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1 Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
Abstract
Long-term exposure to intermittent hypoxia may lead to important cardiovascular dysfunctions, such as hypertension. Rodent models of chronic intermittent hypoxia (CIH) have been used to study the mechanisms underlying the increase in mean arterial pressure (MAP) observed after exposure to CIH. Several studies suggest that the hypertension of rats submitted to CIH is associated with an increase in sympathetic activity. However, there are no studies documenting the direct measurement of sympathetic activity in conscious freely moving rats exposed to CIH. Therefore, the present study aimed to evaluate whether or not the increase of MAP in rats exposed to CIH is associated with an increase in sympathetic activity. To reach this goal, we analysed the effect of ganglionic blockade on baseline MAP as well as the plasma levels of catecholamines. Rats submitted to CIH (fractional inspired O2 of 6%, for 40 s in every 9 min, 8 h day–1) for 35 days (n = 31) exhibited a significant increase in MAP compared with control rats (n = 28) maintained under normoxia (112 ± 2 versus 103 ± 1 mmHg, P = 0.0003). The injection of the ganglionic blocker hexamethonium resulted in a similar fall in MAP in CIH and control groups (–46 ± 2 versus –41 ± 3 mmHg). However, hexamethonium after previous antagonism of the angiotensin II type 1 (AT1) receptors with losartan produced a larger decrease in MAP in the CIH than in the control group (–58 ± 2 versus –50 ± 2 mmHg, P = 0.0165). The injection of losartan itself produced no major changes in the baseline MAP in both groups. The measurement of plasma catecholamines showed an increase in plasma noradrenaline (10.12 ± 0.90 versus 4.74 ± 0.32 ng ml–1, P = 0.0042) in rats exposed to CIH compared with control rats. These data provide strong evidence to support the concept that rats submitted to CIH exhibit an increase in sympathetic activity, which seems to be determinant in the maintenance of hypertension in this experimental model.
(Received 18 August 2006;
accepted after revision 26 October 2006; first published online 3 November 2006)
Corresponding author B. H. Machado: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil. Email: bhmachad{at}fmrp.usp.br
The development of hypertension is one of the most important cardiovascular dysfunctions observed in patients with obstructive sleep apnoea (OSA; Hoffmann et al. 2004; Caples et al. 2005). A large body of evidence illustrates that the observed increase in arterial blood pressure in OSA patients is associated with the intermittent episodes of hypoxia, suggesting a correlation between long-term exposure to intermittent hypoxia and hypertension (Hla et al. 1994; Fletcher, 2000; Caples et al. 2005). However, other variables as well as the hypoxia stimulus are present in OSA patients, such as obesity, alcohol intake, smoking and ageing (Kiely & McNicholas, 2000), which make the understanding of the mechanisms underlying the increase in arterial pressure in these patients difficult. The rodent chronic intermittent hypoxic model, developed by Fletcher et al. (1992c), allows a better evaluation of the neural and hormonal mechanisms associated with the several cardiovascular dysfunctions consequent on the intermittent hypoxia exposure without the influence of the above-mentioned variables.
It has been demonstrated that rats submitted to chronic intermittent hypoxia (CIH) for 5 weeks exhibited a sustained increase in arterial pressure, which was prevented by previous carotid body denervation (Fletcher et al. 1992a,c). Moreover, other studies have also shown that hypercapnia (Fletcher et al. 1995) or sleep disruption/arousals (Fletcher, 2001) have no additional effect on the increase in arterial pressure evoked by CIH in rats, showing that the hypertension observed in this experimental model is caused by intermittent stimulation of the peripheral chemoreceptors by hypoxia rather than any other stimuli. Although these findings have clearly demonstrated that the hypertension in rats submitted to CIH is a consequence of long-term exposure to intermittent hypoxia, the mechanisms underlying this increase in arterial pressure remain to be fully understood.
