Impaired control of renal sympathetic nerve activity following neonatal intermittent hypoxia in rats

Apneas and recurring oxygen desaturations can occur in preterm infants and young children. To investigate long-term effects of neonatal intermittent hypoxia on baroreflex control of sympathetic nerve activity, we studied 5-7-month-old (adult) Sprague-Dawley rats exposed to chronic intermittent hypoxia (CIH, n=9; 8% O2 for 90 s alternating with 90 s 21% O2, 12h/day) for their first 30 postnatal days or controls exposed to normoxia (C, n=9). In adult CIH and C rats, baseline heart rate, mean arterial pressure, and plasma concentration of epinephrine and norepinephrine were similar. Baroreflex sensitivity was evaluated in anesthetized rats by changes in renal sympathetic nerve activity (RSNA) in response to i.v. infusions of phenylephrine (PE,1.5 microg/min/100g) and sodium nitroprusside (SNP, 1.5 microg/min/100g). Acute intermittent hypoxia (AIH, 18 min) induced elevations in RSNA by over 30% of baseline about three times more often in the CIH group than in the C group. After AIH, the gain of the baroreflex sympatho-excitatory response increased by approximately two times in C and did not change in CIH rats. The gain of sympatho-inhibitory responses to SNP at the maximum decrease in MAP was similar in the two groups in normoxia and was not affected by AIH. We conclude that postnatal intermittent hypoxia causes long-lasting impairment in chemoreceptor and baroreceptor control of renal nerve activity.     

慢性间歇性缺氧大鼠肾脏组织蛋白质组的变化

目的:比较慢性间歇性缺氧大鼠与正常大鼠肾脏组织蛋白质双向电泳图谱,寻找和鉴定慢性间歇性缺氧大鼠肾脏组织中的差异蛋白表达谱。方法:以固相pH梯度等电聚焦为第一向和垂直SDS-PAGE为第二向,分别对正常对照大鼠和慢性间歇性缺氧大鼠的肾脏组织蛋白质样品进行二维分离,2-DE图谱经ImageMaster 2D Platinum V5.0软件分析,选取4个差异蛋白点用基质辅助激光解吸附离子化飞行时间质谱(MALDI-TOF-MS)进行鉴定。结果:通过对2-DE图谱蛋白斑点的匹配及对比分析,与慢性间歇性缺氧相关的差异表达蛋白斑点为112个;经质谱鉴定的4个差异表达的蛋白斑点,慢性间歇性缺氧组量下调的差异点1个,即线粒体ATP合成酶δ亚基;上调的差异点3个,分别为己糖激酶、儿茶酚-O-甲基转移酶、脱嘌呤/脱嘧啶核酸内切酶/氧化还原因子-1。结论:大鼠肾脏组织慢性间歇性缺氧损伤相关的差异蛋白表达变化可能通过多种途经影响肾脏功能。     

慢性间歇低氧对幼鼠认知及相关脑区CREB的影响

目的:观察慢性间歇低氧(CIH)对幼鼠认知的影响并探讨其潜在的机制。方法:取八臂迷宫训练成功的SPF级健康雄性SD幼鼠40只,随机分为:间歇低氧2周(2IH)、4周组(4IH),对照2周(2C)、4周组(4C),建立IH幼鼠模型,低氧结束后进行八臂迷宫测试,观察海马和前额叶皮层超微结构变化及cAMP反应元件结合蛋白(CREB)mRNA和磷酸化CREB蛋白的表达。结果:4组幼鼠的记忆错误次数比较均有显著差别(均P0.05);IH各组海马及前额叶皮层神经元均出现早期凋亡和变性,尤以4IH组最为明显,对照组则基本正常;与相应对照组相比,2IH、4IH组幼鼠海马和前额叶皮层CREB mRNA和p-CREB蛋白的表达水平显著降低(均P0.05),且以4IH组最低(均P0.01),差异显著,两对照组之间无显著差异(P0.05)。结论:慢性间歇低氧诱导海马和前额叶皮层神经元超微结构改变,还下调CREB的基因转录和抑制CREB蛋白磷酸化,抑制记忆相关蛋白的合成,这可能是引起学习记忆能力下降的重要机制之一。     

