Geração de expiração ativa : mecanismos centrais e implicações nas alterações cardiorrespiratórias associadas à hipóxia intermitente
Lemes, Eduardo Vieira
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The exposure to periods of hypoxemia and reoxygenation, as observed in patients with obstructive sleep apnea (OSA), promotes compensatory increases in ventilation, sympathetic activity and blood pressure (BP), by mechanisms not fully understood. In the present study, we investigated the central mechanisms responsible for the cardiorespiratory changes induced by acute intermittent hypoxia (AIH; 10 episodes of 6-7% O2 for 45 sec, every 5 min hyperoxia) either in adult male rats (270-280 g) anesthetized with urethane (1.2 g / kg, ip) or in in situ working heart-brainstem preparations of juvenile male rats (65-75 g). In in situ preparations, the AIH promoted long-term facilitation (LTF), of at least 1 hour, in the phrenic nerve (PN), abdominal (AbN) and thoracic sympathetic (tSN) activities (n=9, P<0.05). In these animals, we observed that the increase in tSN activity induced by AIH occurred during the late part of expiratory period, namely late-expiratory (late-E) phase, coupled with the emergence of late-E bursts in AbN activity. Considering studies showing the role of serotonin (5-HT) as the mediator of cardiorespiratory changes elicited by AIH, we verified that ketanserin (5-HT2 antagonist) microinjections in the RTN/pFRG in anesthetized rats, during AIH exposure, prevented the increase in abdominal motor activity (ABD) evoked by AIH (n=5, P<0.05), indicating the involvement of 5-HT2 receptor of RTN/pFRG in the generation of active expiration induced by AIH. We also showed that repeated activation of 5-HT2 receptors (3x every 5 min) in the RTN/pFRG of in situ preparation, using DOI, promoted LTF of the PN, AbN and tSN activities (n=9, P<0.05). Interestingly, the increase in the late-E AbN activity induced by DOI in the RTN/pFRG was critical for the development of sympathetic overactivity during late-E phase (n=9, P<0.05), similarly to the pattern observed in in situ preparations subjected to AIH. Microinjections of vehicle in the RTN/pFRG did not change PN, AbN and tSN activities. The increase in respiratory and sympathetic activities promoted by DOI microinjection in the RTN/pFRG was associated to sensitization/facilitation of CO2- drive to breath, since the exposure to hypocapnia eliminated the respiratory activity in control in situ preparation, but not in preparation that received DOI into the RTN/pFRG (n=9, P<0.05). Furthermore, we verified that the DOI-induced sensitization in the RTN/pFRG, which was determinant for the development of respiratory and sympathetic LTF, also depended on glutamatergic neurotransmission in the RTN/pFRG (n=9, P<0.05), because microinjections of kynurenic acid (glutamate receptor antagonist) were able to eliminate the respiratory and sympathetic LTF. Indeed, we found that glutamatergic neurotransmission of the RTN/pFRG is essential for the generation of active expiration, since kynurenic microinjections in the RTN/pFRFG of control in situ preparations abolished the late-E bursts in AbN and tSN induced by hypercapnia. Altogether, our data indicate that interactions between serotonergic and glutamatergic mechanisms in the RTN/pFRG is an essential mechanism for the occurrence of active expiration and late-E sympathetic overactivity after AIH exposure. Moreover, our findings suggest that the activation of 5-HT2 receptors in the RTN/pFRG modulates the excitation of central chemoreceptors of this area, through sensitization/facilitation of glutamatergic mechanisms.