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Chronic intermittent hypoxia impairs endothelium-dependent dilation in rat cerebral and skeletal muscle resistance arteries

¹Department of Physiology, Medical College of Wisconsin, Milwaukee 53226; and Departments of ²Population Health Sciences and ³Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin 53706

Submitted 28 July 2003 ; accepted in final form 16 September 2003

	ABSTRACT

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The goal of the present study was to evaluate the effects of relatively short-term chronic intermittent hypoxia (CIH) on endothelial function of resistance vessels in the skeletal muscle and cerebral circulations. Sprague-Dawley rats were exposed to 14 days of CIH (10% fraction of inspired oxygen for 1 min at 4-min intervals, 12 h/day, n = 6). Control rats (n = 6) were housed under normoxic conditions. After 14 days, resistance arteries of the gracilis muscle (GA) and middle cerebral arteries (MCA) were isolated and cannulated with micropipettes, perfused and superfused with physiological salt solution, and equilibrated with 21% O₂-5% CO₂ in a heated chamber. The arteries were pressurized to 90 mmHg, and vessel diameters were measured via a video micrometer before and after exposure to ACh (10^–7–10^–4 M), sodium nitroprusside (10^–6 M), and acute reduction of PO₂ in the perfusate/superfusate (from 140 to 40 mmHg). ACh-induced dilations of GA and MCA from animals exposed to CIH were greatly attenuated, whereas responses to nitroprusside were similar to controls. Dilations of both GA and MCA in response to acute reductions in PO₂ were virtually abolished in animals exposed to CIH compared with controls. These findings suggest that exposure to CIH reduces the bioavailability of nitric oxide in the cerebral and skeletal muscle circulations and severely blunts vasodilator responsiveness to acute hypoxia.

acetylcholine; gracilis artery; middle cerebral artery; vascular reactivity

Impaired endothelial function in the vessels that lie immediately proximal to the microcirculation could increase vascular resistance and promote the development of hypertension. On the other hand, it has been hypothesized that elevated blood pressure could produce endothelial dysfunction (20). Impaired relaxation or paradoxical vasoconstriction in response to ACh and blunted responses to physiological dilator stimuli such as reduced oxygen availability and increased shear stress have been observed in several experimental models of hypertension (13, 14, 20); however, it is not clear whether this endothelial dysfunction is a cause or a consequence of the elevation in arterial pressure.

To our knowledge, no studies have evaluated the effect of intermittent hypoxia per se on endothelial function in the absence of hypertension. Therefore, the goal of the present study was to test the hypothesis that chronic intermittent hypoxia (CIH), applied for a relatively brief duration that does not result in a sustained increase in arterial pressure, impairs responses to vasodilator stimuli in resistance arteries of the cerebral and skeletal muscle circulations.

	MATERIALS AND METHODS

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Animals. Age-matched, male Sprague-Dawley rats (Harlan Teklad; Madison, WI) weighing 250–400 g at the time of arrival were used for all experiments. Each rat was fed standard rat chow (Purina) and provided drinking water ad libitum during exposure to either intermittent normoxia or hypoxia. All rats were housed in an animal care facility at the University of Wisconsin-Madison, which is approved by the American Association for the Accreditation of Laboratory Animal Care, and all protocols were approved by the Medical School's Animal Care and Use Committee. On the day of the study, rats exposed to normoxic and hypoxic conditions were weighed and anesthetized with an injection of pentobarbital sodium (50 mg/kg ip, Abbott Laboratories; Chicago, IL), and a carotid artery was cannulated with polyethylene tubing for arterial pressure measurement before the isolation of cerebral and skeletal muscle resistance arteries (see Preparation of isolated vessels).

