Blockade of NK-1 receptors in the lateral commissural nucleus tractus solitarii of awake rats had no effect on the cardiovascular responses to chemoreflex activation
Abstract:The neurotransmission of the chemoreflex in the nucleus tractus solitarii (NTS), particularly of the sympatho-excitatory component, is not completely understood. There is evidence that substance P may play a role in the neurotransmission of the chemoreflex in the NTS. Microinjection of substance P (50 pmol/50 nl, N = 12, and 5 nmol/50 nl, N = 8) into the commissural NTS of unanesthetized rats produced a significant increase in mean arterial pressure (101 ± 1 vs 108 ± 2 and 107 ± 3 vs 115 ± 4 mmHg, respectively… Show more
“…Lower doses of SP (0.001 and 0.01 nmol/100 nl) had no cardiovascular effects. The pressor/tachycardic effect of a dose close to the ED 50 was blocked by previous injection of a NK-1 antagonist as reported previously (44). Most studies in anesthetized animals using low doses of SP (0.00007-0.06 nmol) have reported short lasting hypotension (4, Fig.…”
The cardiovascular effects of substance P (SP) microinjections in the nucleus tractus solitarii (NTS) were evaluated in conscious rats. We chose this model because it is an effective way to access some of the cardiovascular effects of neurotransmitters in the NTS without the inconvenience of blunting pathways with anesthetic agents or removing forebrain projections by decerebration. The cardiovascular responses to SP injections were also evaluated after chronic nodose ganglionectomy. We found that, in conscious rats, SP microinjections into the NTS induced hypertension and tachycardia. Unilateral and bilateral SP injections into the NTS caused a slow increase in blood pressure and heart rate that peaked 1.5-5 min after injection and lasted for 20-30 min. Nodose ganglionectomy increased the duration of the pressor and tachycardic effects of SP and enhanced the pressor response. These data show that SP in the NTS is involved in pressor pathways. The supersensitivity to SP seen after nodose ganglionectomy suggests that vagal afferent projections are involved in those pressor pathways activated by SP in the NTS.
“…Lower doses of SP (0.001 and 0.01 nmol/100 nl) had no cardiovascular effects. The pressor/tachycardic effect of a dose close to the ED 50 was blocked by previous injection of a NK-1 antagonist as reported previously (44). Most studies in anesthetized animals using low doses of SP (0.00007-0.06 nmol) have reported short lasting hypotension (4, Fig.…”
The cardiovascular effects of substance P (SP) microinjections in the nucleus tractus solitarii (NTS) were evaluated in conscious rats. We chose this model because it is an effective way to access some of the cardiovascular effects of neurotransmitters in the NTS without the inconvenience of blunting pathways with anesthetic agents or removing forebrain projections by decerebration. The cardiovascular responses to SP injections were also evaluated after chronic nodose ganglionectomy. We found that, in conscious rats, SP microinjections into the NTS induced hypertension and tachycardia. Unilateral and bilateral SP injections into the NTS caused a slow increase in blood pressure and heart rate that peaked 1.5-5 min after injection and lasted for 20-30 min. Nodose ganglionectomy increased the duration of the pressor and tachycardic effects of SP and enhanced the pressor response. These data show that SP in the NTS is involved in pressor pathways. The supersensitivity to SP seen after nodose ganglionectomy suggests that vagal afferent projections are involved in those pressor pathways activated by SP in the NTS.
“…The transmitter within these NK 1 -containing neurons may include glutamate, since (1) microinjection of SP in the cNTS results in blood pressure elevation (Zhang et al, 2000), and (2) increased blood pressure may result from activation of NTS glutamatergic neurons projecting to sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM; (Mazzone et al, 1997; Mauad and Machado, 1998; Babic and Ciriello, 2004; Bailey et al, 2004). However, the SP-induced elevation in blood pressure is not blocked by bilateral microinjection of an NK 1 receptor antagonist in the lateral cNTS (Zhang et al, 2000), suggesting a lack of direct involvement of these receptors in mediating chemoreflexes. In contrast, NK 1 receptors in the NTS are highly implicated in bronchopulmonary reflexes that defend the lungs against injury from inhaled agents by the induction of apnea, cough, and hypotension (Mutoh et al, 2000).…”
Section: Discussionmentioning
confidence: 99%
“…The excitatory transmitters in these sensory vagal inputs include glutamate and substance P (SP; Helke et al, 1980; Douglas et al, 1982; Kalia et al, 1984; Kawano and Chiba, 1984; Kawano and Masuko, 1997; Kawano and Masuko, 1995; Lindefors et al, 1986; Srinivasan et al, 1991), a tachykinin peptide that preferentially acts through G protein coupled neurokinin-1 (NK 1 ) receptors (Rodier et al, 2001; Rico et al, 2003; Bonham et al, 2004). Moreover, brainstem SP-induced activation of NK 1 receptors can modulate cardiovascular and respiratory responses evoked through the respective baro- and chemoreceptor reflexes (Gillis et al, 1980; Lindefors et al, 1986; Hall et al, 1989; Massari et al, 1998; Zhang et al, 2000; Nattie and Li, 2002). These observations are consistent with the electron microscopic autoradiographic localization of NK 1 receptor binding sites to postsynaptic neurons in the NTS (Jia et al, 1996; Baude and Shigemoto, 1998).…”
