ArticleCentral cardiovascular regulation and 5-hydroxytryptamine receptors
Introduction
Central 5-HT pathways are known to innervate areas involved in cardiovascular regulation (Fig. 1) , however the role of 5-HT in such regulation has been confusing, the effects varying from one laboratory to another and from species to species. For instance, 5-HT or 5-HT analogues, when given centrally, were found to produce either depressor or pressor effects (see [28]), suggesting that 5-HT can be either sympathoexcitatory or inhibitory. This has now been clarified and has led to the realization that central 5-HT containing pathways involved in cardiovascular regulation involve two major receptor subtypes, 5-HT1A and 5-HT2 (2A), activation of the former causing central sympathoinhibition and the latter sympathoexcitation (see [35]). However, more recently, investigations into the role of 5-HT receptors and pathways in cardiovascular regulation have sadly declined so that, in a recent review [5] there is no mention of central, let alone peripheral cardiovascular effects, caused by different 5-HT receptors. In addition to central and peripheral cardiovascular effects, 5-HT receptors have also been implicated in other autonomic areas such as airways, bladder (see [39]), and blood volume regulation 27, 36. Interestingly, 5-HT1A and 5-HT2 receptors are still the main receptor subtypes involved in these autonomic effects. However, 5-HT3 receptors, which are involved in processing visceral afferent information, may also play a subtle role in cardiovascular regulation.
Section snippets
5-HT1A receptors
The archetypical 5-HT1A receptor agonist 8-OH-DPAT was first reported to cause central sympathoinhibition and increase vagal tone to the heart in anaesthetized cats 17, 34, 40 and then in rats and most other species tested (see [35]). However, in cats, 8-OH-DPAT, as with the other 5-HT1A agonists, ipsapirone and flesinoxan, while causing a centrally mediated fall in blood pressure, does not cause an associated generalised sympathoinhibition; for instance there is a delay in the inhibition of
Role of 5-HT1A receptors in the control of vagal preganglionic neurones, i.e., parasympathetic outlfow
Vagal preganglionic neurones are known to play a fundamental role in the control of the heart, the airways, the pancreas and the gastrointestinal tract, and are predominantly located in the nucleus ambiguus and the dorsal motor vagal nucleus. Data indicate that central 5-HT pathways are important for the reflex regulation of these neurones in all species investigated. The first observation to indicate that such a system plays a role was the observation that d-lysergic acid diethylamide could
5-HT3 receptors
The DVN and the NTS are probably the areas in which the densest concentration of 5-HT3 receptors are located, predominantly presynaptically (see [30]). Interestingly, excitation of DVN neurones by 5-HT could be completely blocked by the ionophorectic application of a 5-HT3 receptor antagonist (Fig. 18) [56]. Further, excitation of these neurones by the 5-HT3 receptor agonist, as well as being blocked by a 5-HT3 receptor antagonist, is also attenuated by AP5, an NMDA receptor antagonist and
Conclusion
Although there is now a much better understanding of the roles of 5-HT in central cardiovascular regulation, precisely what these roles are and how they relate to different 5-HT-containing brain regions and the interplay between different receptor subtypes to elicit changes induced by these regions remains to be determined.
Acknowledgements
I wish to thank Pfizer Ltd., Kent, U.K. for a travel grant towards the cost of attending this meeting, and the Wellcome Trust and British Heart Foundation for support, plus my many colleagues, whose work I have cited and with whom I have also very much enjoyed working.
References (59)
- et al.
5-Hydroxytryptamine3 receptor modulation of excitatory amino acid release in the rat nucleus tractus solitarius
Neurosci. Lett.
(1995) - et al.
A review of central 5-HT receptors and their function
Neuropharmacology
(1999) Physiopharmacological interactions between stress hormones and central serotonergic systems
Brain Res
(1993)The subretrofacial vasomotor nucleus; anatomical, chemical and pharmacological properties and role in cardiovascular regulation
Prog. Neurobiol.
(1994)- et al.
Evidence for expression of the 5-hydroxytryptamine-2B receptor protein in the rat central nervous system
Neuroscience
(1997) - et al.
Thirst and vasopressin secretion following central administration of angiotensin II in rats with lesions of the septal area and subfornical organ
Neuroscience
(1985) - et al.
Ventrolateral medullary pressor areaSite of hypotensive and sympatho-inhibitory effects of (±) 8-OH-DPAT in anaesthetised dogs
Eur. J. Pharmacol.
(1989) - et al.
Evidence that 5-HT3 receptors in the nucleus tractus solitarius and other brainstem areas modulate the vagal bradycardia evoked by activation of the von Bezold-Jarisch reflex in the anesthetized rat
Brain Res
(1998) Central 5-HT1A receptors and vagal tone to the airways
Trends Pharmacol. Sci.
(2000)- et al.
Evidence that the putative 5-HT1A receptor agonists, 8-OH-DPAT and ipsapirone, have a central hypotensive action that differs from that of clonidine in anaesthetised cats
Eur. J. Pharmacol.
(1987)