NMDA receptor-mediated modulation of ventilation in obese Zucker rats

Lee, Shin-Da; Nakano, Hitoo; Farkas, G

doi:10.1038/sj.ijo.0801663

Cited by 14 publications

(26 citation statements)

References 29 publications

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“…The obese Zucker rat, a genetic model of morbid obesity, presents many of the same metabolic and cardiopulmonary deficits as noted in obese humans, including increased risks of type 2 diabetes mellitus, 1 hypertension, 2 respiratory dysfunction, [3][4][5] upper airway narrowing 6 and poor exercise capacity. 7,8 Various factors, such as insulin resistance, nocturnal hypoxia, hypertension and poor exercise capacity, often observed in the obesity, may directly or indirectly contribute to the excessive rates of cardiovascular diseases and vascular dysfunctions.…”

Section: Introductionmentioning

confidence: 99%

Altered insulin-mediated and insulin-like growth factor-1-mediated vasorelaxation in aortas of obese Zucker rats

2006

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Objective: Insulin and insulin-like growth factor-1 (IGF-1) have vasorelaxant effects in vivo, which is dependent on nitric oxide (NO) production. The aim of this study was to investigate the vasorelaxant responses mediated by insulin and/or IGF-1 in aortas of obese Zucker rats. Methods: The thoracic aortas of eight lean and eight obese Zucker rats (6 months old) were isolated for vasorelaxation analysis. Insulin-induced and IGF-1-induced vasorelaxant responses were evaluated by the isometric tension of aortic rings in the organ bathes. The roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS) in vasorelaxant responses were examined by treating selective inhibitors, such as wortmannin (an inhibitor of PI3K) and N o -nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). In addition, the vascular responses to sodium nitroprusside (SNP), a direct vasodilator of vascular smooth muscle, were examined. Results: The insulin-induced vasorelaxation in aortas of obese rats was significantly decreased, whereas the IGF-1-induced vasorelaxation was significantly increased, compared with that in lean rats. After the pre-administration of wortmannin or L-NAME, the altered insulin-induced or IGF-1-induced vasorelaxation was abolished. There was no significant difference in the SNP-induced vasorelaxation between lean and obese rats. Conclusion: Our findings suggested that the decreased insulin-mediated vasorelaxation in obese rats appeared to be counteracted by the increased IGF-1-mediated vasorelaxation. Furthermore, the NO-dependent pathway was involved in the altered vasorelaxant responses. However, the SNP-induced vasorelaxation was not changed in obese rats.

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Section: Introductionmentioning

confidence: 99%

Altered insulin-mediated and insulin-like growth factor-1-mediated vasorelaxation in aortas of obese Zucker rats

2006

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“…[27][28][29] Studies have found that the NMDA and NO modulation processes of chemoreceptor reflexes are impaired in obese Zucker rats 15,26 and the chemoreceptor reflex control interacts with baroreflex. 30 A previous study showed that the gain of the baroreflex-mediated bradycardia is reduced by the microinjection of NMDA receptor antagonists into the nucleus tractus solitarii.…”

Section: Discussionmentioning

confidence: 99%

“…9 The underlying mechanism of baroreflex attenuation in obesity is not yet well known; however, there is increasing evidence that it is at least partly related to autonomic nervous system dysfunction and particularly to the sympathetic overactivity that accompanies obesity. 10 The obese Zucker rat, a genetic model of morbid obesity, presents many of the same deficits as those noted in obese humans, including hypertension, 11 cardiac remodeling, 12 impaired baroreflex, 13 impaired chemoresponse [14][15][16] and poor exercise capacity. [17][18] Enhanced central sympathetic discharge, abnormal hemodynamics and attenuated BRS were found in obese Zucker rats.…”

Section: Introductionmentioning

confidence: 99%

“…13 Our previous studies indicate that altered glutamatergic mechanisms exerting an effect on NMDA receptors, as well as nitroxidergic mechanisms, are partially responsible for blunted chemoresponses in obese Zucker rats. 15,26 Whether the abnormal BRS observed in obese Zucker rats is associated with altered NMDA receptor-mediated modulation and/or nitroxidergic modulation has not been previously studied. We hypothesized that the altered BRS in obese Zucker rats is mediated by altered glutamatergic NMDA and nitroxidergic modulation.…”

