Elsevier

Brain Research Bulletin

Volume 56, Issue 5, 15 November 2001, Pages 425-439
Brain Research Bulletin

Article
Central cardiovascular regulation and 5-hydroxytryptamine receptors

https://doi.org/10.1016/S0361-9230(01)00612-8Get rights and content

Abstract

Evidence is provided to support the view that central 5-HT1A and 5-HT2 receptors are the major receptor subtypes important in cardiovascular regulation. Data are also provided to implicate 5-HT1B/1D/1F receptors in central cardiovascular regulation. Activation of 5-HT2 receptors generally causes sympathoexcitation and a rise in blood pressure and this is mainly mediated by 5-HT2A receptors. However, presympathetic vasomotor neurones located in the hindbrain (RVLM), controlling sympathetic outflow to the heart, are not activated in the same way as other presympathetic vasomotor neurones, although activation of 5-HT2 receptors located in the midbrain can activate sympathetic outflow to the heart. Furthermore, at least in the rat, these midbrain 5-HT2A receptors are also responsible for the release of vasopressin by activation of a central angiotensinergic pathway. The ability of vasopressin directly and/or indirectly to modify renal sympathetic outflow involves the activation of central 5-HT2B receptors, which in turn, when activated via the i.c.v. route, can cause selective renal sympathoexcitation. Evidence is also provided which indicates that the reflex control of parasympathetic outflow to the heart and to other organs involves central 5-HT1A receptors located in the vicinity of these preganglionic vagal neurones. Finally, 5-HT3 receptors are implicated in the afferent regulation of central sympathetic and parasympathetic tone.

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.

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