The early effects of chronic hypoxia on the cardiovascular system in the rat: role of nitric oxide

Experiments were performed under Saffan anaesthesia on normoxic (N) rats and on chronically hypoxic rats exposed to 12% O₂ for 1, 3 or 7 days (1, 3 or 7CH rats): N rats routinely breathed 21% O₂ and CH rats 12% O₂. The 1, 3 and 7CH rats showed resting hyperventilation relative to N rats, but baseline heart rate (HR) was unchanged and arterial blood pressure (ABP) was lowered. Femoral vascular conductance (FVC) was increased in 1 and 3CH rats, but not 7CH rats. When 1–7CH rats were acutely switched to breathing 21% O₂ for 5 min, ABP increased and FVC decreased, consistent with removal of a hypoxic dilator stimulus that is waning in 7CH rats. We propose that this is because the increase in haematocrit and vascular remodelling in skeletal muscle help restore the O₂ supply. The increases in FVC evoked by acute hypoxia (8% O₂ for 5 min) and by infusion for 5 min of α-calcitonin gene-related peptide (α-CGRP), which are NO-dependent, were particularly accentuated in 1CH, relative to N rats. The NO synthesis inhibitor l -NAME increased ABP, decreased HR and greatly reduced FVC, and attenuated increases in FVC evoked by acute hypoxia and α-CGRP, such that baselines and responses were similar in N and 1–7CH rats. We propose that in the first few days of chronic hypoxia there is tonic NO-dependent vasodilatation in skeletal muscle that is associated with accentuated dilator responsiveness to acute hypoxia and dilator substances that are NO -dependent.     

Effects of chronic systemic hypoxia on contraction evoked by noradrenaline in the rat iliac artery

Comparisons were made between responses evoked by noradrenaline (NA) in iliac artery rings from normoxic (N) rats and chronically hypoxic (CH) rats kept in 12 % O(2) for 3-4 weeks. At P(O(2)) of 100 mmHg, cumulative concentration-response curves (CCRC) to NA were greatly depressed in endothelium-intact (E+) rings, but not endothelium-denuded (E-) rings, of CH rats relative to N rats. However, CCRCs evoked by NA in E+ and E- rings during nitric oxide (NO) synthase inhibition were similar in N and CH rats. Reducing P(O(2)) to 55 mmHg depressed CCRCs to NA in E+ and E- rings of CH and N rats in the absence and presence of NO synthase inhibition. At P(O(2)) of 100 mmHg, CCRCs evoked by phenylephrine were comparable in E+ and E- rings of N and CH rats as were CCRCs for the relaxation evoked by isoprenaline, which were similarly rightward shifted by NO synthase inhibition. However, CCRCs evoked by the NO donor sodium nitroprusside were leftward shifted in E- rings of CH rats relative to N rats. Further, in the presence of the alpha(2) adrenoceptor inhibitor rauwolscine, CCRCs to NA were comparable in E+ rings of CH and N rats. Thus, the depressive effects of chronic hypoxia on NA-evoked contractions of iliac artery are additional to those of acute hypoxia. We propose that they reflect a facilitation of the contribution of NO to alpha(2) adrenoceptor-evoked relaxation that includes an increased sensitivity of the vascular smooth muscle of arteries from CH rats to NO.     

The effect of progressive hypoxia on the respiratory and cardiovascular systems of the chicken

1. During the initial stages of progressive hypoxia the intact, unanaesthetized chicken shows increases in heart rate and respiratory frequency with no change in arterial blood pressure and oxygen consumption. During the later stages, heart rate, diastolic and mean blood pressure and oxygen consumption fall, while respiratory frequency increases further.

2. Following bilateral cervical vagotomy and adrenergic β-receptor blockage there is no tachycardia, but the late bradycardia and fall in blood pressure do occur during progressive hypoxia. Respiratory frequency remains at a low level after vagotomy.

3. It is suggested that the initial tachycardia is dependent on both the sympathetic and parasympathetic nervous systems, and that the former helps maintain arterial pressure during the early stages of hypoxia. Bradycardia and hypotension seem to be due to anoxia itself, and the vagus is essential for the increase in respiratory frequency.

     

Vascular changes in the rat brain during chronic hypoxia in the presence and absence of hypercapnia

Changes in brain vascularity in adult rats during adaptation to chronic normobaric hypoxia with or without elevated CO(2) were morphometrically investigated. Immunohistochemistry with anti-rat endothelial cell antigen (RECA-1) antibody was carried out for the vascular analysis. After the rats were subjected to hypoxia for 2 to 8 weeks (wks)(10 percent O(2) in N(2)), the total area of blood vessels was measured in 6 brain regions. After 2 wks of hypoxia, the blood vessel area was found to be significantly increased in the frontal cortex, striatum, hippocampus, thalamus, cerebellum, and medulla oblongata, by 44% , 96% , 65% , 50% , 102% and 97% , respectively. The ratio of large vessels with an area > 500 micro m(2) was also increased in all brain regions. Hypoxic adaptation in brain vascularity did not change during 8 wks of hypoxia, and the hypoxia-induced levels measured in the vasculature returned to control levels 2 wks after the termination of hypoxia in areas of the brain other than the cortex and thalamus. In addition, hypoxia-induced changes in terms of the total vascular area and vessel size distribution were significantly inhibited by the elevation in CO(2), whereas chronic hypercapnia without hypoxia had no effect on brain vascularity. These findings suggested that adaptations in brain vascularity in response to hypoxia are rapidly induced, and there are regional differences in the reversibility of such vascular changes. Carbon dioxide is a potent suppressor of hypoxia-induced vascular changes, and may play an important role in vascular remodeling during the process of adaptation to chronic hypoxia.     

