Integrated Cardio-Respiratory Mechanisms within the brainstem: Involvement of the Caudal Pressor Area, the Nucleus of the Solitary Tract and the Retrotrapezopid Nucleus. / Mecanismos Cardio-Respiratórios Integrados na Região Bulbar: Participação da Área Pressora Caudal, dos Núcleos do Trato Solitário e do Núcleo Retrotrapezóide.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2009

RESUMO

Cardiovascular responses are integrated at different levels of the central nervous system (CNS). In the brainstem, there are different areas related to the cardiovascular control. It is well known that in the ventrolateral medulla there are, at least, three important regions involved with cardiovascular control: the rostral ventrolateral medulla (RVLM), the caudal ventrolateral medulla (CVLM) and the caudal pressor area (CPA). The RVLM is the main source of excitatory input to sympathetic preganglionic neurons playing a crucial role for tonic and reflex control of the cardiovascular system. The caudal ventrolateral medulla (CVLM) contains the GABAergic sympathoinhibitory neurons that project to RVLM. Besides these two regions, the NTS is the site of the first synapse of the viscerosensory afferent fibers in the brainstem including those related to cardiovascular and respiratory afferents. Besides the circuitry described above, more recent studies have also shown a new site, the CPA, located in the caudal end of the ventrolateral medulla, which provides excitatory signals that affect sympathetic activity to the cardiovascular system in rats. Therefore, the aim of the present study was to investigate the involvement of the NTS (commissural and/or intermediate regions) on the stimulation or inhibition of the CPA. Male Holtzman rats (280-350 g; n = 6-8) anesthetized with urethane (1.2 g/kg, i.v.) were used. Unilateral microinjection of L-glutamate (1 mM - 100 nL) into the CPA resulted in an increase in mean arterial pressure (MAP, D = +28 3 mmHg, vs. controle: D = +2 2 mmHg, p<0.05) and heart rate (HR, D = +20 1 bpm, vs. controle: D = +3 3 bpm, p<0.05). Electrolytic lesions of the commissural NTS (commNTS) (1 mA x 10s) abolished the pressor and tachycardic responses at 10 (D = +5 7 mmHg and D = +4 3 bpm), 30 (D = +7 3 mmHg and D = +6 3 bpm) and 60 minutes (D = +11 3 mmHg and D = +5 1 bpm) produced by injection of L-glutamate into the CPA. In the same way, muscimol (GABA-A receptor agonist) (2 mM - 60 nL) injected into the commNTS abolished the pressor and tachycardic responses at 10 (D = +5 5 mmHg and D = +5 3 bpm), 30 (D = +8 5 mmHg and D = +7 2 bpm) and 60 minutes (D = +11 6 mmHg and D = +5 2 bpm) produced by injection of L-glutamate into the CPA. On the other hand, the injection of Lglutamate unilaterally into the CPA 10, 30 and 60 minutes after the injection of muscimol into the intermediate NTS produced no change on MAP increase (D = +11 2, +27 4 and +24 7 mmHg, respectively) and HR (D = +30 12, +32 15 and +24 8 bpm, respectively). It seems that the activation of the CPA depends on the integrity of the commNTS neurons. Does the CPA integrity depend on NTS activation? Bilateral injection of muscimol (GABA-A agonist, 2 mM 60 nl) into the CPA produced a decrease in MAP (D = -18 2 mmHg, p<0.05) and HR (D = -21 6 bpm, p<0.05). The depressor and bradycardia responses produced by L-glutamate into the commNTS was abolished at 10 (D = -5 3 mmHg and D = +8 9 bpm), 30 (D = -5 2 mmHg and D = +7 4 bpm) and 60 minutes (D = -6 4 mmHg and D = +10 6 bpm) after muscimol injection into the CPA. On the other hand, the depressor and bradicardic responses produced by L-glutamate into the intermediate NTS was not changed at 10 (D = -41 9 mmHg and D = -67 26 bpm), 30 (D = -31 12 mmHg and D = -23 4 bpm) and 60 minutes (D = -32 8 mmHg and D = -21 3 bpm) after muscimol injection into the CPA. Our next question was to know if the inhibition of the CPA will change the cardiovascular reflexes. Baroreflex curves were generated by lowering MAP with sodium nitroprusside (30 mg/kg) and increasing MAP by constricting an abdominal aortic snare. The relationship between MAP and sympathetic nerve discharge (SND) (baroreflex curves) revealed no change after muscimol injection into the CPA. After inhibition of the CPA, the baroreflex operated around a comparable MAP (MAP50) in all groups of rats. The lower and upper plateau, as well the baroreflex range was not different from the control group. The chemoreflex was actvated by i.v. injections of sodium cyanide (NaCN 50 mg/kg). The activation of chemoreflex with NaCN produced a rise in MAP (D = +16 4 mmHg, vs. saline D = +2 2 mmHg, p<0.05), an increase in SND (D = +236 11% of resting, p<0.01) and an increase in phrenic nerve discharge (PND). Muscimol injection into the CPA reduced the pressor (D = +9 2 mmHg, vs. saline D = +18 4 mmHg, p<0.05), sympathoexcitatory (D = +88 18%, vs. saline D = +217 33 %, p<0.01) and the increase in PND produced by chemoreflex activation with NaCN. Carotid chemoreceptor afferents terminate predominantly in commNTS. The next experiment was designed to test and to confirm the interaction between the commNTS and the CPA neurons by anatomical approaches. We tested whether glutamatergic or GABAergic. The rats were exposed to hypoxia (8% O2, n = 5) or to normal air (n = 4). Fos-immunoreactivity was used to identify commNTS neurons that were activated by hypoxia. NTS or CPA neurons were classified as glutamatergic or GABAergic based on whether they contained VGLUT2 mRNA or GAD67 mRNA. The vast majority of the commNTS (64 13%), intermediate NTS (41 9%) and CPA (26 9%) neurons that were immunoreactive for Fos contained VGLUT2 mRNA, whereas only a small proportion of the same class of neurons contained GAD-67 mRNA (commNTS: 7 4%; intermediate NTS: 16 9% and CPA: 5 3%). Therefore, our results are the first to show the existence of an interaction between the commNTS and CPA in terms of cardiovascular control. However we know that commNTS neurons receive inputs from peripheral chemoreceptors and the stimulation of commNTS depends on CPA integrity. These data suggest that CPA contributes to resting MAP, sSND and to the sympathoexcitatory effect during stimulation of peripheral chemoreceptors.

ASSUNTO(S)

farmacologia 1. atividade simpática. 2. pressão arterial. 3. núcleo do trato solitário. 4. bulbo ventrolateral. 5. sistema nervoso central.

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