Type I and II metabotropic glutamate receptors mediate depressor and bradycardic actions in the nucleus of the solitary tract of anaesthetized rats

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Abstract

The potential role of metabotropic glutamate (mGlu) receptors in cardiovascular function in the nucleus of the solitary tract was examined following the microinjection of a number of selective mGlu receptor compounds into this site of anaesthetized rats. The prototypic mGlu receptor selective agonist 1S,3R-1-amino-cyclopentane dicarboxylate elicited depressor and bradycardic actions following microinjection into the nucleus tractus solitarius, which were similar to those produced by l-glutamate. Similarly, decreases in blood pressure and heart rate were observed upon administration of the type I and II selective mGlu receptor agonists, (R,S)-3,5-dihydroxyphenylglycine (DHPG) and 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC), respectively. These actions of DHPG were selectively attenuated by (±)-1-aminoindane-1,5-dicarboxylate, a type I mGlu receptor antagonist, whilst cardiovascular responses to APDC were unaffected by this compound. Interestingly, the proposed type II antagonist, (2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-doic acid, reduced the cardiovascular responses to intra-nucleus tractus solitarius administration of both APDC and DHPG. The type III mGlu receptor agonist, l-2-amino-4-phosphonobutyrate, however, failed to elicit any cardiovascular actions when microinjected into the nucleus tractus solitarius. These studies provide new evidence for functional type I and II mGlu receptors in modulating cardiovascular responses in the nucleus tractus solitarius.

Introduction

The nucleus of the solitary tract is the site of termination for a number of populations of primary afferent neurons, including baroreceptor afferents projecting from the aortic arch and carotid sinus (Kumada et al., 1990). Given this evidence, it is not surprising that the nucleus tractus solitarius has an important role in central regulation of blood pressure, via involvement in the arterial baroreceptor reflex. A number of different neurotransmitters and neuromodulators have been shown to modulate cardiovascular activity within the nucleus tractus solitarius (Lawrence and Jarrott, 1996). Indeed, a major role for the excitatory amino acid, l-glutamate (Glu) in central cardiovascular control has been well established, with evidence supportive of Glu being the primary neurotransmitter at baroreceptor afferent neurones (Lawrence and Jarrott, 1996). Additionally, two other major projections involved in the baroreflex pathway are also glutamatergic (Arnolda et al., 1992). These projections exist from the nucleus tractus solitarius to caudal ventrolateral medulla and from the rostral ventrolateral medulla to the intermediolateral column of the spinal cord.

Glu receptors have been reported to be present on baroreceptor afferent terminals in the nucleus tractus solitarius (Lewis et al., 1988) and transmitter-like release of Glu occurs following electrical stimulation of the vagus nerve (Allchin et al., 1994) and baroreceptor activation after administration of phenylephrine (Lawrence and Jarrott, 1994). Injection of Glu into the nucleus tractus solitarius of anaesthetized rats induces cardiovascular responses, which are similar to the depressor and bradycardic responses elicited by baroreflex activation (Talman et al., 1980), and are considered to be due to activation of ion-channel gated Glu receptors. Likewise, microinjections of the ionotropic Glu receptor agonists N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate into the nucleus tractus solitarius cause decreases in blood pressure and heart rate which mimic the response to Glu. Interestingly, the ionotropic Glu receptor antagonist, kynurenate attenuated the cardiovascular responses to NMDA, AMPA and kainate, but not those of Glu (Leone and Gordon, 1989) suggesting a non-ionotropic Glu component of action in this nucleus.

In addition to the ion-channel gated Glu receptors, a family of G-protein-coupled metabotropic glutamate (mGlu) receptors have been identified, which are linked to a number of second messenger systems, including calcium mobilization, phosphoinoside hydrolysis and cyclic AMP accumulation (Conn and Pin, 1997). Recent evidence provided by molecular cloning studies has indicated the presence of at least eight subtypes of mGlu receptors, with a number of spliced variants having also been described. Pharmacologically, mGlu receptors can be distinguished from ionotropic Glu receptors by using the mGlu receptor selective agonists (±)1S,3R-1-amino-cyclopentane-1,3-dicarboxylic acid (tACPD) and l-2-amino-4-phosphonobutyrate (l-AP4). Moreover, the G-protein coupled mGlu receptors may also have roles in cardiovascular regulation in the nucleus tractus solitarius as injections of tACPD into the nucleus tractus solitarius produce dose-dependent depressor and bradycardic responses in anaesthetized rats (Pawloski-Dahm and Gordon, 1992). This same study also showed that l-AP3, a non-selective mGlu receptor antagonist, decreased blood pressure and heart rate following microinjection into the nucleus tractus solitarius.

The electrophysiological studies of Glaum and Miller (1992)demonstrated that, in slices of coronal brainstem, 1S,3R-ACPD can directly depolarize solitary neurones, in addition to having other pre- and postsynaptic actions at amino acid-utilizing neurones within the nucleus tractus solitarius. These actions of 1S,3R-ACPD on solitary neurones were blocked by a number of mGlu receptor phenylglycine antagonists, some of which also elicited agonist-like responses (Glaum et al., 1993). We have previously described evidence for functional mGlu receptors in the nucleus tractus solitarius which can modulate the release in vivo and in vitro of various amino acids (Jones et al., 1998a, Jones et al., 1998b). In particular, the in vitro release experiments in the nucleus tractus solitarius slice preparation have shown that both type I and II mGlu receptors are present via the use of subtype-specific mGlu receptor agonists and antagonists (Jones et al., 1998b).

The aim of the present study was to examine roles for the different subtypes of mGlu receptors in cardiovascular processing in nucleus tractus solitarius by microinjecting a number of mGlu receptor agonists and antagonists into the nucleus tractus solitarius of anaesthetized rats and monitoring blood pressure and heart rate responses.

Section snippets

Surgical procedures

Experiments were performed in accordance with the NHMRC Code of practice for the care and use of animals for experimental purposes in Australia. Male Sprague–Dawley rats (280–400 g) were anaesthetized with pentobarbitone sodium (60 mg/kg, i.p.) and catheters were inserted into the carotid artery and jugular vein for blood pressure monitoring and drug administration, respectively. Pulsatile blood pressure was monitored via a pressure transducer connected to a polygraph (Grass Instruments,

Preliminary characterization: Glu and mGlu receptor compounds

The effects of the unilateral microinjection into the nucleus tractus solitarius of Glu and a number of selective and non-selective mGlu receptor drugs were examined in anaesthetized rats (Table 1). There were no significant differences in the basal mean arterial pressure values prior to drug injections (P>0.05, ANOVA). However, there was a range of 149 bpm in basal heart rate values prior to drug injections (Table 1) which resulted in a significant difference in basal heart rate values between

Discussion

The present studies were designed to investigate possible roles for mGlu receptor subtypes in cardiovascular control in the nucleus tractus solitarius of anaesthetized rats. It should be noted that basal heart rate and, to a lesser extent, mean arterial pressure values varied between animals, which most likely reflects the difficulty in matching levels of anaesthesia, and hence autonomic control, between anaesthetised animals. Nevertheless, these are the first in vivo studies to report that

Acknowledgements

These studies were supported in part by an Australian Research Council Small Grant and by a Dora Lush Postgraduate Research Scholarship (N.M.J.) from the National Health and Medical Research Council, of which P.M.B. and R.E.W. are Research Fellows.

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