The increase in arterial blood pressure in rats submitted to CIH seems to be dependent on several factors, mainly neural and hormonal changes, which may affect the regulation of the cardiovascular system at central and peripheral levels. With respect to the sympathetic nerve activity, experiments by Fletcher et al. (1992b) demonstrated that the chemical sympathectomy caused by 6-OH-dopamine, administered before exposure to CIH, prevented the increase in arterial pressure in rats. Similar results were observed in another study, in which denervation of the renal sympathetic nerves was performed before exposure to CIH (Bao et al. 1997), showing that the increase in arterial pressure observed in rats submitted to CIH is dependent on the integrity of the sympathetic nervous system to the kidneys. Based upon these studies, several studies have attributed the maintenance of the hypertension observed in rats after exposure to CIH to an increase in sympathetic outflow (Sica et al. 2000; Fletcher, 2001; Prabhakar et al. 2005). A recent study by Lai et al. (2006) documented that the baroreflex sensitivity is reduced in rats submitted to CIH, which may contribute to an increase in the sympathetic outflow. Although these studies provide evidence that sympathetic activity is important for the development of hypertension in rats submitted to CIH, there is no direct and conclusive evidence that the sympathetic nerve activity is increased and correlates with the increase in the baseline arterial pressure observed in this experimental model.
In addition to a possible increase in sympathetic nerve activity, there is evidence that hormonal changes may also contribute to the hypertension in rats exposed to CIH. The increase in the vascular response to endothelin-1 in rats submitted to CIH is accompanied by an increase in the expression of endothelin A receptors, suggesting that endothelin contributes to the hypertension in rats exposed to CIH (Allahdadi et al. 2005). The renin–angiotensin system also plays an important role in this experimental model, since the blockade of angiotensin II type 1 (AT1) receptors during CIH exposure prevented the increase in arterial pressure (Fletcher et al. 1999). However, the contribution of angiotensin II and the AT1 receptors in the maintenance of hypertension after CIH has not been evaluated.
Taking into account that the neural and hormonal mechanisms involved in the maintenance of hypertension in rats exposed to CIH are not yet completely understood, in the present study we evaluated the role of sympathetic activity and of angiotensin II. To reach this goal, we analysed (a), the fall in arterial pressure in response to the antagonism of AT1 receptors combined with ganglionic blockade and (b), the plasma level of catecholamines in rats submitted to CIH.
Methods
Animals
The experiments were performed on male Wistar rats, weighing 293 ± 2 g, obtained from the Animal Care facility of the University of São Paulo at Ribeirão Preto, Brazil. All experimental approaches were approved by the Animal Care and Ethical Committee of the School of Medicine of Ribeirão Preto, University of São Paulo (protocol 030/2004). The animals were divided into two experimental groups: rats that were exposed to the episodes of intermittent hypoxia (CIH group, n = 31) and rats that were maintained under normoxic conditions (control group, n = 28).
Chronic intermittent hypoxia
Both CIH and control rats were housed in collective cages (five animals per cage) and maintained inside Plexiglass chambers (volume, 210 l) equipped with gas injectors as well as sensors of O2, CO2, humidity and temperature. The CIH group was submitted to a protocol consisting of 5 min of normoxia (fractional inspired O2, FIO2, 20.8%) followed by 4 min of pure N2 injection into the chamber to reduce the FIO2 from 20.8 to 6%. After 40 s at this FIO2 level, pure O2 was injected into the chamber to return the FIO2 back to 20.8%. This 9 min cycle was repeated 8 h per day (from 9.30 am to 5.30 pm) for 35 days. During the remaining 16 h, the animals were maintained at an FIO2 of 20.8%. The N2 and O2 injections into the chamber were regulated by a solenoid valve system whose opening–closing control was performed by a computerized system (Oxycycler, Biospherix, Redfield, NY, USA). In other chambers, in the same room, the control group was exposed to an FIO2 of 20.8%, 24 h a day for 35 days. The control rats were also exposed to a similar valve noise owing to the frequent injection of O2 to maintain the FIO2 at 20.8%. In both CIH and control chambers, the gas injections were performed at the upper level of the chamber in order to avoid direct jets of gases into the cages of the animals, which might cause additional stress to the animals.
