Chronic intermittent hypoxia versus continuous hypoxia: Same effects on hemorheology?

Abstract

Although both chronic intermittent hypoxia (CIH) and chronic continuous hypoxia (CCH) have effects on hemorheology, we do not know whether their roles are the same. In this study, we explored the effect of simulated-apnea CIH on hemorheology in experimental rats and compared with the effect of CCH. 45 adult SD rats were randomly divided into the normoxic control group, CCH and CIH groups. CIH rats were given nitrogen and air alternately for 8 hours per day and the experiment lasted for 5 weeks. The control group were placed in the normoxia animal chambers, and the CCH rats were housed in the same chambers which were continuously given normobaric hypoxia (FiO₂ = 10%). After the preparations, the blood samples were taken and the hemorheology were determined. Compared with control group, the whole blood apparent viscosity, plasma viscosity, hematocrit, erythrocyte aggregation index and electrophoresis index, platelet aggregation rate and fibrinogen significantly increased in CIH group and CCH group. The whole blood viscosity, plasma viscosity, hematocrit and fibrinogen values were much higher in CCH group than in CIH group. However, there was not significantly difference in RBC deformation index or rigidity index among the three groups and no significantly differences were found in the effects on RBC rheological property between CIH and CCH. Our results suggest that intermittent hypoxia and continuous hypoxia increase whole blood viscosity, impair the functions of red blood cells and promote the platelet aggregation in model rats. Moreover, CCH had a greater effect on blood rheology than CIH.

Keywords

Chronic intermittent hypoxia continuous hypoxia hemorheology rat

1 Introduction

Obstructive sleep apnea syndrome (OSAS) is a type of sleep-disordered breathing and is characterized by recurrent episodes of partial or complete upper airway obstruction [33]. As a prevalent chronic disease, OSAS has been considered as a significant risk factor for many morbidity and mortality including cancer-related deaths [5 , 36]. However, the mechanisms of cardiovascular events induced by OSAS have not been clearly understood. The resulting literature has consistently shown that the profound and repeated intermittent hypoxia (IH) during sleep is the prime culprit and is recognized as a potential major contributor in the pathogenesis of OSA-related comorbidities [7, 31], which provoke the increased risk of cardiovascular diseases including hypertension, myocardial infarction, ischaemic stroke, atrial fibrillation and others [7 , 48]. These complications may depend on the severity of the nocturnal apnea periods causing exposure to IH. High incidence of cardiovascular complications occurring in the morning hours is a supportive fact [8 , 22].

Hemorheology is concerned with the flow properties of cellular and plasmatic components of blood and has been as diagnostic and predictive tool in cardiovascular diseases [4]. The resistance of blood to flow is known as blood viscosity, which depends on hematocrit but also on the ability of red blood cells (RBCs) to deform and aggregate [4]. These latter haemorheological factors may considerably modulate blood flow resistance [4] and can be influenced by chronic continuous hypoxia (CCH) exposure at high altitude [37]. Polycythaemia in various models (mice, rats and guinea pigs) appears to be involved in CCH-induced pulmonary hypertension by increasing blood viscosity [17].

By understanding the effects of CCH on hemorheology, it has been speculated that the pathophysiologic mechanisms of these cardiovascular events in OSAS may be related with the rheologic properties of blood. However, the effect of chronic intermittent hypoxia (CIH) on blood rheological changes is not completely investigated. Although such researches had previously been carried out, they had inconsistent results [11, 49]. In addition, no data are currently available regarding comparisons of blood viscosity and other blood properties after CIH or CCH exposures. By establishment of an experimental CIH pattern in rats mimicking episodic hypoxia seen in humans with OSA, the present study was to further explore the effect of CIH on hemorheology and was to understand whether CIH or CCH had the same effect on blood rheology.

2 Material and methods

2.1 Animals and experimental protocols

All experiments were performed on a total of 45 adult Sprague-Dawley rats, each weighing 180–200 g, which were obtained from the Wuhan University Center for Animal Experiments. Rats were randomly divided into the normoxic control group (n = 15), the CCH group (n = 15), and the CIH group (n = 15). The animal protocols employed in this study were approved by the Committee on the Use of Animals for Teaching and Research of the Medical School of Wuhan University. These protocols also conformed to the China Committee of Experimental Animal Care, and the regulations were in keeping with NIH guidelines.