Metabolic effects of trekrezan during adaptation of rats to intermittent hypoxic hypoxia

The animals were adapted to intermittent hypoxic hypoxia in a flow pressure chamber for 3 days. Each one-day training session consisted of 4 elevations to an altitude of 6000 m for 20 min (15 m/sec, 20-min intervals between assents). Trekrezan (25 mg/kg intraperitoneally) was injected immediately after the end of daily training over 3 days. We showed that trekrezan increased the degree of adaptive metabolic changes in the brain, heart, and liver of rats during adaptation to hypoxic hypoxia. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 1, pp. 53–56, January, 2008     

慢性间歇性低氧对幼鼠脑区AMPK通路的影响

目的:探讨慢性间歇性低氧对幼鼠脑区腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)通路的影响。方法:第一部分:将3~4周龄的SD幼鼠随机分为4组(n=8):2周空气模拟对照(2AC)组、2周慢性间歇低氧(2IH)组、4周空气模拟对照(4AC)组和4周慢性间歇低氧(4IH)组。第二部分:将3~4周龄的SD幼鼠随机分为2组(n=8):4周慢性间歇性低氧组(4IH)和4周慢性间歇性低氧用药组(4IHI)。造模结束后行八臂迷宫测试,TUNEL法检测细胞凋亡,RT-qPCR法了解腺苷A2a受体的mRNA表达,Western blot法测定AMPK及哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)的磷酸化水平。结果:与对照组相比,2IH组和4IH组的参考记忆错误(RME)、工作记忆错误(WME)和总错误(TE)次数明显增加,差异有统计学显著性(P0.01);4IH与2IH组比较,各项错误次数亦明显增加(P0.01)。4IHI组比4IH组RME、WME和TE次数减少,差异有统计学显著性(P0.01)。与对照组相比,2IH组和4IH组海马和前额皮层区的神经元凋亡增多,以4IH组凋亡明显(P0.05);4IHI组凋亡较4IH组减少(P0.05)。2IH组和4IH组海马和前额皮层区腺苷受体A2a的mRNA和AMPK磷酸化蛋白的水平升高,mTOR磷酸化蛋白的水平下降,4IH组较2IH组改变明显(P0.05)。4IHI组较4IH组海马和前额皮层区的AMPK磷酸化蛋白水平下降,mTOR磷酸化蛋白水平升高(P0.05)。结论:慢性间歇性低氧诱导神经元凋亡,从而引起幼鼠学习记忆障碍,呈时间依赖性。慢性间歇性低氧上调腺苷A2a受体,激活海马和前额皮层区AMPK,抑制mTOR的活性,诱导神经元凋亡,进而影响幼鼠学习记忆能力。     

Exogenous ghrelin accentuates the acute hypoxic ventilatory response after two weeks of chronic hypoxia in conscious rats

Aim: Ghrelin has been implicated as a modulator of numerous physiological pathways. To date, there have not been any studies describing the role of ghrelin in modulating the chemoreflex control of pulmonary ventilation. Yet the respiratory system impacts, at least to some degree, on virtually all homeostatic control systems. Chronic hypoxia (CH) can cause fundamental changes in ventilatory control, evident by alterations in the acute hypoxia ventilatory response (HVR). As ghrelin plays an important role in metabolic homeostasis, which is tightly linked to ventilatory control, we hypothesized that ghrelin may modulate HVR, especially following CH. Methods: Whole body plethysmography was used to measure the HVR (8% O₂ for 10 min) in male Sprague–Dawley rats (body wt ∼180–220 g) before and after 14 days of CH (CH = 10% O₂). During CH, rats received daily subcutaneous injections of either saline (control; n = 5) or ghrelin (150 μg kg⁻¹ day⁻¹; n = 5). The HVR was measured in another four rats that had received daily injections of ghrelin during normoxia for 7 days. Results: Ghrelin did not significantly alter basal ventilatory drive or acute HVR in normoxic rats. However, the acute HVR was accentuated following CH in ghrelin-treated rats compared with saline-treated rats. Conclusions: These results describe the impact that ghrelin has in altering ventilatory control following CH and, although the mechanisms remain to be fully elucidated, provide guidance for future ghrelin-based studies interpreting physiological data indirectly related to the chemoreflex control of pulmonary ventilation.     

