GABAergic Modulation - 糖尿病鼠在缺氧和高二氧化碳下GABA 和NMDA受體對呼吸反應的調節; GABAergic and NMDA-mediated modulati

During the acute and late phase of the ventilatory response to hypoxia, non-DM rats injected with either control values or bicuculline had no change in any of the various parameters (f, VT , VE, Ti, Te, VT / Ti, PIF, PEF and EF50 ) (Table 2, Table 3, Fig 2). In contrast, during room air breathing, DM rats injected with either control values or bicuculline had no change in any of the various parameters (f, V_T , V_E, T_i, T_e, V_T / T_i,PIF, PEF and EF50 ) (Table 1, Fig 2). In contrast, DM rats exhibited an increased ventilation (V_E), frequence (f) and mean inspiratory flow (V_T/ T_i) following bicuculline administration in acute hypoxic exposure(Table 2, Fig 2). During the late phase of the ventilatory response to hypoxia, DM rats injected with either control values or bicuculline had no change in any of the various parameters (f, V_T , V_E, T_i, T_e, V_T / T_i,PIF, PEF and EF50 ) (Table 3, Fig 2). GABAergic modulation in hypercapnia, DM and non-DM rats injected with either control values or bicuculline had no change in any of the various parameters (f, VT , VE, Ti, Te, VT / Ti, PIF, PEF and EF50 ) (Table 4, Table 5, Table 6, Fig 4).

18 4.4.3 NMDA Modulation

During the acute and late phase of the ventilatory response to hypoxia, non-DM rats injected with either control values or dextromethorphan had no change in any of the various parameters (f, VT

and VE) (Table 8, Table 9, Fig 6). In contrast, during room air breathing, DM rats injected with either control values or dextromethorphan had no change in any of the various parameters (f, VT , VE, Ti, Te, V_T / T_i,PIF, PEF and EF50 ) (Table 8, Table 9, Fig 8). In contrast, during acute hypoxic breathing, DM rats injected with either control values or bicuculline had no change in any of the various parameters (f, VT , VE, Ti, Te, VT / Ti, PIF, PEF and EF50 ). During the late phase of the ventilatory response to hypoxia, DM rats injected with either control values or dextromethorphan had no change in any of the various parameters (f, VT , VE, Ti, Te, VT / Ti, PIF, PEF and EF50 ) (Table8, Table9, Fig 6).

NMDA modulation in hypercapnia DM and non-DM R rats injected with either control values or bicuculline had no change in any of the various parameters (f, VT , VE, Ti, Te, VT / Ti, PIF, PEF and EF50 ) (Fig 6, Table 2).

C h a p t e r 5 Discussion

20 5.5 DISCUSSION

Our major findings:

Our major findings can be summarized as follows:

Part 1: 1) Antagonism of GABA_A receptors does not change ventilation at rest or during ventilatory challenges in non-DM Wistar rats; 2) Breathing at rest in DM Wistar rats is modulated by endogenous GABA acting on GABAA receptors; 3) Ventilation during hypoxic, exposure is modulated by endogenous GABA acting on GABAA receptors in DM Wistar rats.

Part 2, 1) Dextromethorphan administration does not alter resting ventilation in Non-DM or DM rats; 2) During the early phase of hypoxic exposure, ventilation appears to does not modulated by NMDA receptors in Non-DM or DM rats; 3) Ventilation during late phase hypoxic, it is not exposure for modulated by NMDA receptor antagonism in DM Wistar rats.