Arterial pressure and heart rate recordings
At the end of experimental protocol, on the 35th day, the rats were anaesthetized with tribromoethanol (250 mg kg–1, I.P.; Aldrich, Milwaukee, WI, USA) and a catheter was inserted into the abdominal aorta through the femoral artery (PE-10 connected to PE-50 tubing, Clay Adams, Parsippany, NJ, USA) for the arterial pressure measurement. Another catheter was inserted into the femoral vein and was used for systemic drug administration. The catheters were tunnelled subcutaneously and exteriorized through the back of the neck. Twenty-four hours later, when the rats had completely recovered from the surgery and adapted to the environment of the recording room, the arterial catheter was connected to a pressure transducer (PT 300 model, Grass Instruments, West Warwick, RI, USA), which was connected to an amplifier (Grass Quad Amplifier, 15LT model, Grass Instruments). The pulsatile arterial pressure (PAP) signals were recorded in a computerized data-acquisition system (Polyview, version 2.5, Grass Instruments), and mean arterial pressure (MAP) and heart rate (HR) were derived from PAP using appropriate computer software (Windaq Waveform Browser, Dataq Instruments, Akron, OH, USA). The cardiovascular parameters were recorded in conscious freely moving rats under normoxic conditions for 30 min.
Ganglionic blockade
After recording of baseline MAP and HR in CIH and control rats for 30 min, hexamethonium, a ganglionic blocker, was injected (25 mg kg–1, I.V.; Sigma, St Louis, MO, USA) and the cardiovascular parameters recorded for the next 5 min. The magnitude of the fall in MAP in both groups was tentatively used to evaluate the contribution of the sympathetic nervous system to the maintenance of the baseline MAP.
Antagonism of AT1 receptor and ganglionic blockade
This protocol was also performed in CIH and control rats after recording of baseline MAP and HR for 30 min. To verify the contribution of angiotensin II and AT1 receptors in the sustained increase of MAP in rats exposed to CIH, an injection of the AT1 receptor antagonist losartan (10 mg kg–1, I.V.; Galena, Campinas, SP, Brazil) was made, and the cardiovascular parameters were recorded for the next 5 min. Thereafter, hexamethonium (25 mg kg–1, I.V.) was injected, and the changes were evaluated in the following 5 min. The contribution of the sympathetic nervous system to the maintenance of arterial pressure of both groups was evaluated by the magnitude of the fall in MAP observed after the hexamethonium injection combined with the previous AT1 receptor antagonism by losartan. The AT1 receptor antagonism was important to prevent activation of the renin–angiotensin system, resulting from the large fall in arterial pressure after ganglionic blockade, which might mask the net effect of the sympathetic withdrawal.
Plasma catecholamine measurements
In selected CIH and control rats (CIH rats, n = 10; control rats, n = 10), after recording of baseline MAP and HR, the animals were killed by decapitation and the trunk blood was collected into tubes containing heparin. The plasma was separated by centrifugation at 1940 g for 20 min at 4°C, and the plasma levels of noradrenaline (NA) and adrenaline (ADR) were determine by HPLC (LC-10 A, Shimadzu Instruments, Duisburg, Germany) with electrochemical detection (L-ECD-6A, Shimadzu Instruments, Duisburg, Germany) with a Shim-pack CLC-ODS (M) (5 µm; Shimadzu) reversed-phase column, as previously described in detail (Garofalo et al. 1996).
Statistical analysis
The data were expressed as means ± S.E.M. and compared using Student's unpaired t test. Differences were considered significant at P < 0.05.
Results
Body weight and baseline MAP and HR
At the end of 35 days of the protocol, CIH rats (n = 31) exhibited a lower body weight (388 ± 6 versus 501 ± 6 g, P < 0.00001) than the control rats (n = 28), despite the fact that at the beginning of the protocol both groups had similar body weights (292 ± 2 versus 295 ± 2 g). Moreover, the rats submitted to CIH exhibited a significant increase in baseline diastolic (97 ± 1 versus 88 ± 1 mmHg, P = 0.0002), mean (112 ± 2 versus 103 ± 1 mmHg, P = 0.0003) and systolic arterial pressure (132 ± 2 versus 120 ± 2 mmHg, P < 0.0001), as well as in baseline HR (389 ± 8 versus 357 ± 6 beats min–1, P = 0.0032) when compared with control rats. Figure 1 summarizes the data related to the baseline MAP and HR of both experimental groups.
