receptor agonists developed for other 5-HT receptor subtypes, including 8-OH-DPAT, which have affinity at the 5-HTy receptor binding site.
Furthermore, ritanserin and metergoline are antagonists with a high affinity for this receptor; although, at present there are no selective ligands. Many
responses previously attributed to other 5-HT receptor subtypes are now thought to be due to the 5-HTy receptor (Eglen etal., 1997). In rat and guinea pig, the density of S-HT? receptor distribution is relatively consistent and
concentrates primarily in hypothalamus, thalamus, hippocampus and brainstem, and in man, peripherally, it has been described in coronary artery (Hoyer etal.,
1994). Smooth muscle relaxation is one functional characteristic of this receptor subtype, whilst activation of the subtype may cause prolonged hypotension (Eglen etal., 1997). 5-HT? receptor activity may also mediate changes in circadian rhythm; a theory proposed after ligands with high affinity at this site increased neuronal firing in hypothalamic cell cultures (see Hoyer etal.,
1.6 Central cardiovascular actions for 5-HT receptors
A detailed review on the role of 5-HT receptors in cardiovascular regulation has been recently published (Ramage, 2001). Taken together, there is ample evidence described above suggesting an important regulatory function for the central serotonergic system in autonomic control, an action proposed over 20 years ago (Kuhn etal., 1980). The location of both serotonergic neurones and 5-H T receptor subtypes in areas known to modulate and direct the
cardiovascular system supports this. Further, the systemic effects of central 5-H T administration on blood pressure and other cardiovascular variables, although not necessarily clear cut, are another important indicator (see Kuhn at
a/., 1980). W hat is now becoming clear is that the interaction between 5-HT and both parasympathetic and sympathetic branches of the autonomic nervous system is a complex system, involving most, or all, of the individual 5-HT
receptor subtypes. It must be stated also that peripherally serotonin plays a strong role in cardiovascular functions, most notably in vascular tissue (see Marwood & Stokes, 1984), but also in other organs under autonomic control, such as the bladder (see Ramage, 2001).
The varied and sometimes conflicting cardiovascular responses achieved by central administration of 5-H T is now thought to be due to a number of factors including:- activation of different 5-H T receptor populations; inter-species differences; dose of 5-HT administered; site of administration; use or not of anaesthetic agents and even type of anaesthetic used. One early study
described a pressor effect and bradycardia associated with 5-HT administration intra-cerebro ventricularly (i.c.v.) in the conscious rat, which could be blocked by pre-treatment with a non-selective 5-HT receptor antagonist (Sukamoto etal.,
1984). It has also been reported that changes in heart rate caused by i.c.v. administration of 5-HT are dose related, with lower doses causing tachycardia and higher doses resulting in bradycardia (Dedeoglu & Fisher, 1991). These dose-related issues may be a result of increased diffusion of 5-H T to brain areas distal to the administration site at higher doses (Coote, 1990).
specifically, the administration of 5-HT into the NTS has also been shown to produce a variety of responses, perhaps unsurprisingly due to the diverse integrative functions of this nucleus. Low doses produced a depressor and bradycardic response in anaesthetized (Laguzzi etal., 1984) and conscious (Callera et al ., 1997a) rat models, whilst higher doses have produced both an increase (Merahi etal., 1992) and a decrease (Feldman & Galliano, 1995) in blood pressure. Another study in rats demonstrated that 5-HT injected into the NTS always produced a depressor and bradycardic response which was
enhanced in spontaneously hypertensive rats (Okada & Bunag, 1994), a pattern that is mirrored by glutamate (see Okada & Bunag, 1994). These responses are likely to involve more than one 5-HT receptor subtype due to the
demonstrated location of a number of these subtypes within the NTS (at varying density, see above). Furthermore clear conclusions are difficult to make due to the limitations of microinjection studies in not being able to target functionally identified neurones.
However, the development of selective compounds, and more refined
techniques, such as in vivo extracellular recordings, is significantly furthering the understanding of which subtypes of 5-HT receptor and which central areas are involved in these responses. Below are descriptions of some of the recent advances into the functioning of the central serotonergic system with respect to cardiovascular regulation, and where the current understanding lies.