Pulmonary venous changes in chronic hypoxia

Summary Lung tissue from 14 normal residents of high altitude regions, 10 patients with chronic bronchitis and emphysema, and 1 patient with Pickwickian syndrome was studied with regard to the occurrence of pulmonary vascular changes. In addition to the well-known pulmonary arterial alterations, lesions in small pulmonary veins were found in the great majority of the cases. These changes, consisting of medial hypertrophy and arterialization and of bundles of smooth muscle cells within the venous intima, have not been described before in man. These findings suggest that alveolar hypoxia acts not only on small pulmonary arteries and arterioles but also on veins of small caliber, probably by inducing venoconstriction.     

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.     

Heart rate changes evoked by hypoxia in the anaesthetized, artificially ventilated cat.

Reflex changes in heart rate evoked by hypoxia were investigated in cats anesthetized with chloralose and ventilated by positive pressure during administration of vecuronium or gallamine. In five cats receiving vecuronium and with aortic pressure stabilized, systemic hypoxia (arterial O2 pressure (Pa, O2) 34.9 mmHg) reduced heart rate by 55.8 +/- 7.5 beats min-1 (mean +/- S.E.M.). After administration of atropine, hypoxia (Pa, O2 32.1 mmHg) increased heart rate by 28.2 +/- 3.4 beats min-1. After subsequent bilateral ablation of carotid sinus and vagus nerves, hypoxia (Pa, O2 31.9 mmHg) increased heart rate by 7.1 +/- 1.8 beats min-1. The cardiac accelerator response to hypoxia was further examined in groups of cats treated with gallamine and atropine. In four vagotomized cats, local perfusion of both carotid sinuses with hypoxic blood (Pa, O2 37.7 mmHg) increased heart rate by 15.5 +/- 2.3 beats min-1. In the same cats, systemic hypoxia (Pa, O2 38.3 mmHg) increased heart rate by 16.4 +/- 2.3 beats min-1. The heart rate increment in cats which had undergone either bilateral adrenalectomy or cardiac sympathectomy was similar to the increment in unoperated cats. The increment was significantly less in cats which had both adrenal glands and cardiac sympathetic nerves ablated. It is concluded that stimulation of the carotid bodies in the cat excites both parasympathetic and sympathetic cardiac nerves simultaneously.     

The role of the pontine respiratory complex in the response to intermittent hypoxia

These experiments were designed to determine the effects of EEG state on the response of rats to intermittent hypoxia and to test the hypotheses that short-term potentiation (STP) and ventilatory long term facilitation (vLTF) are state dependent; and that neurons with NMDA receptors in the dorso-ventral pontine respiratory group (dvPRG) modulate the development of STP and vLTF in rats. Low-doses of urethane anaesthesia (<1.3 g/kg) that do not cause significant respiratory depression or reductions in sensitivity to hypoxia result in cycling between EEG states that superficially resemble wake and slow wave sleep in rats and are accompanied by changes in breathing pattern that closely resemble those seen when unanaesthetized rats cycle between wake and SWS. When changes between these states were accounted for, intermittent, poikilocapnic hypoxia did not produce a significant vLTF. However, there was a persistent STP of tidal volume and vLTF did develop after blockade of NMDAr in the region of the PBrKF complex by microinjection of MK-801. Blockade of NMDA-type glutamate receptor-mediated processes in the dorsal pons also caused animals to cycle into State III, but did not alter the response to either continuous or intermittent hypoxia indicating that the response to hypoxia was not state dependent. This shows that neurons in the region of the PRG inhibit STP and vLTF, but no longer do so if PRG NMDA receptor activation is blocked.     

The effect of progressive hypoxia on the respiratory and cardiovascular systems of the pigeon and duck

1. During the initial stages of progressive hypoxia in ducks and pigeons (P(a, O2) 100 --> 60 mm Hg) there were no significant changes in heart rate, blood pressure or oxygen uptake, but respiratory frequency increased.2. As hypoxia became more profound (P(a, O2) 60 --> 30 mm Hg), there was a significant tachycardia, and blood pressure fell slightly in both animals. Respiratory frequency continued to increase in both species, and ducks were able to maintain their oxygen uptake at control levels at a lower P(a, O2) than pigeons.3. The response to progressive hypoxia of pigeons and ducks was compared with that of the domestic fowl. The former two birds could maintain control of their cardiovascular system at a lower environmental oxygen concentration than the latter. Arterial P(O2) followed a similar course in all three birds in relation to environmental oxygen content. Pigeons and ducks were therefore able to endure a lower arterial P(O2) than chickens.     