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The injection of hexamethonium alone in specific groups of CIH (n = 13) and control rats (n = 10) produced a similar fall in MAP (–46 ± 2 versus –41 ± 3 mmHg), despite the fact that these groups exhibited significant differences with respect to the baseline MAP (114 ± 2 versus 103 ± 3 mmHg, P = 0.0074).
Effect of AT1 receptor antagonism and ganglionic blockade on MAP and HR
Figure 2 illustrates traces from two rats, representative of their respective groups, showing the effects of the sequential injections of losartan and hexamethonium on PAP, MAP and HR of CIH (n = 8) and control rats (n = 8).
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Figure 4 summarizes the data indicating a significant increase in plasma levels of NA in the CIH group (n = 10) in comparison with the control group (n = 10; 10.12 ± 0.90 versus 4.74 ± 0.32 ng ml–1, respectively, P = 0.0042). This figure also shows that the plasma levels of ADR in both groups were not statistically different (14.64 ± 1.05 versus 12.67 ± 1.20 ng ml–1, in CIH and control groups, respectively).
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Several studies have been performed using the experimental model of CIH in order to evaluate the mechanisms involved in the sustained increase of arterial pressure observed after long-term exposure to intermittent hypoxia (Fletcher, 2001; Prabhakar et al. 2001, 2005). Although it is generally accepted that the increase in arterial pressure of rats submitted to CIH is associated with an increase in sympathetic activity, the direct measurement of the sympathetic nerve activity in conscious freely moving rats remains a technical challenge in terms of recording and the comparison of data obtained from multifibre recordings. The present concept of sympathetic overactivity in CIH rats is based upon studies showing that sympathectomy either chemical sympathectomy caused by 6-OH-dopamine or renal sympathetic nerve denervation, before CIH, prevented the increase in arterial pressure (Fletcher et al. 1992b; Bao et al. 1997), but there is no evidence that the increase in MAP in this experimental model is maintained by an increase in sympathetic activity. In the present study, we evaluated the sympathetic activity of CIH rats by ganglionic blockade combined with AT1 receptor antagonism and by the measurement of the plasma levels of catecholamines.
Ganglionic blockade has been extensively used as an index of total sympathetic activity (Guild et al. 2005). By the evaluation of the magnitude of the fall in MAP produced by ganglionic blockade, it is possible to assess indirectly the sympathetic activity to the resistance vessels. However, in the present study, we verified that the fall in MAP in response to hexamethonium alone was similar in CIH and control rats, a finding that at first might suggest that the sympathetic activity in CIH rats was not altered. To check this possibility, in another group of rats, we antagonized the AT1 receptors before producing ganglionic blockade for two reasons: first, to evaluate the contribution of angiotensin II and the AT1 receptors to the maintenance of hypertension in CIH rats; and second, to avoid the possibility that the activation of the renin–angiotensin system during the large fall in MAP produced by ganglionic blockade might bring the baseline MAP to similar level in CIH and control rats as a consequence of the vasoconstrictor effect of angiotensin II. The activation of this hormonal system at the very low level of MAP after hexamethoniun might mask the net effect of sympathetic withdrawal on the MAP.
The injection of losartan produced no changes in MAP of both groups, indicating that angiotensin II and AT1 receptors were not playing a major role in the maintenance of high arterial blood pressure in CIH rats. In contrast, the ganglionic blockade performed after AT1 receptor antagonism produced a greater fall in MAP in the CIH than in the control group. Interestingly, the difference in the magnitude of the fall in MAP observed in CIH and control rats (–58 ± 2 versus –50 ± 2 mmHg, respectively) is similar to the difference between the baseline MAP in CIH and control rats (112 ± 2 versus 103 ± 2 mmHg, respectively). Moreover, after the double blockade, the MAP in CIH and control rats reached similar levels. These data support the concept that the increase in baseline arterial pressure of CIH is mediated by an increase in sympathetic outflow to the vascular beds.
In order to provide additional evidence in favour of a possible increase in sympathetic activity in CIH rats, we also measured the plasma levels of catecholamines because they reflects the sympathetic drive to the resistance vessels (Yamaguchi & Kopin, 1979; Hirakawa et al. 1997). Our data documented that plasma NA in rats submitted to CIH was higher than in control rats, supporting the concept that rats submitted to CIH exhibit sympathetic overactivity. Nevertheless, no changes in plasma ADR were observed in CIH rats.