N-乙酰-L-半胱氨酸对慢性间歇性缺氧大鼠血压变化及内皮功能的影响

 目的:观察N-乙酰-L-半胱氨酸(N-acetyl-L-cystein,NAC)对慢性间歇性缺氧（chronic intermittent hypoxia,CIH）大鼠的血压变化及其内皮功能变化,探讨CIH引起高血压的机制。方法:30只健康雄性Sprague-Dawley(SD)大鼠随机分成正常对照组、CIH组(缺氧55 s,复氧 55 s）及NAC干预CIH组（缺氧55 s,复氧55 s,NAC 300 mg·kg-1·d-1,灌胃）。尾套法测量大鼠尾动脉收缩压;实时荧光定量PCR测定胸主动脉内皮型一氧化氮合酶（endothelial nitric oxide synthase, eNOS）和内皮素1（endothelin-1, ET-1）mRNA的表达情况。使用Western blotting方法检测胸主动脉eNOS表达。胸主动脉及血清ET-1水平均采用放射免疫法测定。硝酸还原酶法测定血清中一氧化氮（nitric oxide,NO）含量。分别采用黄嘌呤氧化酶法和硫代巴比妥酸法测定外周血浆超氧化物歧化酶（superoxide dismutase, SOD）和丙二醛（malondialdehyde,MDA）水平。使用化学比色法测定胸主动脉组织匀浆中超氧阴离子(O-·2)含量。结果:CIH组大鼠尾动脉收缩压较对照组升高（P＜0.01）,NAC干预CIH组大鼠的尾动脉收缩压较CIH组显著降低（P＜0.05）。CIH组胸主动脉中eNOS mRNA和蛋白水平以及血清NO水平低于对照组（P＜0.01）,NAC干预组两者表达明显高于CIH组(P<0.05);CIH 组胸主动脉ET-1 mRNA和蛋白水平表达高于对照组（P＜0.01）,而NAC治疗使表达减低(P<0.05）。CIH组血清MDA和ET-1水平以及胸主动脉匀浆O-·2水平均高于对照组（P＜0.01）,而NAC干预组这些指标水平均低于CIH组（均P＜0.05）;CIH组血清SOD活性低于对照组（P＜0.01）,而NAC治疗组SOD活性增加（P＜0.05）。结论: NAC通过减少自由氧的产生,保护主动脉组织内皮功能,从而缓解血压升高,推测氧化应激参与CIH致高血压内皮功能障碍的发生机制。     