Hypoxic exposure. Rats were exposed to CIH for 12 h/day (from 1800 hours to 0600 hours) for 14 days. In the hypoxia chamber, rats were housed three per cage, in accordance with space recommendations set forth in the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, Revised 1985). Oxygen concentrations in the chamber were monitored using a heated zirconium sensor (Fujikura America; Pittsburgh, PA) connected to solenoid valves that controlled the flow of oxygen and nitrogen. The valves were operated by a microprocessor-controlled timer. This system was set to provide hypoxic exposures at 4-min intervals. The first minute of each exposure was transitional, with nitrogen flushed into the chamber at a rate sufficient to achieve a fraction of inspired oxygen (FI_O2) of 0.10 within 60 s and to maintain this level of FI_O2 for an additional minute. Oxygen was then introduced at a rate sufficient to achieve a FI_O2 of 0.209 within 30 s and to maintain this level of FI_O2 for the remainder of the 4-min interval. Daily checks of chamber oxygen concentrations during hypoxia and normoxia were made using a TED60T oxygen sensor (Teledyne; City of Industry, CA). Figure 1 provides an illustration, obtained via a mass spectrometer, of the FI_O2 profile produced by our intermittent hypoxia protocol. The temperature of the chamber was maintained at 22 ± 1°C, and the relative humidity was maintained between 30 and 70%.

View larger version (32K): [in this window] [in a new window]   Fig. 1. Representative trace of the atmospheric changes that occurred during exposure to intermittent hypoxia. Percent O2 was determined by continuous sampling from the chamber using a mass spectrometer. Intermittent hypoxia was achieved by flushing nitrogen into the chamber until the O2 concentration reached 10%. Hypoxia was maintained for 1 min, after which oxygen was flushed into the chamber to reestablish normoxia, as described in MATERIALS AND METHODS.

Normoxic exposure. Three rats were maintained in standard housing conditions of the animal care facility, whereas three rats were maintained for 14 days under normoxic conditions in the hypoxia chamber, where they were subjected to the same noises and airflow perturbations experienced by the hypoxia-exposed rats.

Preparation of isolated vessels. The small muscular branch of the femoral artery supplying the gracilis muscle was freed from surrounding tissue and allowed to equilibrate in situ for 30 min with the application of warm physiological salt solution (PSS). After the equilibration period, the artery was carefully excised. The anesthetized rats were then decapitated, and the brain was quickly removed and transferred to a Lucite-coated petri dish for removal of the middle cerebral artery (MCA). The MCA and the gracilis artery were located using a dissecting microscope (Leica; Buffalo, NY) and carefully isolated to separate the vessel from the surrounding parenchymal tissue. Both vessels were immediately immersed in warmed PSS bubbled with 21% O₂-5% CO₂-74% N₂. The PSS used in these experiments had the following ionic composition (in mM): 119.0 NaCl, 4.7 KCl, 1.6 CaCl₂, 1.18 NaH₂PO₄, 1.17 MgSO₄, 24.0 NaHCO₃, 5.5 dextrose, and 0.03 EDTA. The arteries were handled by the adhering connective tissue only to avoid damage to the endothelium and smooth muscle layers.

The proximal and distal ends of the MCA and gracilis artery were cannulated with glass micropipettes (100–150 µm, FHC; Brunswick, ME) and secured to the pipettes using 10-0 nylon sutures in a superfusion-perfusion chamber (10, 21). The vessels were stretched to the in situ length, and side branches were singly ligated with small strands teased from a 6-0 silk suture (Ethicon; Somerville, NJ) to ensure optimal pressurization. The inflow pipette was connected to a reservoir perfusion system that allowed the intraluminal pressure and luminal gas concentration to be controlled. Vessel diameter was measured using television microscopy and a video micrometer. Any vessel that did not exhibit significant levels of active tone (as evidenced by a substantial increase in resting diameter upon exposure to Ca²⁺-free PSS) was not used in this study. The level of resting tone in the vessel was calculated as follows: , where T is resting tone (in %), D is the diameter increase in the maximally relaxed vessel, and D_max represents the maximum diameter of the vessel at that pressure.