GABA modulation of Ventilation in DM

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 (7). GABA can exert its effect via either ionotropic (GABA_A and GABA_C) receptors to produce fast synaptic inhibition, or metabotropic (GABAB) receptors to produce slow, prolonged inhibitory signals(8) . GABA may be involved as a neurotransmitter in the generation, the transmission, and the modulation of respiratory related neural activities (22-24, 28, 30). In the present study, bicuculline, a selective antagonist of GABA_A receptors, was chosen because previous studies have shown that GABA inhibits respiratory activity mainly via GABA_A receptors(22). In GABAergic neurons, GABA_A receptors facilitate Cl^- flux into neurons, resulting in hyperpolization, whereas antagonism of GABAA receptors by bicuculline will decrease Cl^- flux, resulting in depolarization and increased excitation (8, 28). Thus, any effect noted in the present study is restricted to a modulatory role exerted by endogenous GABA acting specifically on GABA_A receptors. GABA_A receptors are located throughout the neural axis and modulate

numerous systems. In the present study, bicuculline was injected systemically, which consequently produced a widespread antagonistic action. Thus, any effect noted herein cannot be localized to any specific system or brain region. The goal of the present study, however, was to determine whether GABAergic mechanisms regulate ventilationv at acute hypoxia in DM Wistar rats. Clearly, additional experiments using a reductionist approach will be required in order to specifically identify those brain areas that are directly responsible.

In non-DM rats, bicuculline administration did not alter resting ventilation, ventilation during hypoxic exposure. Indeed, in normal human subjects, increasing brain GABA concentration by vigabatrin administration, an agent which prevents the breakdown of GABA, had no effects on resting ventilation or on chemical ventilatory drive (17). Thus, consistent with the human literature, GABA does not exert a significant effect on the control of respiration in normal rats.

In contrast, bicuculline administration elevated resting ventilation, ventilation during hypoxic exposure in age-matched DM Wistar rats. Following 8 weeks of chronic artificial respiratory loading in rats, brain GABA levels are increased and responsible for depressing ventilation (44). Thus, the increased chest wall loading or the airway narrowing that is present in diabetes (15) may represent a possible stimulus responsible for the altered GABAergic mechanisms. In the present study, bicuculline administration significantly increased resting ventilation in DM rats, which was attributed to an increase in tidal volume and not breathing frequency. The selective effect on tidal volume is consistent with previous reports indicating that direct exogenous central administration of GABA or GABA_A receptor agonist produces a dose-dependent depression in respiratory amplitude with only minor effects noted on respiratory frequency (26, 30). During hypoxia, the respiratory drive is determined by a balance between the stimulation of peripheral chemoreceptors and the central depression of hypoxia on respiration (49). It has been postulated that the late phase of the ventilatory response to hypoxia is modulated by a variety of neurotransmitters, including GABA (28, 49). Brain GABA content is elevated during hypoxic(57) and hypercapnic exposures (25, 30). The rise in

ventilation following treatment with bicuculline during hypoxia is consistent with previous studies in either anesthetized cats (37), in sedated newborn piglets (26), or in anesthetized rats (49).

NMDA modulation of Ventilation in DM

Glutamate, an excitatory neurotransmitter, has an important role in the central mechanisms of respiratory control(28).The NMDA receptor family has been extensively studied due to their pivotal roles in regulating synaptic plasticity, learning, psychosis and cell death in various neuropathological conditions(10, 34, 39). NMDA receptors are ligand-gated ion channels, or ionotropic receptors, that allow the transmembrane flux of Na+, K+ and Ca++ ions after the binding of glutamate and glycine to their respective binding sites on the NMDA receptor complex. NMDA receptors exist as heteromeric tetramers and are thought to be most commonly composed of two NR1 subunits and two NR2 subunits(40).

In previous experiments, insulin was shown to significantly increase native NMDA receptor activity in rat hippocampus and recombinant receptors expressed in Xenopus oocytes (9, 35). This increase in activity is due to a rapid insulin-induced increase in the surface expression of NMDA receptors from intracellular pools (48). These observations suggest that in diabetes there may be a reduced cell surface expression of NMDA receptors. Such a reduced expression could underlie some of the adverse effects of diabetes in the CNS. Presently, using rats made diabetic by streptozotocin (STZ) administration, reduction of [³H]-AMPA binding varied in different brain structures, being more pronounced in the striatum, cerebral cortex, and hippocampus and almost absent in the cerebellum. It has reported that there is no effect on brain NMDA receptor levels when measured in horizontal sections of ventral brain by NMDA sensitive L-[³H]glutamate binding site autoradiography. The effect of STZ-induced diabetes appeared to be specific to the AMPA subtype of glutamate receptors, as the same treatment did not modify L-[³H]glutamate binding to NMDA receptors(19).