2.2 Hypoxia exposures

Animal chambers in our laboratory have been built in which rats can be housed for days, inducing repetitive IH cycles around the clock for weeks mimicking that seen in humans with OSA. Rats were placed under one of three experimental conditions: normoxia, continuous hypoxia, or intermittent hypoxia for 5 consecutive weeks. All chambers had the same size and dimensions, and equal numbers of rats were in each chamber. IH exposure was as following. Rats were housed in chambers, which were alternately given 30 s of normobaric hypoxia (10% FiO₂ at the nadir) and 60 s of normoxia (FiO₂ = 21%) for 8 h each day. Normobaric hypoxia was generated by flushing the chambers with alternating mixtures of 100% oxygen and 100% nitrogen, under a time-concentration cycled mode in a 90-second-long cycle, at a stable and sufficient rate controlled by the gas control delivery system. After the IH exposure every day, the animals were kept into chambers by flushing into air (FiO₂ = 21%). Normoxic and continuous hypoxic exposures were continuous for 24 h per day. The normoxic control rats were placed in the normoxia animal chambers (FiO₂ = 21%), while the CCH rats were housed in identical chambers which were kept the FiO₂ of 10% by flushing into nitrogen with stable flow. All rats had ad libitum access to food and water throughout all experiments, and the room temperature was maintained at 23 to 25°C.

2.3 Hemorheology study

According to the experimental protocols, after the last time of hypoxia exposure or at the equivalent time in the control group, the rats were anesthetized with 20% urethane (5 ml/kg) by intraperitoneal injection. A carotid arterial catheter was cannulated to allow the withdrawal of blood samples to measure the hemorheology parameters, in which, 3 ml disposable syringe anticoagulated blood with sodium heparin (30 U/m1) were for the test of whole blood apparent viscosity and plasma viscosity, another 4 ml anticoagulated blood with sodium citrate (1:9) were for the determination of platelet aggregation, hematocrit and plasma fibrinogen concentration. Haemorheological parameters were determined within 2 h after collection of blood samples and in line with the guidelines for haemorheological measurements [3]. At the end of the experiments, all animals were killed with an intravenous administration of 10% potassium chloride solution.

Whole blood apparent viscosity was measured with 0.8 ml heparinized whole blood in the sample pool of viscometer by a self-cleaning rotary cone-plate micro-viscometer (LBY-N6A, Puli Co., Beijing, China) at shear rates of 10 s^–1, 80 s^–1 and 150 s^–1at 37°. Another 2 ml heparin-anticoagulated blood was centrifuged at 3,000 rpm for 15 min, then 0.8 ml of supernatant was taken for the determination of plasma viscosity. The indices of erythrocyte rheology were calculated by the results of whole blood apparent viscosity under different shear rates according to the equations [4], including erythrocyte aggregation index, rigidity index, deformation index and electrophoresis index. The hematocrit was determined by micro-capillary tube method. A moderate amount of anticoagulated blood with sodium citrate was centrifuged at 12,000 rpm for 10 min and the hematocrit was tested by a microhematocrit tester (STS-6100, Puli Co., Beijing, China).

Adenosine diphosphate (ADP) -induced platelet aggregation rate was measured by a optical turbidimetry (Coaggremeterlby-NJ2, Puli Co., Beijing, China). 2 ml anticoagulated blood with sodium citrate was centrifuged at 800 rpm×10 min for the preparation of platelet-rich plasma. While the platelet-poor plasma was prepared after removal of platelet in the rest blood which was centrifuged at 3,000 rpm for 10 minutes. Then the ADP — an inducer of platelet aggregation (Shanghai Institute of Biochemistry, Chinese Academy of Science, China), was added into the platelet-rich plasma with the final concentration of 40 μmol/l, which was incubated for 5 min at 37°. The platelet aggregation was determined at 3 min, 5 min, 10 min by the turbidimetry and was expressed as the maximum percentage change in light transmittance.

The fibrinogen level was measured according to the manufacturer’s instructions by an ELISA Kit (LianShuo Biotech Co., Shanghai, China). 1 ml of sodium citrate anticoagulant blood was centrifuged at 3,000 rpm for 15 min. Then the supernatant was taken for the determination of fibrinogen concentration at 37°.

