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β-Noradrenergic receptor activation specifically modulates the generation of sighs in vivo and in vitro.

Viemari JC, Garcia AJ, Doi A, Elsen G, Ramirez JM - Front Neural Circuits (2013)

Bottom Line: By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected.Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR.Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response.

View Article: PubMed Central - PubMed

Affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR 7289, CNRS, Aix Marseille Univesité , Marseille, France.

ABSTRACT
The pre-Bötzinger complex (preBötC), an area that is critical for generating breathing (eupnea), gasps and sighs is continuously modulated by catecholamines. These amines and the generation of sighs have also been implicated in the regulation of arousal. Here we studied the catecholaminergic modulation of sighs not only in anesthetized freely breathing mice (in vivo), but also in medullary slice preparations that contain the preBötC and that generate fictive eupneic and sigh rhythms in vitro. We demonstrate that activating β-noradrenergic receptors (β-NR) specifically increases the frequency of sighs, while eupnea remains unaffected both in vitro and in vivo. β-NR activation specifically increased the frequency of intrinsically bursting pacemaker neurons that rely on persistent sodium current (I(Nap)). By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected. Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR. Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response. The β-NR action on the preBötC may be an important mechanism in modulating behaviors that are specifically associated with sighs, such as the regulation of the early events leading to the arousal response.

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Activation of β-NR modulates fictive sigh. (A) ∫VRG activity recorded from a slice under control conditions. (B) Isoproterenol 20 μM (β-NR agonist) activates β-NR and increases specifically the frequency of sigh activity. (C–F) Histograms show the effects of isoproterenol on sigh burst frequency (E) without affecting respiratory activity (C), sigh burst amplitude (D), or the sigh burst area (F) (*p < 0.05, n = 10).
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Figure 4: Activation of β-NR modulates fictive sigh. (A) ∫VRG activity recorded from a slice under control conditions. (B) Isoproterenol 20 μM (β-NR agonist) activates β-NR and increases specifically the frequency of sigh activity. (C–F) Histograms show the effects of isoproterenol on sigh burst frequency (E) without affecting respiratory activity (C), sigh burst amplitude (D), or the sigh burst area (F) (*p < 0.05, n = 10).

Mentions: We previously reported that NE plays a major role in modulating respiratory rhythmogenesis (Viemari et al., 2004; Viemari, 2008). As illustrated in Figure 3A, NE enhanced the frequency of fictive inspiratory activity, but also sigh like activity (670 ± 120%, n = 7, P < 0.001, Friedman test). Application of the α1-NR antagonist prazosin (50 μM) prior to the NE application had no effect on baseline eupnea as previously reported (Viemari and Ramirez, 2006) and on baseline sigh like frequency. Moreover, prazosin did not affect the NE-mediated increase in sigh frequency (745 ± 270%, n = 4, Friedman test, Figures 3B,C) and duration (Figure 3D) suggesting that the NE-induced increase in sigh activity frequency was not mediated by α1-NRs. Similarly, application of the α2-NR antagonist yohimbine did not block the sigh-increasing effect of NE as sigh frequency was still increased (n = 3, data not shown). Application of the β-NR agonist isoproterenol (20 μM) significantly increased the fictive sigh frequency by 400 ± 65% (n = 10, P = 0.0022, Wilcoxon rank test, Figures 4A,B,E) without affecting the fictive eupnea frequency (P = 0.94, Figure 4C), the sigh amplitude (P = 0.28, Wilcoxon rank test, Figure 4D) or the sigh duration (P = 0.62, Wilcoxon rank test, Figure 4F). Similarly, the duration of the fictive post-sigh apnea was not different in the presence of isoproterenol (5.9 ± 0.07 s vs. 6.1 ± 0.1 s, n = 12, P = 0.63, Wilcoxon rank test). Application of the β-NR antagonist propranolol (50 μM, n = 4.4) prior to applying isoproterenol blocked the effect on fictive sighs, confirming that the modulation of sigh frequency involved specifically the activation of the β-NR (data not shown). From these results we conclude that β-NR preferentially modulate the fictive sigh rhythm.