低压氧舱慢性间断性缺氧诱导大鼠膈神经长时程易化

目的:长时程易化(long-term facilitation,LTF)是反映呼吸可塑性的重要电生理指标,与睡眠呼吸紊乱疾病密切相关。3~5个低氧周期的急性间断性缺氧可以诱导膈神经LTF,而持续一周以上的慢性间断性缺氧(chronic intermittent hypoxia,CIH)可以诱导更大的增强的LTF(enhanced LTF)。以往制备CIH大鼠LTF模型多用氧(10%)+氮(90%)混合气(5 min)、常氧(5 min)交替通气,每天12 h,连续7 d以上,实验需要大量混合气,费用较高。我们模拟高原缺氧制备了低压氧舱大鼠CIH模型,表达增强的膈神经LTF。方法:成年SD大鼠置于密闭容器内进行5 min低压缺氧、5 min常氧交替通气,每天12 h,持续7 d。通过空气抽提进行低压缺氧,使舱内气压逐渐下降到210~220 mmHg,相当于海拔约9000 m。第8 d,动物进行急性间断性缺氧,诱导膈神经LTF表达。对照组大鼠只进行急性间断性缺氧,统计学分析两组动物膈神经LTF的表达变化。结果:低压氧舱CIH大鼠较正常对照组对缺氧反应更加敏感,表现为缺氧期膈神经放电的频率和幅度快速增加。在急性间断性缺氧结束后30 min和60 min,CIH组大鼠膈神经放电幅度较基础水平分别增加了(116.3±6.5)%和(106.1±19.2)%,而对照组分别增加(60.4±7.8)%和(48.2±11.0)%,两组之间有显著性差别(P(0.01),表明CIH诱导了比对照组更加强大的LTF,形成增强的LTF。结论:我们建立了低压氧舱CIH大鼠膈神经LTF模型,为进一步研究LTF的发生机理、揭示与睡眠呼吸紊乱疾病的相关性提供了实验平台。     

Repeated measurement of hypoxic ventilatory response as an intermittent hypoxic stimulus

Measurement of hypoxic ventilatory response (HVR) involves an exposure to hypoxia which, if repeated over several days might act as an intermittent hypoxic stimulus. The purpose of this study was to measure HVR repeatedly over 5 days to determine whether it was affected by repeated measurement. Nine healthy male subjects completed an isocapnic HVR test, on one occasion, followed 5 days later by one measurement each day for 5 days. Each test lasted approximately 5-8 min with inspired oxygen concentration declining to as a low as 5-6%. No systematic trend was observed in HVR over the 5-day period (p>0.05). There were no significant differences in HVR between any of the test days. Regression failed to show any trend in HVR over the five sequential days. The calculated mean coefficient of variation for HVR for each subject was 27%. There is no evidence that the short exposure to hypoxia as part of HVR measurement is a co-intervention when measured repeatedly over 5 days in physiological studies.     

Developmental plasticity of the hypoxic ventilatory response in rats induced by neonatal hypoxia

Neonatal hypoxia alters the development of the hypoxic ventilatory response in rats and other mammals. Here we demonstrate that neonatal hypoxia impairs the hypoxic ventilatory response in adult male, but not adult female, rats. Rats were raised in 10% O₂ for the first postnatal week, beginning within 12 h after birth. Subsequently, ventilatory responses were assessed in 7- to 9-week-old unanaesthetized rats via whole-body plethysmography. In response to 12% O₂, male rats exposed to neonatal hypoxia increased ventilation less than untreated control rats (mean ± s.e.m. 35.2 ± 7.7% versus 67.4 ± 9.1%, respectively; P = 0.01). In contrast, neonatal hypoxia had no lasting effect on hypoxic ventilatory responses in female rats (67.9 ± 12.6% versus 61.2 ± 11.7% increase in hypoxia-treated and control rats, respectively; P > 0.05). Normoxic ventilation was unaffected by neonatal hypoxia in either sex at 7–9 weeks of age ( P > 0.05). Since we hypothesized that neonatal hypoxia alters the hypoxic ventilatory response at the level of peripheral chemoreceptors or the central neural integration of chemoafferent activity, integrated phrenic responses to isocapnic hypoxia were investigated in urethane-anaesthetized, paralysed and ventilated rats. Phrenic responses were unaffected by neonatal hypoxia in rats of either sex ( P > 0.05), suggesting that neonatal hypoxia-induced plasticity occurs between the phrenic nerve and the generation of airflow (e.g. neuromuscular junction, respiratory muscles or respiratory mechanics) and is not due to persistent changes in hypoxic chemosensitivity or central neural integration. The basis of sex differences in this developmental plasticity is unknown.     