The primary purpose of the current study, however, was to assess the role of NMDA receptors in modulating ventilation. The non DM and DM rats were used as their own control such that weight differences between both phenotypes cannot account for our finding in NMDA receptor-mediated modulation. Dextromethorphan administration had no effects at rest in both non DM and DM rats.

No finding in NMDA modualtion of ventilatory response to hypoxia and hypercapnia. In under the hypoxia and hypercapnia environment, as if is comes from regarding the ventilatory response influence is the elsewhere function no by the NMDA modualtion means. Possibly is change NMDA receptors which causes of diabetes. But was about the reason not to be still clear.

Significance: When stay on acute hypoxia situation in general person have promptly responses to modulate avoid to dsmage. In the diabetes mellitus, they cannot promptly to modulated for hypoxia. That was to deepen on sleep apnea episode damage for apparatus. In the present study, humans and animals have demonstrated that intermittent hypoxia and reduced sleep duration due to sleep fragmentation, as occur in obstructive sleep apnea, exert adverse effects on glucose metabolism(27). Blunted ventilatory responses to acute hypoxia in diabetes mellitus appeared to be suppressed by endogenous GABA by acting specifically on GABA_A receptors. Altered GABAergic modulation of acute ventilatory response in diabetes might potentially impact sleep apnea episode (acute hypoxia) related ventilatory compensation.

Table and Figure

Table 1. Ventilatory parameters in non-DM and DM rats treated with vehicle or bicuculline on hypoxia resting time.

Hypoxia Non-DM rats DM rats

Body Weight, g 476.3969.23 387.6375.89

BG mg/dl 777.19 433.6990.30

Resting Vehicle Bicucuclline Vehicle Bicuculline

f, breaths/min 93.75±6.27 90.25±6.09 75.98±3.84 97.01±4.49 VT, ml 2.71±0.04 2.64±0.22 2.93±0.09 2.93±0.10

VE, ml/min 245.95±11.09 235.31±6.29 216.90±15.95 245.02±14.48

Ti, sec 0.25±0.01 0.23±0.00 0.32±0.00 0.28±0.00

Te, sec 0.46±0.03 0.50±0.03 0.52±0.02 0.49±0.00

PIF, ml/sec 18.13±0.81 18.23±1.07 14.62±0.57 17.88±1.16 PEF, ml/sec 13.43±0.22 12.83±0.42 12.71±1.60 16.81±0.74 EF50, ml/sec 0.73±0.07 0.64±0.02 0.67±0.14 0.76±0.05

VT /Ti 11.05±0.47 11.26±0.83 9.19±0.28 10.44±0.21

Non-DM rats = non- diabetes mellitus rats, DM rats = diabetes mellitus rats, BG = blood glucose, f = Frequency, TV

=Tidal Volume, VE=Minute Volume, Ti = Inspiratory Time, Te = Expiratory Time, PIF = Peak Inspiratory Flow, PEF = Peak Expiratory Flow, EF50 = The flow at the point 50% of TV is expired, VT /Ti = mean inspiratory flow. Values are means  SD (n=8). *P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05Non DM vehicle and bicuculline to compare have a significant difference. ＋P<0.05 DM vehicle and bicuculline to compare have a significant difference.

Table 2. Ventilatory parameters in non-DM and DM rats treated with vehicle or bicuculline on hypoxia 4 min.