Response to reduced PO₂. After the initial control period in PSS equilibrated with 21% O₂, the responses of gracilis arteries and MCA to reduced PO₂ were assessed in each group. PO₂ reduction was achieved by simultaneous perfusion and superfusion of the arteries for 25 min with PSS equilibrated with 0% O₂-5% CO₂-95% N₂ as previously described (10). Under these conditions, control values for PO₂ during 21% O₂ perfusion and superfusion are 140 Torr, whereas equilibration of the PSS reservoirs with 0% O₂ reduces both the luminal and extraluminal PO₂ to 35–45 Torr (10). After exposure of the vessels to hypoxia, the perfusate and superfusate were reequilibrated with 21% O₂ for 20 min, and recovery from reduced PO₂ was verified by measuring the vessel diameter.

Response to vasodilator agents and Ca²⁺-free solution. The responses of resistance arteries to the endothelium-dependent vasodilator ACh (10^–7–10^–4 M) and the nitric oxide (NO) donor sodium nitroprusside (10^–6 M, Sigma; St. Louis, MO) were assessed in cerebral and skeletal muscle vessels in each group of rats. When these drugs were administered, the superfusion was stopped in the bath, the vessel was pressurized by clamping the outflow pipette, and an appropriate amount of drug was added to the tissue chamber to achieve the final desired concentration in the superfusion solution. Vessel diameter was monitored continuously and was measured at the point of its maximum value after the addition of the dilator agent.

After the response of the arteries to the various vasodilator stimuli had been determined, vessel diameter was determined after the vessels were maximally dilated with Ca²⁺-free relaxing solution containing the following constituents (in mM): 92.0 NaCl, 4.7 KCl, 1.17 MgSO₄·7H₂O, 20.0 MgCl·6H₂O, 1.18 NaH₂PO₄, 24.0 NaHCO₃, 0.026 EDTA, 2.0 EGTA, and 5.5 dextrose.

Statistical analysis. All data are expressed as means ± SE. Responses to incremental doses of ACh were analyzed with two-way repeated-measures ANOVA. Significant differences between the individual means after two-way ANOVA were determined using a Student-Newman-Keuls post hoc test. Differences in the responses to hypoxia, nitroprusside, and maximal dilation in calcium-free solution between groups were determined utilizing an unpaired t-test.

	RESULTS

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Mean arterial pressure, body weight, and vessel diameter. Table 1 summarizes data describing the rats exposed to normoxia or intermittent hypoxia for 14 days. Although resting diameter (Table 1) and maximum diameter of the vessels in Ca²⁺-free solution tended to be reduced in arteries of animals receiving hypoxic exposure, the difference between animals exposed to normoxia (gracilis: 178 ± 6.0 µm; MCA: 192 ± 13.4 µm) and those exposed to CIH (gracilis: 169 ± 11.9 µm; MCA: 164 ± 8.6 µm) was not statistically significant. In addition, there was no significant difference in body weight or mean arterial pressure between groups.

Response of resistance arteries to ACh and sodium nitroprusside. Figures 2 and 3 summarize the response of resistance arteries to ACh in animals exposed to normoxia or intermittent hypoxia. In these experiments, cerebral and skeletal muscle arteries from animals maintained under normoxic conditions for 14 days demonstrated a pronounced dilation to incremental doses of ACh (10^–7–10^–4 M), similar to previous results (10). There were no significant differences in the responses to ACh (10^–5 M) in vessels of animals exposed to standard normoxic conditions (gracilis: 17 ± 1.7 µm; MCA: 19 ± 1.3 µm) or housed under normoxic conditions in the hypoxia chamber (gracilis: 24 ± 2.0 µm; MCA: 21 ± 0.5 µm). However, dilation of skeletal muscle and cerebral arteries to ACh was significantly reduced in animals exposed to intermittent hypoxia for 14 days (Figs. 2 and 3). The responses of skeletal muscle and cerebral resistance arteries from rats administered normoxia and intermittent hypoxia to the NO donor sodium nitroprusside are summarized in Fig. 4. In contrast to vessel responses to ACh, exposure to CIH had no effect on the vascular relaxation in response to sodium nitroprusside in either skeletal muscle or cerebral resistance arteries.

View larger version (12K): [in this window] [in a new window]   Fig. 2. Response to10–7–10–4 M ACh in gracilis arteries of rats exposed to normoxia or chronic intermittent hypoxia (CIH) for 14 days (n = 6 rats/group). Data are presented as mean changes in diameter (in µm) ± SE from control measured before the application of ACh. *Significant difference from the response of vessels from normoxic control animals, P < 0.05.

