Serotonergic Modulation of Neurovascular Transmission: A Focus on Prejunctional 5-HT Receptors/Mechanisms

Abstract

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. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.

The history and rationale of the development of new drugs for migraine treatment

“…33 Triptans pharmacological effect is exerted through activation of vascular smooth muscle 5-HT 1B receptor (vasoconstriction) and presynaptic 5-HT 1D receptors (lessening trigeminovascular neuron firing of CGRP). 33,34 Shortly thereafter, three triptans were launched in the market: sumatriptan, referential triptan, zolmitriptan, and naratriptan. While zolmitriptan's pharmacological profile resembled that of sumatriptan, naratriptan differed due to its slower onset of action, and lower potency but longer half-life.…”

“…Pharmacological and efficacy data of some oral migraine prophylactic drugs[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] …”

Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPβS in Rats

“…Simultaneous recordings of heart rate (measured with a 7P4F tachograph) and blood pressure were obtained using a model 7D Grass polygraph manufactured by Grass Instrument Co. (Quincy, MA, USA)". Subsequently, this set was randomly divided into two groups (n = 30 each; see Figure 8), i.e.,: (i) Group 1 (anaesthetised rats without vagotomy), which remained with both vagus nerves intact to analyse the possible influence of the CNS on the blood pressure effects of ADPβS via vagal compensatory reflex mechanisms; and (ii) Group 2 (anaesthetised rats with vagotomy), which underwent a bilateral cervical vagotomy to avoid the possible central influence of reflex responses resulting from activation of the vagus nerve (e.g., the von Bezold-Jarisch-like reflex responses [55]) in response to the blood pressure effects of ADPβS. It is noteworthy that additional slow i.v.…”