Non-DM rats DM rats

Hypoxia 4 min Vehicle Bicucuclline Vehicle Bicuculline f, breaths/min 132.86±3.57 141.17±0.97 107.84±3.66 140.20±5.56

VT, ml 3.76±0.83 3.53±0.53 3.29±0.52 3.72±0.43^＋

VE, ml/min 469.84±116.80 470.95±64.04 335.51±74.04^* 464.69±73.21^＋ Ti, sec 0.19±0.00 0.19±0.00 0.26±0.00 0.21±0.00 Te, sec 0.35±0.05 0.31±0.03 0.38±0.05 0.30±0.05 PIF, ml/sec 29.55±4.47 28.67±2.22 19.52±2.34^* 28.86±0.94 PEF, ml/sec 27.49±5.91 24.56±3.09 17.38±3.49 24.54±2.75 EF50, ml/sec 1.69±0.43 1.62±0.15 1.14±0.29 1.59±0.27 VT /Ti 19.49±4.35 18.81±2.40 12.70±2.06^* 17.90±1.68^＋

*P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05Non DM vehicle and bicuculline to compare have a significant difference. ＋P<0.05 DM vehicle and bicuculline to compare have a significant difference.

Table 3. Ventilatory parameters in non-DM and DM rats treated with vehicle or bicuculline on hypoxia 30 min

Non-DM rats DM rats

Hypoxia 30 min Vehicle Bicucuclline Vehicle Bicuculline f, breaths/min 140.75±3.12 154.13±3.10 126.59±2.87 116.62±1.65 VT, ml 3.00±0.03 2.71±0.04 2.91±0.04 3.21±0.04 VE, ml/min 402.17±0.68 397.64±3.19 357.78±5.37 363.10±1.91 Ti, sec 0.19±0.00 0.17±0.00 0.21±0.00 0.21±0.00 Te, sec 0.27±0.01 0.25±0.01 0.30±0.01 0.33±0.01 PIF, ml/sec 22.51±0.34 22.00±0.12 19.43±0.06 20.80±0.11 PEF, ml/sec 20.41±0.18 21.36±0.06 16.83±0.14 17.79±0.55 EF50, ml/sec 1.31±0.02 1.26±0.03 1.15±0.04 1.09±0.02

VT /Ti 15.92±0.02 15.89±0.07 13.94±0.00 14.97±0.07

Table 4. Ventilatory parameters in non-DM and DM rats treated with vehicle or bicuculline on hypercapnic resting time.

Hypercapnic Non-DM rats DM rats

Resting Vehicle Bicucuclline Vehicle Bicuculline

f, breaths/min 83.36±5.40 89.24±1.45 66.05±2.31 71.28±11.09

VT, ml 2.93±0.20 2.41±0.04 2.84±0.01 3.10±0.02

VE, ml/min 251.00±46.50 205.74±1.92 183.65±5.38 225.07±42.63 Ti, sec 0.28±0.00 0.24±0.00 0.32±0.01 0.33±0.01 Te, sec 0.52±0.04 0.56±0.00 0.62±0.02 0.61±0.06 PIF, ml/sec 16.74±1.75 16.29±0.05 13.58±0.29 15.21±1.44 PEF, ml/sec 14.38±1.59 12.11±0.18 11.52±0.03 13.08±2.10 EF50, ml/sec 0.77±0.15 0.54±0.02 0.51±0.03 0.69±0.24

VT /Ti 10.41±0.77 9.99±0.04 9.99±0.04 9.45±0.42

Table 5. Ventilatory parameters in non-DM and DM rats treated with vehicle or bicuculline on hypercapnic 15 min.

Non-DM rats DM rats

Hypercapnic 15 min Vehicle Bicucuclline Vehicle Bicuculline f, breaths/min 132.74±2.58 146.95±3.00 120.69±0.40 127.42±0.48 VT, ml 5.06±0.05 4.44±0.10 4.63±0.08 4.90±0.05 VE, ml/min 660.84±14.53 637.29±1.16 551.48±8.19 625.97±4.87 Ti, sec 0.22±0.00 0.20±0.00 0.24±0.00 0.23±0.00 Te, sec 0.25±0.01 0.22±0.00 0.27±0.00 0.25±0.00 PIF, ml/sec 30.82±0.76 29.82±0.62 25.69±0.45 28.87±0.36 PEF, ml/sec 42.73±1.10 41.65±0.99 35.78±0.22 39.75±0.06 EF50, ml/sec 2.49±0.13 2.52±0.03 2.25±0.01 2.55±0.03

VT /Ti 22.65±0.59 21.69±0.05 21.69±0.05 20.90±0.09

*P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05Non DM vechicle and bicuculline to compare have a significant difference. ＋P<0.05 DM vechicle and bicuculline to compare have a significant difference.