3 Statistical analysis

The data were analyzed for a normal distribution using box plots. A one-way repeated measures analysis of variance (one-way ANOVA) followed by a Dunnett multiple comparison tests were used to compare the parameters of hemorheology among normoxia, CCH and CIH groups. The groups were compared if the overall F value was significant (P < 0.05). That is, statistical comparisons between the normoxic group or the CIH group and the continuous hypoxia exposure group, and other pairwise multiple comparisons were made using the Dunnett multiple comparison. All values are expressed as means±standard error (SE). A p-value <0.05 is considered as a significantdifference.

4 Results

4.1 Inspired PO₂ during hypoxia exposures

Experimental animals were randomly divided into the normoxic control group, the CCH, and the CIH group, their hypoxic degree and durations in a 90-second-long cycle were shown in Table 1. The traces of oxygen in chambers during normoxic, intermittent hypoxic, and continuous hypoxic exposures were shown in Fig. 1.

4.2 The whole blood apparent viscosity and plasma viscosity

The results were shown in Table 2. Compared with normoxic control group, the whole blood apparent viscosity at different shears and plasma viscosity significantly increased in CIH group and CCH group. However, the blood viscosity indices were much higher in CCH group than in CIH group.

4.3 The erythrocyte rheology

The results were shown in Table 3. Compared with normoxic control group, the hematocrit, erythrocyte aggregation index and electrophoresis index were remarkable higher in CIH group and CSH group. The value of hematocrit in CCH group was much higher than that in CIH group. However, there was not significantly difference in RBC deformation index and rigidity index among the three groups. And furthermore, no significantly differences were found in the effects on RBC rheological property between CIH group and CCH group.

4.4 The platelet aggregation rate and fibrinogen

The results were shown in Table 4. Compared with normoxic group, both CIH group and CCH group had obviously higher platelet aggregation rate at 3 min, 5 min, and 10 min. And the level of fibrinogen was found higher in both CIH group and CCH group. However, the degree of platelet aggregation rate and the level of fibrinogen in CCH group were much higher than in CIH group.

5 Discussion

Hemorheology is an important subject which studies the rheological properties of blood and blood cells. It consists of blood of liquidity, namely viscosity; the RBC rheology, primarily RBC aggregation and deformation; and the effects of blood biochemical substances mainly fibrinogen on the blood rheology. Whole blood apparent viscosity is a reflection of macro-indicators in blood rheological properties and is determined by hematocrit, plasma viscosity, erythrocyte aggregation and deformability, aggregation and adhesiveness of platelets, etc [10, 16]. In which, however, hematocrit is primary factor that determine whole blood viscosity. Several prospective trials confirmed that the increased whole blood viscosity is a major risk factor for ischemic heart disease and stroke [25, 42]. Plasma viscosity is another important determinant of whole blood viscosity, in which, fibrinogen is an important determinant. It was described that there was a correlation between fibrinogen and the degree of nocturnal breathing disorder in patients with stroke [46].

IH is defined as repeated episodes of hypoxia interspersed with normoxic breathing [31]. Repetitive IH during OSAS contributes to cardiovascular injury and may be a major cause of cardiovascular complications [7 , 48]. However, the OSA-related IH is characterized by cycles of hypoxemia with re-oxygenation that is distinctly different from continuous hypoxia. Furthermore, it is very difficult to reproduce this special hypoxic model in human being. Thus it is extremely important to use animal models that can mimic some manifestations of OSA over a long time [13].

Taking these into consideration, to investigate the effect of CIH on rheological properties of blood and plasma and compared with the effect of continuous hypoxia, the present study addressed the use of an IH preparation in which rats were exposed to repetitive IH cycles simulating the recurrent episodic hypoxia of OSA. Our observational data showed that IH had obvious effects on blood rheology.