Prevention of pulmonary vascular changes of chronic alveolar hypoxia by inhibition of angiotensin I-converting enzyme in the rat.

To test the hypothesis that the renin-angiotensin system is involved in the development of the pulmonary vascular patholigic changes of chronic alveolar hypoxia, two groups of rats were exposed to 0.5 atm. for 21 days. One group received SQ 20,881 (2 mg. per kg.) every 8 hours subcutaneously and the second group received normal saline. A third group of rats was maintained at normobaria. Rats receiving SQ 20,881 had significantly less pulmonary arterial hypertrophy and right ventricular hypertrophy than hypobaric animals. SQ 20,881-treated rats showed a significant increase in adrenal weight but a marked reduction in the thickness of the zona glomerulosa, as compared with the other groups. Our findings indicate that angiotensin II is necessary in the development of the pulmonary vascular structural changes of chronic alveolar hypoxia.     

The time course of cardiovascular changes in lactation in the rat

1. Cardiovascular changes in lactating rats have been traced from the first day post-partum to the end of the third week of lactation. The pattern of changes showed three phases.2. Between days 1 and 5 of lactation there were sharp rises in both cardiac output and in the blood flow/g tissue for most organs, but little change in the distribution of the cardiac output.3. Between days 5 and 15 of lactation cardiac output remained steady. The blood flow to tissues actively involved in the body's response to lactation (mammary glands, liver, gastrointestinal tract) also remained at high steady levels, but the blood flow to other tissues declined due to a redistribution of the cardiac output away from them and towards the growing mammary glands and splanchnic organs.4. Between days 15 and 22 of lactation there were further rises in both cardiac output and in the blood flow/g tissue for most organs.5. It is suggested that the increases in organ blood flows that occurred in the first few days after parturition (days 1-5) and at the end of lactation (days 15-22) were largely dependent on increases in cardiac output and may represent the maternal response to rapidly rising demands from the young at these times.     

低氧后心肌钙瞬变变化与β-肾上腺素受体脱敏的关系

目的:慢性低氧时,心脏对β-肾上腺素受体激动的反应出现脱敏现象,细胞内钙[Ca²⁺]_i瞬变的幅度降低、时程延长,本研究观察上述变化在低氧时发生和发展的时间过程和对应关系。方法:在年龄对等的正常及慢性低氧1d、3d、1周、2周、3周、4周和8周的大鼠,分别分离正常及慢性低氧条件下的心室肌细胞,以Fura-2为[Ca²⁺]_i的指示剂,用光谱荧光法测定心肌细胞的[Ca²⁺]_i瞬变及其对心肌β-受体激动后反应的变化。结果:在低氧1d、3d、1周等时间内,电刺激引起的[Ca²⁺]_i瞬变、咖啡因引起的[Ca²⁺]_i瞬变及电刺激引起的[Ca²⁺]_i瞬变对β-受体激动剂异丙肾上腺素的增加反应无明显变化;在低氧2周以上时,电刺激引起的[Ca²⁺]_i瞬变的幅度开始降低,而时程开始延长,其对异丙肾上腺素的反应也开始降低。咖啡因引起的[Ca²⁺]_i瞬变幅度也开始降低;在低氧3周和4周时,上述变化程度逐渐加重;在低氧8周时各参数的变化有所恢复,但与4周时的变化程度无明显差异。结论:低氧2-4周时,心脏的β-肾上腺素受体发生脱敏现象,脱敏的机制与3种调节[Ca²⁺]_i瞬变的蛋白质:L-型钙通道、ryanodine受体操纵的钙通道和钙泵等活性的降低有关,后者也可能是低氧时心脏功能降低的重要机制。低氧4-8周时,心脏对低氧产生了适应和代偿。     

Selected pulmonary biochemical and hematological changes produced by prolonged hypoxia in the rat

Rats were exposed to 12% O2 (1 atm) for 48 hr, then 10% O2 for the duration of the exposures. Significant elevations in enzymes of the glutathione peroxidase system were found in the lungs of rats killed 3.5, 7.5, and 12.5 days of exposure compared to air-breathing controls. Superoxide dismutase was also elevated after hypoxia but nonsignificantly. Animals killed 12.5 days after exposures exhibited 75% (P less than 0.05) more thiobarbituric acid reactive products in their lungs compared to controls. These results along with significant increases of lung lipid peroxidation and in an augmentation of protective antiperoxidative lung defense capabilities. Hypoxia also resulted in enzyme elevations of lung phosphofructokinase and pyruvate kinase, which may indicate an adaptive increase in lung glycolytic capabilities which would be helpful in maintaining lung tissue energy requirements during hypoxia. In addition, it was confirmed that red blood cell count, hemoglobin and hematocrit values increased after prolonged hypoxia. The results of this study might also reflect enzyme elevation/induction due to cellular reparative-proliferative processes following hypoxia.