Fig 1. DM and Non DM rats for hypoxia

Fig. 1. The ventilation(VE), tidal volume(TV), breathing frequency(f) and TV/Ti of non-DM (vacant circular) and DM (full circular) rats during room air and during 10% O2 hypoxic exposure(black bar). *p

＜0.05 indicates a significant difference from the value of vehicle at the same time-point. Values represent mean ± SDE.

Fig 2 Bicuculline and DMSO for hypoxia Non-DM DM

Fig. 2. The effects of vehicle (vacant circular) and bicuculline (full circular)administration on ventilation(VE), tidal volume(TV), breathing frequency(f) and TV/Ti of non-DM and DM rats during room air and during 10% O2 hypoxic exposure(black bar). *p＜0.05 indicates a significant difference from the value of vehicle, bicuculline, at the same time-point. Values represent mean ± SDE.

Fig.3 DM and Non DM rats for hypercapnic

Time(min)

Fig. 3. The ventilation(VE), tidal volume(TV), breathing frequency(f) and TV/Ti of non-DM (vacant circular) and DM (full circular) rats during room air and during 8% CO2 hypercapnic exposure(black bar). *p ＜0.05 indicates a significant difference from the value of vehicle, at the same time-point.

Values represent mean ± SDE.

Fig 4. Bicuculline and DMSO for hypercapnic Non-DM DM

Fig. 4. The effects of vehicle (vacant circular) and bicuculline (full circular)administration on ventilation(VE), tidal volume(TV), breathing frequency(f) and TV/Ti of non-DM and DM rats during room air and during 8% CO2 hypercapnic exposure(black bar). *p＜0.05 indicates a significant

difference from the value of vehicle, bicuculline, at the same time-point. Values represent mean ± SDE.

Table 6. Ventilatory parameters in non-DM and DM rats treated with vehicle or dextromethorphan on hypoxia resting time.

Non-DM rats DM rats

Body Weight, g 468.0742.00 339.9257.78

BG mg/dl 97.2914.82 421.71106.51

Resting Vehicle Dextromethorphan Vehicle Dextromethorphan f, breaths/min 81.29±1.50 92.09±1.80 82.80±9.37 90.60 ±8.98 VT, ml 2.81±0.04 2.64±0.08 2.63±0.03 2.71 ±0.02 VE, ml/min 224.01±7.11 245.17±10.01 207.90±22.99 230.51 ±17.64 Ti, sec 0.33±0.00 0.28±0.01 0.33±0.01 0.31±0.01 Te, sec 0.49±0.01 0.47±0.01 0.47±0.03 0.43±0.02 PIF, ml/sec 14.75±0.37 17.12±0.86 13.05±0.56 14.06±1.05 PEF, ml/sec 13.02± 0.50 13.27±0.43 11.46±1.46 12.49± 1.65 EF50, ml/sec 0.70±0.03 0.76±0.04 0.67±0.15 0.73±0.13 VT /Ti 8.62± 0.07 9.55±0.52 7.94±0.24 8.81±0.23

Non-DM rats = non- diabetes mellitus rats, DM rats = diabetes mellitus rats, BG = blood glucose, f = Frequency, TV

=Tidal Volume, VE=Minute Volume, Ti = Inspiratory Time, Te = Expiratory Time, PIF = Peak Inspiratory Flow, PEF = Peak Expiratory Flow, EF50 = The flow at the point 50% of TV is expired, VT /Ti = mean inspiratory flow. Values are means  SD (n=14). *P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05Non DM Saline and dextromethorphan to compare have a significant difference. ＋P<0.05 DM Saline and dextromethorphan to compare have a significant difference

Table 7. Ventilatory parameters in non-DM and DM rats treated with vehicle or dextromethorphan on hypoxia 4 min.

