Search

New Findings What is the central question of this study? Intermittent hypercapnia is a concomitant feature of breathing disorders. Hypercapnic stimuli evoke a form of respiratory plasticity known as phrenic long-term depression in experimental animals. This study was performed to investigate the putative role of serotonin receptors in the initiation of phrenic long-term depression in anaesthetized rats., What is the main finding and its importance? Phrenic nerve long-term depression was revealed in animals pretreated with the serotonin broad-spectrum antagonist, methysergide. This study highlights that serotonin receptors modulate respiratory plasticity evoked by acute intermittent hypercapnia in anaesthetized rats., This study was performed to test the hypothesis that intermittent hypercapnia can evoke a form of respiratory plasticity known as long-term depression of the phrenic nerve (pLTD) and that 5-HT receptors play a role in the initiation of pLTD. Adult male urethane-anaesthetized, vagotomized, paralysed, mechanically ventilated Sprague-Dawley rats were exposed to an acute intermittent hypercapnia protocol. One group received i.v. injection of the non-selective 5-HT receptor antagonist methysergide and another group received i.v. injection of the selective 5-HT1A receptor antagonist WAY-100635 20 min before exposure to intermittent hypercapnia. A control group received i.v. injection of saline. Peak phrenic nerve activity and respiratory rhythm parameters were analysed at baseline (T0), during each of five hypercapnic episodes, and 15, 30 and 60 min (T60) after the last hypercapnia. Intravenous injection of methysergide before exposure to acute intermittent hypercapnia induced development of amplitude pLTD at T60 (decreased by 46.1 ± 6.9%, P = 0.003). Conversely, in control and WAY-100635-pretreated animals, exposure to acute intermittent hypercapnia did not evoke amplitude pLTD. However, a long-term decrease in phrenic nerve frequency was evoked both in control (42 ± 4 breaths min−1 at T0 versus 32 ± 5 breaths min−1 at T60; P = 0.036) and in methysergide-pretreated animals (42 ± 2 breaths min−1 at T0 versus 32 ± 3 breaths min−1 at T60; P = 0.028). In WAY-100635 pretreated animals, frequency pLTD was prevented. These results suggest that 5-HT receptors modulate respiratory plasticity induced by acute intermittent hypercapnia in anaesthetized rats. [ABSTRACT FROM AUTHOR]

Summary Obstructive sleep apnoea (OSA) is characterized by periods of upper airway collapse accompanied by repeated episodes of hypoxia. In experimental animals repeated bouts of hypoxia may evoke sustained augmentation of phrenic nerve activity, known as phrenic long-term facilitation (pLTF). This form of physiological compensation might contribute to stable breathing, minimizing the occurrence of apnoeas and/or hypopnoeas during sleep in patients with OSA. Serotonin (5-HT) has been shown to modulate respiratory neuronal activity, possibly via projections originating in the raphe nuclei. Our model focuses on the effects of 5-HT1A receptors blockade by selective antagonist WAY-100635 into the caudal raphe region on phrenic long-term facilitation after exposure to acute intermittent hypoxia (AIH) episodes. Adult, male, urethane-anaesthetized, vagotomized, paralyzed and mechanically ventilated Sprague-Dawley rats were exposed to AIH protocol. Experimental group received microinjection of WAY-100635 into the caudal raphe nucleus, whereas the control group received saline into the same site. Peak phrenic nerve activity and respiratory rhythm parameters were analysed during five hypoxic episodes, as well as at 15, 30 and 60 min after the end of hypoxias. In the control group, 1 h post-hypoxia pLTF was developed. Microinjections of selective 5-HT1A receptor antagonist WAY-100635 into the raphe nuclei prior to the AIH protocol prevented induction of pLTF. These results suggest that 5-HT1A receptor activation at supraspinal level is important for induction of pLTF, which is suggested to be an important respiratory neuroplasticity model in animal studies that possibly correlates with OSA in humans. [ABSTRACT FROM AUTHOR]

Abstract: The aim was to investigate the role of 5-HT1A receptor activation in induction and preservation of phrenic long-term facilitation (pLTF) at two different time points, before exposures to episodic hypoxia and after pLTF was induced. Adult, male, urethane anesthetized, vagotomized, paralyzed, and mechanically ventilated Sprague–Dawley rats were exposed to an acute intermittent hypoxia (AIH) protocol. Experimental groups of animals received an intravenous injection of WAY-100635, before the onset of the first hypoxic stimulus (WAY0), and after pLTF was induced (WAY60). Peak phrenic nerve activity (pPNA), burst frequency (f), and respiratory rhythm parameters were analyzed during the five hypoxic exposures (TH1-5), as well as at 15min (T15), 30min (T30), and 60min (T60) after the end of the last hypoxic episode. In the control group, pPNA was elevated from baseline (121.6±7.3%, P <0.001) at 60min after episodic hypoxia indicating pLTF. Administration of WAY-100635 prior to hypoxic stimulation prevented the induction of pLTF. Additionally, administration of WAY-100635 after pLTF developed impaired preservation of pLTF. In conclusion, there is an important role for 5-HT1A receptors in induction as well as in preservation of pLTF in urethane anesthetized rats. [Copyright &y& Elsevier]

Exposure to acute intermittent hypoxia (AIH) evokes persistent increase in respiratory activity that lasts up to 60 min after hypoxic episodes have ceased. This persistent increase in phrenic nerve activity (PNA) is known as phrenic long-term facilitation (LTF). AIH-induced phrenic LTF in anesthetized rats is serotonin dependant. The present study was performed to determine whether microinjection of methysergide (4 mM, 20 ± 5 nl), a broad spectrum 5-HT receptor antagonist, into the caudal raphe nuclei influences phrenic LTF. Peak integrated PNA and respiratory frequency were recorded at 15, 30, and 60 min after five 3-min episodes of normocapnic hypoxia in urethane-anesthetized, vagotomized, paralyzed and ventilated male Sprague–Dawley rats. In control animals, phrenic nerve amplitude was elevated 66.7 ± 8.6% from baseline 1 h after episodic hypoxia, indicating phrenic LTF. Experimental microinjections of methysergide prior to AIH exposure attenuated phrenic LTF (amplitude increase 2.62 ± 2.9% over baseline). We conclude that methysergide microinjections into the caudal raphe region attenuated phrenic LTF induced by AIH, indicating involvement of 5-HT receptor activation at a supraspinal level. [ABSTRACT FROM AUTHOR]

Highlights: [•] Phrenic long-term facilitation (pLTF) is a form of respiratory neuroplasticity. [•] Amplitude pLTF is seen as prolonged increase in peak phrenic nerve activity after episodes of acute intermittent hypoxia. [•] The effects of sevoflurane and isoflurane monoanesthesia on amplitude pLTF were tested on Sprague-Dawley rats. [•] In the control group pLTF was induced at 60min after the last hypoxic episode compared to baseline values. [•] Amplitude pLTF was abolished during both sevoflurane and isoflurane monoanesthesia. [Copyright &y& Elsevier]