Chronic intermittent hypoxia (CIH) is a frequent concomitant of sleep apnea, which can increase sympathetic nerve activity through mechanisms involving chemoreceptor inputs to the commissural nucleus of the solitary tract (cNTS). These chemosensory inputs co-store glutamate and substance P (SP), an endogenous ligand for neurokinin-1 (NK 1 ) receptors. Acute hypoxia results in internalization of NK 1 receptors, suggesting that CIH also may affect the subcellular distribution of NK 1 receptors in subpopulations of cNTS neurons, some of which may express tyrosine hydroxylase, the ratelimiting enzyme for catecholamine synthesis (TH). To test this hypothesis, we examined dual immunolabeling for the NK 1 receptor and TH in the cNTS of male mice subjected to 10 days or 35 days of CIH or intermittent air. Electron microscopy revealed that NK 1 receptors and TH were almost exclusively localized within separate somatodendritic profiles in cNTS of control mice. In dendrites, immunogold particles identifying NK 1 receptors were prevalent in the cytoplasm and on the plasmalemmal surface. Compared with controls, CIH produced a significant region-specific decrease in the cytoplasmic (10 and 35 days, P< 0.05, unpaired Student t-test) and extrasynaptic plasmalemmal (35 days, P< 0.01, unpaired Student t-test) density of NK 1 immunogold particles exclusively in small (<0.1 µm) dendrites without TH immunoreactivity. These results suggest that CIH produces a duration-dependent reduction in the availability of NK 1 receptors preferentially in small dendrites of non-catecholaminergic neurons in the cNTS. The implications of our findings are discussed with respect to their potential involvement in the slowly developing hypertension seen in sleep apnea patients.
“…Of the numerous neurotransmitters found in the NTS, glutamate is the principal excitatory neurotransmitter and has been recognized to play a pivotal role in regulating cardiovascular functions in the NTS (Seagard et al, 2001;Talman et al, 1980;Talman, 1997). Studies have also suggested that substance P (SP), acting at neurokinin-1 (NK1) receptors (Feldman, 1995;Zhang et al, 2000), plays a role in neuromodulation of cardiovascular control in the NTS (Boscan et al, 2002;Gillis et al, 1980;Potts, 2006), though a role for the peptide in transmission of baroreflex signals has been controversial. For example, administration into the NTS of SP or agonists for NK1 receptors evoked contradictory arterial baroreceptor responses (Bauman et al, 2002;Carter and Lightman, 1985;Feldman, 1995;Kubo and Kihara, 1987;Nagashima et al, 1989;Talman and Reis, 1981).…”
Substance P (SP) and glutamate are implicated in cardiovascular regulation by the nucleus tractus solitarii (NTS). Our earlier studies suggest that SP, which acts at neurokinin 1 (NK1) receptors, is not a baroreflex transmitter while glutamate is. On the other hand, our recent studies showed that loss of NTS neurons expressing NK1 receptors leads to loss of baroreflex responses and increased blood pressure lability. Furthermore, studies have suggested that SP may interact with glutamate in the NTS. In this study, we sought to test the hypothesis that NK1 receptors colocalize with glutamate receptors, either N-methyl-D-aspartate (NMDA) receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors or both in the NTS. We performed double-label immunofluorescent staining for NK1 receptors and either NMDA receptor subunit 1 (NMDAR1) or AMPA receptor subunit (GluR2) in the rat NTS. Because vesicular glutamate transporter 2 (VGLUT2) containing fibers are prominent in portions of the NTS where cardiovascular afferent fibers terminate, we also performed double-label immunofluorescent staining for NK1 receptors and VGLUT2. Confocal microscopic images showed that NK1 receptors-immunoreactivity (IR) and NMDAR1-IR colocalized in the same neurons in many NTS subnuclei. Almost all NTS neurons positive for NK1 receptor-IR also contained NMDAR1-IR, but only 53.4% to 74.8% of NMDAR1-IR positive neurons contained NK1 receptors-IR. NK1 receptor-IR and GluR2-IR also colocalized in many neurons in NTS subnuclei. A majority of NK1 receptor-IR positive NTS neurons also contained GluR2-IR, but only 45.8% to 73.9% of GluR2-IR positive NTS neurons contained NK1 receptors-IR. Our results also showed that fibers labeled for VGLUT2-IR were in close apposition to fibers and neurons labeled for NK1 receptor-IR. The data support our hypothesis, provide an anatomical framework for glutamate and SP interactions, and may explain the loss of baroreflexes when NTS neurons, which could respond to glutamate as well as SP, are killed.
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