Endogenous Opioids Modulate Ventilation and Peak  Oxygen Consumption in Obese Zucker Rats

Lee, Shin-Da; Nakano, Hitoo; Gosselin, Luc E.; Krasney, J. A.; Schlenker, Evelyn H.; Farkas, G

doi:10.1164/ajrccm.162.3.9909058

Cited by 19 publications

(34 citation statements)

References 33 publications

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“…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. [9][10][11][12] Abnormalities in vascular functions have been described in obese animals and obese humans such as increased risks of atherosclerosis, endothelial abnormalities, altered vascular inflammatory markers, altered vascular contractile properties, and the imbalance of vasodilators and vasoconstrictors.…”

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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“…13,24 Resting ventilation In the present study, baseline (saline) ventilatory and metabolic variables (Table 1) for both lean and obese rats were within the range of previously published values. 5,18 The primary purpose of the current study, however, was to assess the role of NMDA receptors in modulating ventilation. Thus, lean and obese rats were used as their own control such that weight differences between both phenotypes cannot account for our ®nding in NMDA receptor-mediated modulation.…”

Section: Discussionmentioning

confidence: 99%

“…5,18 A cylindrical plexiglas chamber with a volume of 4 l was used for the measurement of breathing pattern. The rat was placed in the chamber within a restrainer, which did not allow backward rotation.…”

Section: Pulmonary Ventilationmentioning

confidence: 99%

NMDA receptor-mediated modulation of ventilation in obese Zucker rats

2001

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BACKGROUND: Ventilation in response to hypoxia is reduced in some obese humans and is believed to represent part of the pathogenesis of obesity hypoventilation syndrome (OHS). Ventilation in response to hypoxic exposure is closely related to the release of excitatory neurotransmitters, in particular glutamate, acting speci®cally on N-methyl-D-aspartate (NMDA) receptors. OBJECTIVES: The aim of the present study was to investigate whether NMDA receptor-mediated mechanisms are responsible for the altered ventilatory response to sustained hypoxia observed in obese Zucker (Z) rats. SUBJECTS: Seven lean and seven 15-week-old obese male Z rats were studied. MEASUREMENTS: Ventilation (V Ç E ) at rest and during 30 min sustained hypoxic (10% O 2 ) exposure was measured by the barometric method. V Ç E was assessed following the blinded-random administration of equal volumes of either saline (vehicle) or dextromethorphan (DM, 10 mgakg), a non-competitive glutamate NMDA receptor antagonist. RESULTS: DM had no effects on resting V Ç E in both lean and obese rats during room air breathing. Lean rats treated with DM exhibited a signi®cant (P`0.05) depression in V Ç E , V T , and V T aT I during either the early (5 min) or the late phase (30 min) of ventilatory response to sustained hypoxia. In contrast, DM administration in obese rats did not change V Ç E , V T , or V T aT I during the early phase of ventilatory response to hypoxia. During the late phase of ventilatory response to hypoxia. obese rats treated with DM exhibited a similar depression in V Ç E and V T as observed in lean rats, but had no signi®cant change in V T aT I during the 30 min hypoxic exposure. CONCLUSION: Our ®ndings indicate that altered glutamatergic mechanisms acting on NMDA receptors are partially responsible for a blunted early phase of ventilatory response to hypoxia noted in obese rats and also contribute to their reduced neural respiratory drive.

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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: 92%

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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Endogenous Opioids Modulate Ventilation and Peak Oxygen Consumption in Obese Zucker Rats

Cited by 19 publications

References 33 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

NMDA receptor-mediated modulation of ventilation in obese Zucker rats

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

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