Non-DM rats DM rats

Hypoxia 4 min Vehicle Dextromethorphan Vehicle Dextromethorphan f, breaths/min 118.74±3.34 136.60 ±1.24 114.27±0.30 120.46±5.31 VT, ml 4.43±0.96 4.23 ±1.02 3.84±0.87 3.90±0.71 VE, ml/min 501.02±116.20 562.32± 104.51 409.32±90.71^* 441.30±101.93 Ti, sec 0.23 ±0.00 0.20±0.01 0.25±0.00 0.24± 0.02 Te, sec 0.37 ±0.05 0.31±0.02 0.35±0.03 0.32 ±0.04 PIF, ml/sec 31.59± 4.67 34.52±5.01 25.07±3.85^* 25.42± 4.87 PEF, ml/sec 26.30 ±7.17 29.65±6.88 22.11±6.20 22.15±5.25 EF50, ml/sec 1.67± 0.51 2.00±0.40 1.51±0.49 1.55±0.35 VT /Ti 19.32±4.43 21.13±4.02 15.47±3.54^* 16.48±4.23

Non-DM rats = non- diabetes mellitus rats, DM rats = diabetes mellitus rats, f = Frequency, TV =Tidal Volume, VE=Minute Volume, Ti = Inspiratory Time, Te = Expiratory Time, PIF = Peak Inspiratory Flow, PEF = Peak Expiratory Flow, EF50 = The flow at the point 50% of TV is expired, VT /Ti = mean inspiratory flow. Values are means  SD (n=14). *P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05Non DM Saline and dextromethorphan to compare have a significant difference. ＋P<0.05 DM Saline and dextromethorphan to compare have a significant difference.

Table 8. Ventilatory parameters in non-DM and DM rats treated with vehicle or dextromethorphan on hypoxia 30 min.

Non-DM rats DM rats

Hypoxia 30 min Vehicle Dextromethorphan Vehicle Dextromethorphan f, breaths/min 138.71± 3.70 123.20 ±1.18 120.92±2.16 129.17±0.27

VT, ml 3.01±0.08 3.30 ±0.09 2.91±0.01 3.15± 0.05 VE, ml/min 399.82 ±5.21 395.20± 5.57 340.50±4.63 379.70± 4.87 Ti, sec 0.19±0.01 0.20 ±0.00 0.22±0.00 0.21± 0.00 Te, sec 0.27±0.01 0.32 ±0.01 0.30±0.01 0.28 ±0.00 PIF, ml/sec 22.42± 0.11 23.38 ±0.43 18.41±0.12 20.25± 0.24 PEF, ml/sec 18.90±0.15 19.12± 0.21 16.08±0.49 16.94 ±0.31 EF50, ml/sec 1.38 ±0.03 1.14± 0.00 1.16±0.04 1.25 ±0.01 VT /Ti 15.79± 0.05 16.81± 0.45 13.01±0.00 14.78±0.14

Non-DM rats = non- diabetes mellitus rats, DM rats = diabetes mellitus rats, f = Frequency, TV =Tidal Volume, VE=Minute Volume, Ti = Inspiratory Time, Te = Expiratory Time, PIF = Peak Inspiratory Flow, PEF = Peak Expiratory Flow, EF50 = The flow at the point 50% of TV is expired, VT /Ti = mean inspiratory flow. Values are means  SD (n=14). *P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05 Non DM Saline and dextromethorphan to compare have a significant difference. ＋P<0.05 DM Saline and dextromethorphan to compare have a significant difference.

Table 9. Ventilatory parameters in non-DM and DM rats treated with vehicle or dextromethorphan on hypercapnic resting time.