Vagal afferent innervation and remodeling in the aortic arch of young-adult fischer 344 rats following chronic intermittent hypoxia

Previously, we have shown that chronic intermittent hypoxia (CIH) impairs baroreflex control of heart rate and augments aortic baroreceptor afferent function. In the present study, we examined whether CIH induces structural changes of aortic afferent axons and terminals. Young-adult Fischer 344 (F344, 4 months old) rats were exposed to room air (RA) or CIH for 35–45 days. After 14–24 days of exposure, they received tracer DiI injection into the left nodose ganglion to anterogradely label vagal afferent nerves. After surgery, animals were returned to their cages to continue RA or CIH exposure. Twenty-one days after DiI injection, the animals were sacrificed and the aortic arch was examined using confocal microscopy. In both RA and CIH rats, we found that DiI-labeled vagal afferent axons entered the wall of the aortic arch, then fanned out and branched into large receptive fields with numerous terminals (flower-sprays, end-nets and free endings). Vagal afferent axons projected much more to the anterior wall than to the posterior wall. In general, the flower-sprays, end-nets and free endings were widely and similarly distributed in the aortic arch of both groups. However, several salient differences between RA and CIH rats were found. Compared to RA control, CIH rats appeared to have larger vagal afferent receptive fields. The CIH rats had many abnormal flower-sprays, end-nets, and free endings which were intermingled and diffused into “bush-like” structures. However, the total number of flower-sprays was comparable (P>0.05). Since there was a large variance of the size of flower-sprays, we only sampled the 10 largest flower-sprays from each animal. CIH substantially increased the size of large flower-sprays (P<0.01). Numerous free endings with enlarged varicosities were identified, resembling axonal sprouting structures. Taken together, our data indicate that CIH induces significant remodeling of afferent terminal structures in the aortic arch of F344 rats. We suggest that such an enlargement of vagal afferent terminals may contribute to altered aortic baroreceptor function following CIH.     

Attenuation of heart rate control and neural degeneration in nucleus ambiguus following chronic intermittent hypoxia in young adult Fischer 344 rats

Chronic intermittent hypoxia (CIH) attenuates baroreflex control of heart rate (HR). In this study, we assessed whether CIH exposure reduced nucleus ambiguus (NA) control of HR and induced neural degeneration in the NA. Fischer 344 (age: 3–4 months) rats were exposed to either room air (RA: normoxia) or intermittent hypoxia for 35–50 days. At the end of these exposures, animals were anesthetized with pentobarbital. HR responses to arterial blood pressure (AP) changes induced by phenylephrine (PE) and sodium nitroprusside (SNP) were measured. In another set of rats, HR and AP responses to l-glutamate (l-Glu) microinjections (10 mM, 20 nl) into the left NA and electrical stimulation of the left cervical vagus nerve at 1–30 Hz (0.5 mA, 1 ms) for 20 s were measured. Brainstem slices at the level of −800, −400, 0, +400, +800 μm relative to the obex were processed in additional rats using Nissl staining. The NA was identified by retrogradely labeling vagal motoneurons using the tracer tetramethylrhodamine dextran (TMR-D) which was injected into the ipsilateral nodose ganglion. We found that CIH significantly 1) reduced the baroreflex control of HR (slope RA: −1.2±0.2 bpm/mmHg; CIH −0.5±0.1 bpm/mmHg; P<0.05); 2) attenuated the HR responses to l-Glu injections into the NA [HR: −280±15 (RA) vs. −235±16 (CIH) beats/min; P<0.05]; 3) augmented the HR responses to electrical stimulation of the vagus (P<0.05); 4) induced a significant cellular loss in the NA region (P<0.05). Thus, CIH induces a cell loss in the NA region which may contribute to attenuation of baroreflex sensitivity and NA control of HR following CIH.     

