RESUMEN
AIM: Recent evidence suggests that adenosine triphosfate (ATP)-mediated purinergic signalling at the level of the rostral ventrolateral medulla contributes to both central and peripheral chemoreceptor control of breathing and blood pressure: neurones in the retrotrapezoid nucleus (RTN) function as central chemoreceptors in part by responding to CO2 -evoked ATP release by activation of yet unknown P2 receptors, and nearby catecholaminergic C1 neurones regulate blood pressure responses to peripheral chemoreceptor activation by a P2Y1 receptor-dependent mechanism. However, potential contributions of purinergic signalling in the RTN to cardiorespiratory function in conscious animals have not been tested. METHODS: Cardiorespiratory activity of unrestrained awake rats was measured in response to RTN injections of ATP, and during exposure to hypercapnia (7% CO2 ) or hypoxia (8% O2 ) under control conditions and after bilateral RTN injections of P2 receptor blockers (PPADS or MRS2179). RESULTS: Unilateral injection of ATP into the RTN increased cardiorespiratory output by a P2-receptor-dependent mechanism. We also show that bilateral RTN injections of a non-specific P2 receptor blocker (pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS) reduced the ventilatory response to hypercapnia (7% CO2 ) and hypoxia (8% O2 ) in unanesthetized rats. Conversely, bilateral injections of a specific P2Y1 receptor blocker (MRS2179) into the RTN had no measurable effect on ventilatory responses elicited by hypercapnia or hypoxia. CONCLUSION: These data exclude P2Y1 receptor involvement in the chemosensory control of breathing at the level of the RTN and show that ATP-mediated purinergic signalling contributes to central and peripheral chemoreflex control of breathing and blood pressure in awake rats.
Asunto(s)
Células Quimiorreceptoras/metabolismo , Bulbo Raquídeo/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Fenómenos Fisiológicos Respiratorios , Adenosina Trifosfato/farmacología , Animales , Masculino , Bulbo Raquídeo/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2Y/farmacología , Ratas , Ratas Wistar , VigiliaRESUMEN
Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of the dopaminergic nigrostriatal pathway. In addition to deficits in voluntary movement, PD involves a disturbance of breathing regulation. However, the cause and nature of this disturbance are not well understood. Here, we investigated breathing at rest and in response to hypercapnia (7% CO2) or hypoxia (8% O2), as well as neuroanatomical changes in brainstem regions essential for breathing, in a 6-hydroxydopamine (6-OHDA) rat model of PD. Bilateral injections of 6-OHDA (24µg/µl) into the striatum decreased tyrosine hydroxylase (TH(+))-neurons in the substantia nigra pars compacta (SNpc), transcription factor phox2b-expressing neurons in the retrotrapezoid nucleus and neurokinin-1 receptors in the ventral respiratory column. In 6-OHDA-lesioned rats, respiratory rate was reduced at rest, leading to a reduction in minute ventilation. These animals also showed a reduction in the tachypneic response to hypercapnia, but not to hypoxia challenge. These results suggest that the degeneration of TH(+) neurons in the SNpc leads to impairment of breathing at rest and in hypercapnic conditions. Our data indicate that respiratory deficits in a 6-OHDA rat model of PD are related to downregulation of neural systems involved in respiratory rhythm generation. The present study suggests a new avenue to better understand the respiratory deficits observed in chronic stages of PD.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Enfermedad de Parkinson/complicaciones , Trastornos Respiratorios/etiología , Adrenérgicos/toxicidad , Animales , Recuento de Células , Concentración de Iones de Hidrógeno/efectos de los fármacos , Ácido Láctico/sangre , Locomoción/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Desempeño Psicomotor , Ventilación Pulmonar/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/metabolismo , Centro Respiratorio/efectos de los fármacos , Centro Respiratorio/metabolismo , Centro Respiratorio/patología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Factores de TiempoRESUMEN
We investigated the role of the autonomic nervous system to cardiovascular responses to obstructive apnea in awake, unrestrained rats, and measured expression of Fos induced by apnea in the brainstem. We implanted a tracheal balloon contained in a rigid tube to allow the induction of apnea without inducing pain in the trachea. During bouts of 15s of apnea, heart rate fell from 371±8 to 161±11bpm (mean±SEM, n=15, p<0.01) and arterial pressure increased from 115±2 to 131±4mmHg (p<0.01). Bradycardia was due to parasympathetic activity because it was blocked by the muscarinic antagonist, methylatropine. The pressor response was due to vasoconstriction caused by sympathetic activation because it was blocked by the α1 antagonist, prazosin. Apnea induced Fos expression in several brainstem areas involved in cardiorespiratory control such as the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), and pons. Ligation of the carotid body artery reduced apnea-induced bradycardia, blocked heart rate responses to i.v. injection of cyanide, reduced Fos expression in the caudal NTS, and increased Fos expression in the rostral VLM. In conclusion, apnea activates neurons in regions that process signals from baroreceptors, chemoreceptors, pulmonary receptors, and regions responsible for autonomic and respiratory activity both in the presence and absence of carotid chemoreceptors.