Section: Introductionmentioning

confidence: 99%

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Altered nitroxidergic and NMDA receptor-mediated modulation of baroreflex-mediated heart rate in obese Zucker rats

et al. 2010

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Arterial baroreflex, an important physiological regulatory system for buffering systemic blood pressure, is impaired in obesity. This study investigated whether the blunted baroreflex function in obesity is attributed to the altered nitroxidergic or N-methyl-Daspartate (NMDA) mechanism. Baroreflex bradycardia responses, blood pressure and heart rate in 30 lean and 30 obese anesthetized Zucker rats (8-12 weeks of age) were assessed after injecting phenylephrine with intravenous preadministration of saline (control), dextromethorphan (DXM, NMDA receptor antagonist, 10 mg kg À1 ) or N(G)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 100 mg kg À1 ). Compared with lean rats (À2.00 ± 0.29 b.p.m. mm Hg À1 ), the baroreflex sensitivity (BRS) in obese rats (-0.43±0.05 b.p.m. mm Hg À1 ) was significantly blunted. The BRS was significantly suppressed by DXM in lean rats but not in obese rats. After administration of L-NAME, BRS was significantly suppressed in lean Zucker rats but not in obese Zucker rats. The normal BRS was significantly suppressed in lean rats after administration of both DXM and L-NAME, and the blunted BRS in obesity was significantly blocked to nearly no BRS after administration of both DXM and L-NAME. This study suggests that BRS is blunted in obese rats and that blunted baroreflex is, at least in part, attributed to altered nitroxidergic or NMDA receptor-mediated modulation.

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“…1,2 The obese Zucker rat, a model of morbid obesity, presents many of the same respiratory deficits as noted in morbidly obese humans, 3,4 including abnormal respiratory control mechanisms. [5][6][7] The underlying mechanisms responsible for these abnormal ventilatory responses in obesity are still unclear, but are related to altered neuromodulation, which have been reported in obese Zucker rats from our previous studies. [5][6][7][8][9][10] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS) and acts at approximately 25-40% of the synapses within the CNS.…”

Section: Introductionmentioning

confidence: 91%

GABAergic modulation of ventilatory response to acute and sustained hypoxia in obese Zucker rats

Lin

Huang

et al. 2004

Int J Obes

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OBJECTIVE:To determine whether altered central and/or peripheral gamma-aminobutyric acid (GABA)ergic mechanisms acting in GABA A receptors contribute to the abnormal ventilatory response to acute and sustained hypoxia in obese Zucker rats. METHODS: In all, 10 lean and 10 obese Zucker rats were studied at 12 weeks of age. Ventilation ( . V E ), tidal volume (V T ), and breathing frequency (f) during room air breathing and in response to sustained (30 min) hypoxic (10% O 2 ) challenges were measured on three separate occasions by the barometric method following the randomized blinded administration of equal volumes of DMSO (vehicle), bicuculline methiodide (B M , 1 mg/kg, peripheral GABA A receptor antagonist), or bicuculline hydrochloride (B HCl , 1 mg/kg, peripheral and central GABA A receptor antagonist). RESULTS: Administration of B M and B HCl in lean animals had no effect on ventilation either during room air breathing or 30 min of sustained exposure to hypoxia. Similarly, B M failed to alter ventilation in obese rats. In contrast, B HCl significantly (Po0.05) increased. V E and V T during room air breathing and 10-30 min of hypoxic exposure in obese rats. During 5 min of acute hypoxic exposure, V T remained elevated with B HCl in obese rats, but the . V E appeared not to be increased with B HCl due to a decrease in f. CONCLUSION: Thus, endogenous GABA modulates both ventilation during room air breathing and ventilatory response to sustained hypoxia in obese, not in lean, Zucker rats by acting specifically on GABA A receptors located within the central, not peripheral, nervous system. However, endogenous GABA does not modulate ventilation but the pattern of breathing during acute hypoxia in obesity in a different manner from that during sustained hypoxia.

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NMDA receptor-mediated modulation of ventilation in obese Zucker rats

Cited by 14 publications

References 29 publications

Altered insulin-mediated and insulin-like growth factor-1-mediated vasorelaxation in aortas of obese Zucker rats

Altered insulin-mediated and insulin-like growth factor-1-mediated vasorelaxation in aortas of obese Zucker rats

Altered nitroxidergic and NMDA receptor-mediated modulation of baroreflex-mediated heart rate in obese Zucker rats

GABAergic modulation of ventilatory response to acute and sustained hypoxia in obese Zucker rats

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