corresponding Gα/β/γ subunits). In the case of the parasympathetic outflow, activation of 5-HT3 (ligand-gated ion channel) receptors favours the release of acetylcholine. Furthermore, in sensory CGRPergic neurons, prejunctional activation of 5-HT7 receptors seems to recruit the endothelin system (via an unknown pathway), favouring the activation of the ET1 receptor and promoting inhibition of CGRP release. Interestingly, (i) in some isolated cases, activation of prejunctional 5-HT3 receptors on parasympathetic fibres facilitates the release of CGRP; and (ii) circulating 5-HT can be recaptured via NET, and subsequently vesiculated and released upon electrical stimulation of the sympathetic outflow. See text for details. AP: action potential; NET: noradrenaline transporters; VGCC: voltage-gated ion channels.
(iii) Endothelium-dependent vasodilatation. In isolated blood vessels of several species without a functional endothelium, the vasodilatation to 5-HT is attenuated, while the vasoconstriction is augmented [2]. This vasodilatation, involving endothelial release of nitric oxide (NO), is mainly mediated by 5-HT1 receptors [2]. Interestingly, in porcine blood vessels, the 5-HT-induced endothelium-dependent vasodilatation involves (i) 5-HT1B/1D receptors in coronary arteries; or (ii) 5-HT2B receptors in pulmonary arteries (see Table 1). (iv) Actions in the CNS. Central administration of 5-HT may produce vasodepressor, vasopressor or biphasic effects, depending on the exact site of application, dose employed, depth of anaesthesia, the species used, etc. [2]. As previously reviewed [2][10], the cardiovascular regulation by central 5-HT neurons involves (i) 5-HT1A receptors (associated with sympatho-inhibition, hypotension, and bradycardia); and (ii) 5-HT2 receptors (associated with sympatho-excitation and hypertension). Indeed, when directly applied in the CNS, 5-HT may produce both sympatho-inhibition and cardiac-vagal stimulation via 5-HT1A receptors [9][14]. In fact, psychiatric conditions that involve alterations in the serotoninergic limbic components are usually accompanied by an autonomic imbalance; for example, posttraumatic stress disorder includes clinical manifestations such as cardiac arrhythmia, tachycardia, high blood pressure, etc. [15][16]. Moreover, anxiety correlates strongly with adrenaline levels in a positive direction [17], while aberrations in the autonomic nervous system (ANS) have been reported in patients with depression or other mood alterations [18]. Hence, central 5-HT is a powerful modulator of the ANS whose complex mechanisms fall beyond the scope of the present research. Interestingly, brain 5-HT can cross the blood–brain barrier via the 5-HT reuptake transporter (SERT) in endothelial cells and, consequently, can reach systemic circulation [19].

3.5. Receptor-Independent Actions of 5-HT

Apart from the above cardiovascular effects of 5-HT mediated by 5-HT receptors, other studies suggest that 5-HT can also play cardiovascular (patho)physiological roles independent of 5-HT receptor activation [2]. For example, (i) rats pretreated with fluoxetine (a SERT inhibitor) were protected from monocrotaline-induced pulmonary hypertension [20]; and (ii) 5-HT uptake can “serotonylate” proteins by transglutaminase-2 [21], a mechanism involved in the mitogenic and profibrotic effects of 5-HT without receptor activation [22].

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