Asunto(s)
Apnea/patología , Apnea/fisiopatología , Tronco Encefálico/fisiopatología , Vigilia , Análisis de Varianza , Animales , Derivados de Atropina/farmacología , Presión Sanguínea/efectos de los fármacos , Tronco Encefálico/efectos de los fármacos , Cuerpo Carotídeo/citología , Células Quimiorreceptoras/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Proteínas Oncogénicas v-fos/metabolismo , Parasimpatolíticos/farmacología , Prazosina/farmacología , Ratas , Ratas Wistar , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The rat retrotrapezoid nucleus (RTN) contains neurons that have a well-defined phenotype characterized by the presence of vesicular glutamate transporter 2 (VGLUT2) mRNA and a paired-like homeobox 2b (Phox2b)-immunoreactive (ir) nucleus and the absence of tyrosine hydroxylase (TH). These neurons are important to chemoreception. In the present study, we tested the hypothesis that the chemically-coded RTN neurons (ccRTN) (Phox2b(+)/TH(-)) are activated during an acute episode of running exercise. Since most RTN neurons are excited by the activation of perifornical and lateral hypothalamus (PeF/LH), a region that regulates breathing during exercise, we also tested the hypothesis that PeF/LH projections to RTN neurons contribute to their activation during acute exercise. In adult male Wistar rats that underwent an acute episode of treadmill exercise, there was a significant increase in c-Fos immunoreactive (c-Fos-ir) in PeF/LH neurons and RTN neurons that were Phox2b(+)TH(-) (p<0.05) compared to rats that did not exercise. Also the retrograde tracer Fluoro-Gold that was injected into RTN was detected in c-Fos-ir PeF/LH (p<0.05). In summary, the ccRTN neurons (Phox2b(+)TH(-)) are excited by running exercise. Thus, ccRTN neurons may contribute to both the chemical drive to breath and the feed-forward control of breathing associated with exercise.
Asunto(s)
Proteínas de Homeodominio/metabolismo , Hipotálamo/fisiología , Locomoción/fisiología , Bulbo Raquídeo/fisiología , Neuronas/fisiología , Esfuerzo Físico/fisiología , Factores de Transcripción/metabolismo , Animales , Análisis de los Gases de la Sangre , Ácido Láctico/sangre , Masculino , Vías Nerviosas/fisiología , Trazadores del Tracto Neuronal , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , EstilbamidinasRESUMEN
During exercise, intense brain activity orchestrates an increase in muscle tension. Additionally, there is an increase in cardiac output and ventilation to compensate the increased metabolic demand of muscle activity and to facilitate the removal of CO(2) from and the delivery of O(2) to tissues. Here we tested the hypothesis that a subset of pontomedullary and hypothalamic neurons could be activated during dynamic acute exercise. Male Wistar rats (250-350 g) were divided into an exercise group (n=12) that ran on a treadmill and a no-exercise group (n=7). Immunohistochemistry of pontomedullary and hypothalamic sections to identify activation (c-Fos expression) of cardiorespiratory areas showed that the no-exercise rats exhibited minimal Fos expression. In contrast, there was intense activation of the nucleus of the solitary tract, the ventrolateral medulla (including the presumed central chemoreceptor neurons in the retrotrapezoid/parafacial region), the lateral parabrachial nucleus, the Kölliker-Fuse region, the perifornical region, which includes the perifornical area and the lateral hypothalamus, the dorsal medial hypothalamus, and the paraventricular nucleus of the hypothalamus after running exercise. Additionally, we observed Fos immunoreactivity in catecholaminergic neurons within the ventrolateral medulla (C1 region) without Fos expression in the A2, A5 and A7 neurons. In summary, we show for the first time that after acute exercise there is an intense activation of brain areas crucial for cardiorespiratory control. Possible involvement of the central command mechanism should be considered. Our results suggest whole brain-specific mobilization to correct and compensate the homeostatic changes produced by acute exercise.