慢性间歇性低压低氧对老年大鼠自发运动行为及黑质多巴胺能神经元的影响

目的:用慢性间歇性低压低氧(CIHH)模型,探讨CIHH对老年大鼠自发运动行为以及黑质多巴胺能神经元的影响。方法:用CIHH模型处理老年大鼠30 d,通过旷场实验检测大鼠自发运动行为的改变,通过实时定量PCR和免疫印迹检测黑质多巴胺能神经元酪氨酸羟化酶(TH)和多巴胺转运体(DAT)表达的变化。结果:老年组大鼠旷场实验中闻嗅行为、探索行为、运动行为和理毛行为与成年组相比均显著下降,CIHH处理后理毛行为没有改变,闻嗅行为、探索行为和运动行为显著改善,但没有达到成年组水平;老年组大鼠黑质多巴胺能神经元TH和DAT的表达与成年组相比均显著下降,老年CIHH组TH和DAT的表达升高,但没有达到成年组水平。结论:CIHH可改善老年大鼠闻嗅行为、探索行为和运动行为,并提高黑质多巴胺能神经元TH和DAT的表达。     

慢性间歇性低压低氧对家兔窦房结肾上腺素能受体反应性的影响

目的:通过细胞内记录方法研究慢性间歇性低压低氧(CIHH)对家兔窦房结肾上腺素能受体反应性的影响。方法:新西兰大白兔随机分为对照组(Con)、CIHH14d组(CIHH14)、CIHH28d组(CIHH28)3组。CIHH组动物置于低压氧舱,分别接受14、28d模拟5000米高原的低压低氧处理(6h/d)。制备离体窦房结标本、描记窦房结自律细胞的生物电活动。通过累加给药法,观察不同浓度的β-肾上腺素能受体激动剂异丙肾上腺素(ISO)(0.01、0.1、1μmol/L)和α1肾上腺素能受体激动剂苯肾上腺素(PE)(0.01、0.1、1μmol/L)对家兔窦房结自律细胞动作电位的影响。结果:(1)CIHH对基础状态下窦房结细胞动作电位各参数无明显影响;(2)ISO浓度依赖性增加窦房结细胞动作电位0期最大除极速率(Vmax)、动作电位幅值(APA)、放电频率(RPF)、舒张期自动去极化速率(VDD),对其它参数无明显影响;(3)CIHH处理动物窦房结细胞对ISO的反应性降低;最大浓度ISO(1μmol/L)下,CIHH14和CIHH28组的VDD、RPF、APA和Vmax的增加明显小于对照组(P0.05);(4)α1肾上腺素能受体激动剂PE(0.01、0.1、1μmol/L)对窦房结细胞动作电位各项参数均无影响。结论:CIHH降低家兔窦房结β肾上腺素能受体反应性,对α1肾上腺素能受体反应性无影响。     

Anatomical changes in selected cardio-respiratory brainstem nuclei following early post-natal chronic intermittent hypoxia

Early post-natal environmental exposures, including chronic intermittent hypoxia (CIH), may lead to long-term alterations in cardio-respiratory control, such as reductions in baroreflex sensitivity and acute hypoxic ventilatory responses in adult rats. Although the mechanisms underlying CIH-induced functional metaplasticity are unclear, anatomical alterations within selected brainstem nuclei may develop after CIH. To examine this issue, male rats were exposed to CIH (RAIH) or room air (RARA) for the first 30 days of life and were microinjected unilaterally in the right nodose ganglion with the neuronal tracer tetramethylrhodamine-dextran (TMR-D) to label brainstem neurons receiving vagal and glossopharyngeal projections. Substantial reductions in labeled afferents within the nucleus tractus solitarii (nTS) and significant increases in the total number of labeled neurons within the ventrolateral medulla (VLM), principally in the nucleus ambiguus (Namb; p<0.01) occurred in RAIH. Furthermore, 5-bromo-2'deoxyuridine labeling revealed enhanced neurogenesis within the Namb in RAIH and could partially account for the increased neuronal population in Namb. Thus, CIH-associated cardio-respiratory metaplasticity is accompanied by substantial structural changes within both the nTS and Namb.     