1.6.1 5-HTiA receptors
Central activation of 5-HTia receptors by i.c.v. administration of the selective 5-H T ia receptor agonist 8-OH-DPAT has been shown to cause a depressor effect and bradycardia in all species tested (see McCall & Clement, 1994), a response that was mirrored in conscious and spontaneously hypertensive rats (Dreteler et al., 1990; Gradin et al., 1985). In cats a differential effect of central 5-H Tia receptor activation on sympathetic outflow has now been described (Ramage et al., 1988). This was demonstrated by the absence of a vasodilation of the hindlimb and a delay in the activation of thoracic preganglionic neurones, after a 5-H Tia agonist-evoked hypotension. Further, the depressor response to
5 - H T i a receptor activation has implicated the major sympathoexcitatory area (located in the RVLM) as a possible zone for this serotonergic modulation (Gillis
e t al ., 1989; Laubie etal., 1989). In addition, one study reported no reduction in sympathetic outflow to the heart after activation of 5 - H T i a receptors in the region of the RVLM (King & Holtman, 1989), again supporting further differential functions for this subtype. One explanation for this latter observation is the proposed topographical organisation of RVLM neurones with respect to their end target (Dampney, 1994), suggesting that 5 - H T i a receptors may only modulate outflows to specific vascular beds.
In the anaesthetized rat, sympathoexcitatory effects of 5-HTia receptor
activation have also been described following low dose i.c.v. administration of a selective agonist (Anderson et al., 1992). This is thought to be mediated by increased release of adrenaline, although due to the presence of this response in the conscious model, some doubt about this mechanism remains (see Ramage, 2001). One possible important distinction in these apparently
opposing effects of 5-H Tia receptor activatiorf is the different central nuclei from which they can be evoked. Depressor responses have been described from the raphe magnus and pallidus, the RVLM and even the dorsal raphe (see McCall & Clement, 1994), whereas pressor responses have been reported from raphe obscurus, the preoptic area but not the paraventricular nucleus in the rat (see Ramage, 2001). With respect to the maintenance of sympathetic outflow i.v. administration of a selective 5-H T ia receptor antagonist was unable to
significantly alter resting blood pressure in the anaesthetized cat (Ramage & Mirtsou-Fidani, 1995), indicating that, under these conditions, 5-HTia receptors capable of modulating the sympathetic nervous system are not under tonic activation.
The ability of 5-H Tia receptors to modulate the parasympathetic nervous
system (Shepheard etal., 1994) can be partially explained by the demonstrated tonic activation of 5 - H T i a receptors during cardiac vagal reflex activation in the
nucleus ambiguus of the cat (Wang & Ramage, 2001). This study confirmed data that described the attenuation of reflex responses to cardiopulmonary receptor activation and upper airway receptor activation by 5 - H T i a receptor
blockade (see Dando etal., 1998). Indeed, application of a 5-H Tia receptor agonist into the IVth ventricle was shown to increase cardiac vagal tone
(Shepheard et al ., 1994). The site of this modulation by 5 - H T i a receptors was assumed to be close to the location of the vagal preganglionic neurones, i.e. the DVN and NA in the medulla. In support of this a study in the rat has
demonstrated the predominant decrease in the activity of these neurones by 5-H T ia receptor ligands (Wang etal., 1995). In addition, a recent study examining functionally identified neurones of the nucleus ambiguus in anaesthetized cats confirmed the modulation of cardiac vagal preganglionic neurones (CVPNs) by 5 - H T i a receptors using the highly selective antagonist W A Y -100635 (Wang & Ramage, 2001). Interestingly, activation of 5-H Tia receptors was able to excite these neurones, which, considering the mechanism of action these of receptors, must occur via interneurones due to the known hyperpolarising action of 5 - H T i a receptors. This has been proposed to be a result of ‘disinhibition’, which involves the switching off of GABAergic
interneurones by activation of 5 - H T i a receptors, resulting in reduced inhibitory drive to the CVPNs and their subsequent increased activity (see Ramage, 2000). A GABAergic modulation of CVPNs has been demonstrated before (DiMicco etal., 1979), and in respect of the serotonergic modulation via 5-HTia receptors this is not restricted to parasympathetic control of the heart, but also includes modulation of parasympathetic control of the bladder, airways and possibly the eye (see Ramage, 2000). Furthermore, although this data indicates an indirect serotonergic modulation of CVPNs there is some
anatomical evidence for fibres projecting to vagal preganglionic neurones in the DVN (Sykes et al., 1994) which may well involve the activation of other
serotonergic receptor subtypes (see below).
In addition, a role for 5-H Tia receptors in NTS has also been implicated (Wang
et al., 1997), with 8-O H -DPA T affecting the ongoing activity of almost all vagally identified NTS neurones, although roughly half these neurones were excited, and half were inhibited by this receptor ligand. Interestingly, out of five neurones that were functionally identified as receiving cardiac vagal afferent input, four were excited by the 5-H Tia receptor agonist. Although this
8-O H -D P A T for the S-H T/ receptor, cannot be ignored (pK, 8.7 for 5-HTia, pK, 7.4 for 5-H T7, see Hoyer, 1994).