β-Noradrenergic receptor activation specifically modulates the generation of sighs in vivo and in vitro.

Viemari JC, Garcia AJ, Doi A, Elsen G, Ramirez JM - Front Neural Circuits (2013)

Activation of β-NR modulates fictive sigh. (A) ∫VRG activity recorded from a slice under control conditions. (B) Isoproterenol 20 μM (β-NR agonist) activates β-NR and increases specifically the frequency of sigh activity. (C–F) Histograms show the effects of isoproterenol on sigh burst frequency (E) without affecting respiratory activity (C), sigh burst amplitude (D), or the sigh burst area (F) (*p < 0.05, n = 10).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824105&req=5

Figure 4: Activation of β-NR modulates fictive sigh. (A) ∫VRG activity recorded from a slice under control conditions. (B) Isoproterenol 20 μM (β-NR agonist) activates β-NR and increases specifically the frequency of sigh activity. (C–F) Histograms show the effects of isoproterenol on sigh burst frequency (E) without affecting respiratory activity (C), sigh burst amplitude (D), or the sigh burst area (F) (*p < 0.05, n = 10).
Mentions: We previously reported that NE plays a major role in modulating respiratory rhythmogenesis (Viemari et al., 2004; Viemari, 2008). As illustrated in Figure 3A, NE enhanced the frequency of fictive inspiratory activity, but also sigh like activity (670 ± 120%, n = 7, P < 0.001, Friedman test). Application of the α1-NR antagonist prazosin (50 μM) prior to the NE application had no effect on baseline eupnea as previously reported (Viemari and Ramirez, 2006) and on baseline sigh like frequency. Moreover, prazosin did not affect the NE-mediated increase in sigh frequency (745 ± 270%, n = 4, Friedman test, Figures 3B,C) and duration (Figure 3D) suggesting that the NE-induced increase in sigh activity frequency was not mediated by α1-NRs. Similarly, application of the α2-NR antagonist yohimbine did not block the sigh-increasing effect of NE as sigh frequency was still increased (n = 3, data not shown). Application of the β-NR agonist isoproterenol (20 μM) significantly increased the fictive sigh frequency by 400 ± 65% (n = 10, P = 0.0022, Wilcoxon rank test, Figures 4A,B,E) without affecting the fictive eupnea frequency (P = 0.94, Figure 4C), the sigh amplitude (P = 0.28, Wilcoxon rank test, Figure 4D) or the sigh duration (P = 0.62, Wilcoxon rank test, Figure 4F). Similarly, the duration of the fictive post-sigh apnea was not different in the presence of isoproterenol (5.9 ± 0.07 s vs. 6.1 ± 0.1 s, n = 12, P = 0.63, Wilcoxon rank test). Application of the β-NR antagonist propranolol (50 μM, n = 4.4) prior to applying isoproterenol blocked the effect on fictive sighs, confirming that the modulation of sigh frequency involved specifically the activation of the β-NR (data not shown). From these results we conclude that β-NR preferentially modulate the fictive sigh rhythm.

Bottom Line: By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected.Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR.Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response.

View Article: PubMed Central - PubMed

Affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR 7289, CNRS, Aix Marseille Univesité , Marseille, France.

ABSTRACT
The pre-Bötzinger complex (preBötC), an area that is critical for generating breathing (eupnea), gasps and sighs is continuously modulated by catecholamines. These amines and the generation of sighs have also been implicated in the regulation of arousal. Here we studied the catecholaminergic modulation of sighs not only in anesthetized freely breathing mice (in vivo), but also in medullary slice preparations that contain the preBötC and that generate fictive eupneic and sigh rhythms in vitro. We demonstrate that activating β-noradrenergic receptors (β-NR) specifically increases the frequency of sighs, while eupnea remains unaffected both in vitro and in vivo. β-NR activation specifically increased the frequency of intrinsically bursting pacemaker neurons that rely on persistent sodium current (I(Nap)). By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected. Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR. Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response. The β-NR action on the preBötC may be an important mechanism in modulating behaviors that are specifically associated with sighs, such as the regulation of the early events leading to the arousal response.

Show MeSH
Related in: MedlinePlus