Proinflammatory and prothrombotic status in emphysematous rats exposed to intermittent hypoxia

Objectives: To develop an “overlap syndrome (OS)” rat model by intermittent hypoxia (IH) exposure on the base of pre-existing emphysema, and to explore whether “OS” exposure results in more severe systemic inflammation, and whether the inflammation changes levels of coagulant/anticoagulant factors and oxidative stress status. Methods: Sixty Wistar rats were put into 4 groups: Control group; IH group, IH exposure; Emphysema group, smoke exposure; Overlap group, smoke exposure and IH exposure. We obtained peripheral blood for apoptosis of CD3⁺CD4⁺, CD3⁺CD8⁺ T lymphocytes and neutrophils, and for endothelial progenitor cell (EPC) counts. Tumor necrosis factor (TNF)-α, interleukin (IL)-6 and coagulant/anticoagulant factors [antithrombin (AT), fibrinogen (FIB), Factor VIII (FVIII) and von Willebrand factor (vWF)] were evaluated. We also obtained tissue blocks of lung, liver, pancreas, and right carotid artery for pathologic scoring and measurements of liver oxidative stress [superoxide dismutase (SOD) activity, catalase (CAT) activity and malondialdehyde (MDA) concentration]. Results: The levels of TNF-α and IL-6, CD3⁺CD4⁺ T lymphocyte apoptosis, EPC counts, coagulant factors and MDA are the highest in Overlap group, the lowest in Control group, when the levels of neutrophil apoptosis, CD3⁺CD8⁺ T lymphocyte apoptosis, AT, SOD and CAT are the lowest in Overlap group, the highest in Control group (all P values < 0.05). Conclusion: In model animals, when IH is combined with emphysema, there will be a more severe or an “overlapped” systemic/multiple organic inflammation, oxidative stress and hyper-coagulability. And the pro-inflammatory and pro-thrombotic status resulted from “OS” exposure may elicit a robust EPC mobilization, which needs further investigation.     

Vascular reactivity to norepinephrine and acetylcholine after chronic intermittent hypoxia in mice

This study assessed the early vascular reactivity changes in mice after exposure to 14 days intermittent hypoxia (IH) with active or inactive sympathetic nervous system (SNS). Hindquarters of mice exposed to 14 days of IH, sham exposed mice or unhandled mice were perfused at constant flow with Krebs-Albumin (5%). Changes in perfusion pressure were assessed after injection of several doses of norepinephrine in anaesthetized mice (active SNS) or in euthanized mice (inactive SNS). Response to several doses of acetylcholine was recorded after precontraction of hindquarter vascular bed by methoxamine in euthanized mice. Vasoconstrictor response was increased after IH for high dose of NE (50 microg) in euthanized mice and for all doses of NE (2-10-50 microg) in anaesthetized mice, but no change in vasodilatation was observed. These findings suggest that 14 days of IH altered vascular reactivity of mice hindquarter in an early pattern. Vasoconstriction was enhanced, particularly with active SNS, while there was no dysfunction of endothelium-relaxation.     

Impaired ventilatory acclimatization to hypoxia in mice lacking the immediate early gene fos B

Earlier studies on cell culture models suggested that immediate early genes (IEGs) play an important role in cellular adaptations to hypoxia. Whether IEGs are also necessary for hypoxic adaptations in intact animals is not known. In the present study we examined the potential importance of fos B, an IEG in ventilatory acclimatization to hypoxia. Experiments were performed on wild type and mutant mice lacking the fos B gene. Ventilation was monitored by whole body plethysmography in awake animals. Baseline ventilation under normoxia, and ventilatory response to acute hypoxia and hypercapnia were comparable between wild type and mutant mice. Hypobaric hypoxia (0.4 atm; 3 days) resulted in a significant elevation of baseline ventilation in wild type but not in mutant mice. Wild type mice exposed to hypobaric hypoxia manifested an enhanced hypoxic ventilatory response compared to pre-hypobaric hypoxia. In contrast, hypobaric hypoxia had no effect on the hypoxic ventilatory response in mutant mice. Hypercapnic ventilatory responses, however, were unaffected by hypobaric hypoxia in both groups of mice. These results suggest that the fos B, an immediate early gene, plays an important role in ventilatory acclimatization to hypoxia in mice.