Based upon studies by Fletcher et al. (1999) showing that the systemic AT1 receptor antagonism during exposure to CIH prevented the increase in MAP, we hypothesized that angiotensin II, acting on peripheral AT1 receptors, might also play a role in the maintenance of hypertension in CIH rats. However, the administration of losartan produced no significant changes in MAP of CIH rats, suggesting that angiotensin II and AT1 receptors do not contribute to the maintenance of high blood pressure in this experimental model. Considering that Collister & Osborn (2005) demonstrated that chronic administration of the AT1 receptor antagonist losartan decreases the baseline MAP of normotensive rats by reducing the baseline sympathetic activity, it is possible that the evidence presented by Fletcher et al. (1999) about the effect of chronic AT1 receptor antagonism in preventing the increase in MAP in CIH rats is, in fact, related to the attenuation in the sympathetic activity produced by losartan. This possibility is also supported by studies showing that losartan can cross the blood–brain barrier (Culman et al. 1999), as well as that plasma angiotensin II can act on AT1 receptors on the blood vessels in the brainstem, with a possible influence on neurones in this region involved in the modulation and generation of sympathetic activity (Paton et al. 2006). The data of the present study support the concept that the maintenance of high blood pressure in rats submitted to CIH is dependent on sympathetic overactivity but not on circulating angiotensin II.
Despite the fact that the evaluation of sympathetic activity by ganglionic blockade and by the measurement of plasma NA reflects the total sympathetic activity, with the present experimental approach it is not possible to determine the contribution of individual vascular beds to the overall effect. However, the tachycardia presented by CIH rats indicates that the thoracic sympathetic nerve activity to the heart is increased. Likewise, studies by Bao et al. (1997), which demonstrated that renal sympathetic nerve denervation, prior to CIH exposure, abolished the increase in arterial pressure, suggested that the renal sympathetic nerve discharge might be increased in CIH rats. However, the level of sympathetic outflow to the different vascular beds and its relationship with hypertension in CIH rats is an important aspect that remains to be investigated.
The observed increase in sympathetic activity in CIH rats is probably associated with changes in important areas of the central nervous system, especially in those related to the generation and/or modulation of sympathetic activity. First, it well known that neuronal activity is sensitivity to low parial pressures of O2, and hypoxia in neurones induces adaptive responses, such as changes in ionic channels, membrane or cytosolic haem proteins, mitochondrial proteins and/or oxygen-sensitive transcription factors including hypoxia-inducible factor-1
and nuclear factor 
ß (NFß) (Semenza, 2000; Peña & Ramirez, 2005; Greenberg et al. 2006). In addition, studies by Greenberg et al. (1999) provided evidence that the neuronal activity of cardiovascular-controlling brainstem areas, such as nucleus tractus solitarii, medullary reticular formation (A1 noradrenergic cell area of the ventrolateral medulla) and mid-line raphe, are altered in rats submitted to CIH. Besides, using an in situ unanaesthetized decerebrated preparation, we observed that juvenile rats submitted to CIH for 10 days exhibited larger sympathoexcitatory, tachypnoeic and bradycardic responses to chemoreflex activation than control rats (Braga et al. 2006), suggesting that the processing of chemoreflex afferents is enhanced in rats submitted to CIH. Therefore, the central mechanisms underlying this observed increase in sympathetic nerve activity in rats submitted to CIH is an important matter that remains to be investigated.
In conclusion, we verified that ganglionic blockade, combined with antagonism of AT1 receptors, produced a larger decrease in MAP of CIH than of control rats. In addition, high plasma levels of NA were observed in CIH rats. These data strongly support the concept that rats submitted to CIH exhibit sympathetic overactivity, which seems to be determinant to the observed increase in arterial pressure observed in this experimental model.
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Acknowledgements
This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (472704/2004-4) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2004/03285-7 and 2004/05410-3).
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P < 0.05 compared with control MAP after losartan; 
P < 0.0001 compared with baseline values. C, magnitude of the fall in mean arterial pressure (
MAP) in response to the combined and sequential antagonism of AT1 receptors (losartan) and ganglionic blockade (hexamethonium) in control and in CIH rats. *P
= 0.0165 compared with control group.