5.1 CIH increasing blood viscosity

The studies about the effects of CIH on blood rheology are limited and the mechanism of blood viscosity change caused by CIH is not clarified. Although higher hematocrit and increased whole blood viscosity values [6, 43] or elevated morning fibrinogen levels and a higher plasma viscosity [8, 40] in patients with OSAS were reported, an experimental chronic intermittent hypobaric hypoxia (CIHH) study had no effect on whole blood viscosity in spite of the elevated hematocrit values [11]. Furthermore, this study showed a decrease in plasma viscosity on rats exposed to CIHH. It is possible that the contrary findings about plasma viscosity may vary according to different hypoxia protocols [22]. In present study, however, we found that the whole blood apparent viscosity and plasma viscosity in CIH and CCH groups were significantly higher when compared with normoxic group (Table 2), and the fibrinogen levels in both groups were significantly higher (Table 4). The findings are consistent with earlier studies [8 , 40]. We have also observed an increase in hematocrit value in intermittent or continuous hypoxia exposed rats (Table 3). The finding is consistent with studies in severe OSA patients [18].

5.2 CIH damaging RBC functions

Erythrocyte deformability is an important factor in the microcirculation system. It has been used to characterize the ability of erythrocyte to change their shapes when passing through micro-vessels [44]. Few investigations have been carried out erythrocyte deformability in CIH exposure and had inconsistent results. Although a reversible effect on RBC filtration period after exposure to high altitude (not exactly IH) was showed, the studies with OSAS patients indicated that erythrocyte deformability was not much effected [8, 43]. However, in female volleyball players, Yo-Yo intermittent recovery test level 1 resulted in increments in RBC deformability [23]. The present study showed that both CIH and CCH rats had significantly higher hematocrit, erythrocyte aggregation index and electrophoresis index than those rats exposed to normoxia. However, intermittent hypoxia and continuous hypoxia had no effects on erythrocyte deformability and rigidity index (Table 3). Our findings are consistent with earlier study [49].

5.3 CIH promoting platelet aggregation

Given the key role of platelets in the known cardiovascular risk induced by OSAS, some investigators hypothesized that OSA severity is predictive of platelet function. A increased platelet and reduced fibrinolytic activity relative to controls were found in the OSAS subjects and thus OSAS seems to be linked to cardiovascular diseases via a hypercoagulable state [2, 45]. However, investigation regarding platelet function in OSAS has considerable difference. Platelet aggregation measured by ADP-induced platelet aggregation tended to be higher in OSAS subjects than in controls, but the difference was not significant. Other studies using different methodologies have indicated increased platelet activation and aggregation in OSA [20] or OSAS was associated with increased nocturnal platelet activity [2], whereas some have found only a slight effect [38] or none at all [47]. The increased platelet activity seen in OSAS patients may be improved or even normalize by CPAP treatment [2 , 38]. It seems that there may be a relationship between platelet activity and OSA severity [20]. In this study, ADP-induced platelet aggregation was chosen as a measure for platelet aggregation. The present study showed that both CIH and CCH rats had significantly higher platelet aggregation rate and levels of fibrinogen than normoxic rats. These implied that intermittent hypoxia and continuous hypoxia may promote platelet aggregation.

5.4 The comparisons of effects in CIH and CCH

Figure. 2 showed the comparisons of whole blood apparent viscosity (at shear rates of 10 s^–1, 80 s^–1 and 150 s^–1) and plasma viscosity, Fig. 3 showed the results of hematocrit and fibrinogen in CIH and CCH groups. As confirmed by our study, exposure to CIH and CCH results in an increase in blood viscosity and the platelet aggregation. Although both CIH and CCH had effects on blood viscosity, including increased hematocrit and blood viscosity, damaged erythrocyte rheology, having higher fibrinogen level and platelet aggregation rate, however, CCH had a greater effect on blood rheology. The CCH rats had higher whole blood apparent viscosity and plasma viscosity, higher levels of hematocrit, fibrinogen and platelet aggregation rate. Their significant differences were found between the two groups. However, we did not demonstrate a significant difference in the effects on RBC rheological property between CIH and CCH.