Hypercapnic Non-DM rats DM rats

Resting Vehicle Dextromethorphan Vehicle Dextromethorphan f, breaths/min 66.19±2.64 82.94±0.42 68.49± 2.30 76.70± 2.81 VT, ml 2.79± 0.01 2.72 ±0.03 2.60±0.07 2.75±0.02 VE, ml/min 183.53±8.88 226.94±6.17 174.08± 1.33 201.43±6.28 Ti, sec 0.35 ±0.01 0.28±0.00 0.36± 0.01 0.34 ±0.00 Te, sec 0.59±0.02 0.52± 0.01 0.56 ±0.02 0.49±0.03 PIF, ml/sec 12.80± 0.69 16.85± 0.37 11.33 ±0.13 12.46± 0.18 PEF, ml/sec 11.12±0.58 12.93 ±0.54 9.76± 0.06 11.22± 0.19 EF50, ml/sec 0.53±0.06 0.63± 0.03 0.50±0.00 0.61±0.04 VT /Ti 7.96 0.21 9.61 ±0.07 7.26 ±0.05 8.18±0.11

Non-DM rats = non- diabetes mellitus rats, DM rats = diabetes mellitus rats, f = Frequency, TV =Tidal Volume, VE=Minute Volume, Ti = Inspiratory Time, Te = Expiratory Time, PIF = Peak Inspiratory Flow, PEF = Peak Expiratory Flow, EF50 = The flow at the point 50% of TV is expired, VT /Ti = mean inspiratory flow. Values are means  SD (n=14). *P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05 Non DM Saline and dextromethorphan to compare have a significant difference. ＋P<0.05 DM Saline and dextromethorphan to compare have a significant difference.

Table 10. Ventilatory parameters in non-DM and DM rats treated with vehicle or dextromethorphan on hypercapnic 15 min.

Non-DM rats DM rats

Hypercapnic 15 min Vehicle Dextromethorphan Vehicle Dextromethorphan f, breaths/min 137.71± 2.31 144.29± 0.83 121.93± 1.41 127.53±4.20 VT, ml 5.51 ±0.12 5.69± 0.02 5.03± 0.03 5.42±0.07 VE, ml/min 744.96±1.09 812.32±7.38 600.16±3.62 678.18±14.02 Ti, sec 0.24±0.00 0.22± 0.01 0.25±0.00 0.24 ±0.01 Te, sec 0.22± 0.00 0.21 ±0.00 0.26± 0.01 0.24±0.01 PIF, ml/sec 32.52± 0.21 36.24± 0.33 26.56± 0.25 29.89±0.36^＋ PEF, ml/sec 51.80 ±0.28 50.84± 0.01 36.25±0.54 41.46± 0.83^＋ EF50, ml/sec 3.55± 0.02 3.59± 0.11 2.48± 0.08 2.80±0.14 VT /Ti 23.43±0.03 26.28±0.56 19.92± 0.06 22.80±0.19^＋

Non-DM rats = non- diabetes mellitus rats, DM rats = diabetes mellitus rats, f = Frequency, TV =Tidal Volume, VE=Minute Volume, Ti = Inspiratory Time, Te = Expiratory Time, PIF = Peak Inspiratory Flow, PEF = Peak Expiratory Flow, EF50 = The flow at the point 50% of TV is expired, VT /Ti = mean inspiratory flow. Values are means  SD (n=14). *P<0.05 DM with Non DM vehicle to compare have a significant difference. ＃P<0.05 Non DM Saline and dextromethorphan to compare have a significant difference. ＋P<0.05 DM Saline and dextromethorphan to compare have a significant differenc

Fig 5. DM and Non DM rats for hypoxia

Fig. 5. The ventilation(VE), tidal volume(TV), breathing frequency(f) and TV/Ti of non-DM (vacant circular) and DM (full circular) rats during room air and during 10% O2 hypoxic exposure (black bar). *p

＜0.05 indicates a significant difference from the value of vehicle at the same time-point. Values represent mean ± SDE.

Fig 6. DxM and saline for hypoxia

Fig. 6. The effects of vehicle (vacant circular) and dextromethorphan (full circular)administration on ventilation(VE), tidal volume(TV), breathing frequency(f) and TV/Ti of non-DM and DM rats during room air and during 10% O2 hypoxic exposure (black bar). *p＜0.05 indicates a significant difference from the value of vehicle at the same time-point. Values represent mean ± SD

在文檔中糖尿病鼠在缺氧和高二氧化碳下GABA 和NMDA受體對呼吸反應的調節; GABAergic and NMDA-mediated modulation of ventilatory response to hypoxia and hypercapnia in diabetes rats (頁 23-53)