It has been previously reported that continuous hypoxia leads to increased hematocrit in mice [12, 41]. Polycythemia may lead to increased viscosity and has been reported as increased [24, 27] or unchanged [1, 14] following intermittent hypoxia. However, the severity of polycythemia following continuous hypoxia was not measured for comparison in previous studies with rats [14 , 27]. High-altitude continuous hypoxia causes polycythaemia and a hypercoagulable state in humans and animals [29–30 , 35], and chronic intermittent hypobaric hypoxia (CIHH) exposure induces a rise in hemoglobin concentration and an increase in erythrocyte mass in both rats and humans [11]. Interestingly, Fagan found that the severity of polycythemia was not different between intermittently and continuously hypoxic mice, although the levels in both groups were higher compared with normoxic group [12].

A few studies on blood rheology in animals had been carried out but had inconsistent results and were not directly compared the findings in intermittent vs. continuous hypoxia. Esteva et al. concerned blood viscosity in rats subjected to an CIHH program [11]. Although CIHH significantly increased the hematocrit, they found that the blood apparent viscosity did not differ and the plasma viscosity significantly decreased. In another experiment, chronic long-term intermittent hypobaric hypoxia was found to elevate whole blood viscosity by increasing plasma viscosity, fibrinogen concentration and hematocrit value without affecting the erythrocyte deformability [49]. While increased haematocrit, blood viscosity and pulmonary vascular resistance were found in rats undergoing 21 days of chronic hypoxic exposure [34].

Because hypoxic effects on hematocrit are heavily dependent on the duration and intensity of the hypoxic stimulus [39], therefore, the intensity, frequency and duration of intermittent hypoxia cycles are likely the major determinants of erythropoiesis and hematocrit. Our hypoxia protocol suggested that the hematocrit value is effective in the increase of whole blood viscosity. However, the higher hematocrit in the present report may also be due to the longer duration and heavier intensity of hypoxia in CCH.

6 Conclusions

According to our findings, both CIH and CCH caused an increase in whole blood viscosity value by increasing hematocrit, plasma viscosity and fibrinogen in rat models. Also, the platelet aggregation increased and some erythrocyte functions damaged. Although there was no significant difference in the effects on RBC rheological property between CIH group and CCH group, however, continuous hypoxia had a greater effect on blood rheology, which may be contributed to the longer duration and heavier intensity of the hypoxic stimulus. The hypoxia-induced changing in blood viscosity was probably attributed to the well-known hypoxic effect on cardiovascular events [21]. Nevertheless, other aspects during IH contribute to the cardiovascular complications, such as matrix metalloproteinases pattern [19] and the release of endothelial microparticles [26], which may modulate inflammatory processes, coagulation and vascular function and be involved in the development and progression of cardiovascular diseases.

Competing interests

The authors have declared that there are no conflicts of interest.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81070065, 81370181).

Authorship

All authors of this research paper have directly participated in the planning, execution and/or analysis of the study. All authors of this paper have read and approved the final version submitted. The contents of this manuscript have not been copyrighted or published previously. The contents of this manuscript are not under consideration for publication elsewhere. The contents of this manuscript will not be copyrighted, submitted, or published elsewhere while the manuscript is under consideration for publication. There are no directly related manuscripts or abstracts, published or unpublished, by any author(s) of this paper.

Footnotes

Acknowledgments

We thank Dr. Jing Feng and Prof. Baoyuan Chen, Respiratory Department, Tianjin Medical University General Hospital, China, for their support with the intermittent hypoxia chamber and the gas control delivery system used in this study.

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, et al., The effects of chronic long-term intermittent hypobaric hypoxia on blood rheology parameters, General Physiology and Biophysics30 (2011), 389–395.

Chronic intermittent hypoxia versus continuous hypoxia: Same effects on hemorheology?

Abstract

Keywords

1 Introduction

2 Material and methods

2.1 Animals and experimental protocols

2.2 Hypoxia exposures

2.3 Hemorheology study

3 Statistical analysis

4 Results

4.1 Inspired PO2 during hypoxia exposures

4.2 The whole blood apparent viscosity and plasma viscosity

4.3 The erythrocyte rheology

4.4 The platelet aggregation rate and fibrinogen

5 Discussion

5.1 CIH increasing blood viscosity

5.2 CIH damaging RBC functions

5.3 CIH promoting platelet aggregation

5.4 The comparisons of effects in CIH and CCH

6 Conclusions

Competing interests

Funding

Authorship

Footnotes

Acknowledgments

References

4.1 Inspired PO₂ during hypoxia exposures