View larger version (13K): [in this window] [in a new window]   Fig. 3. Response to 10–7–10–4 M ACh in middle cerebral arteries of rats exposed to normoxia and CIH for 14 days (n = 6 rats/group). Data are presented as mean changes (in µm) ± SE from the diameter measured before application of ACh. *Significant difference from the response of vessels from normoxic control animals, P < 0.05.

View larger version (11K): [in this window] [in a new window]   Fig. 4. Responses to sodium nitroprusside (10–6 M) in isolated gracilis arteries (A) and middle cerebral arteries (B) from animals exposed to normoxia or CIH for 14 days (n = 5–6). Data are presented as means ± SE. There was no significant difference in the response of vessels to nitroprusside in normoxic control animals and animals exposed to CIH.

Responses of resistance arteries to acute reductions in PO₂. Figure 5 summarizes the responses of skeletal muscle (A) and cerebral resistance arteries (B) to acute hypoxia in rats exposed to normoxia or intermittent hypoxia for 14 days. Arteries from rats exposed to normoxia demonstrated a significant increase in diameter in response to reduced PO₂, as previously reported in both skeletal muscle (10) and cerebral resistance arteries (21). However, gracilis arteries (Fig. 5A) and MCA (Fig. 5B) from rats receiving intermittent hypoxia for 14 days failed to dilate in response to an acute reduction in perfusate and superfusate PO₂ from 140 to 35–45 Torr. As in the case of ACh, there was no significant difference in the vasodilator responses to acute hypoxia in vessels from animals exposed to standard normoxic conditions (gracilis: 16 ± 1.2 µm; MCA: 15 ± 2.5 µm) or housed under normoxic conditions in the hypoxia chamber (gracilis: 25 ± 1.3 µm; MCA: 13 ± 1.2 µm). However, gracilis arteries (Fig. 5A) and MCA (Fig. 5B) from rats receiving intermittent hypoxia for 14 days failed to dilate in response to an acute reduction in perfusate and superfusate PO₂ from 140 to 35–45 Torr.

View larger version (10K): [in this window] [in a new window]   Fig. 5. Responses to simultaneous reduction of perfusate and superfusate O2 concentration from 21% to 0% O2 in isolated gracilis arteries (A) and middle cerebral arteries (B) of animals exposed to normoxia or CIH for 14 days (n = 5–6). Data are presented as mean changes in diameter from the 21% O2 control value (in µm) ± SE. *Significant difference from the response of arteries from normoxic control animals, P < 0.05.

Maximal relaxation in calcium-free PSS. Figure 6 shows the responses to calcium-free PSS in skeletal muscle (A) and cerebral resistance arteries (B) from rats administered normoxia or intermittent hypoxia for 14 days. Maximal dilation of both vessel types was unaltered by exposure to intermittent hypoxia. There was also no significant difference in the resting active tone of gracilis arteries from rats administered normoxia (%tone: 16 ± 2.9, n = 5) and intermittent hypoxia (%tone: 23 ± 2.8, n = 6) or in the resting active tone of MCA from animals administered normoxia (%tone: 23 ± 7.2, n = 5) or intermittent hypoxia (%tone: 19 ± 3.5, n = 5).

View larger version (11K): [in this window] [in a new window]   Fig. 6. Maximal dilation of gracilis (A) and middle cerebral (B) arteries (n = 4–5) in Ca2+-free physiological salt solution. Data are presented as changes in mean internal diameter (in µm) ± SE. There were no significant differences in the response of vessels from animals exposed to normoxia versus CIH.

	DISCUSSION

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In the present study, exposure to CIH for 14 days significantly impaired endothelium-dependent vasodilator responses to ACh (Figs. 2 and 3) and acute hypoxia (Fig. 5) in resistance arteries from the skeletal muscle and cerebral vascular beds but did not alter vessel responses to the NO donor sodium nitroprusside (Fig. 4) or maximal dilation of the arteries in Ca²⁺-free PSS (Fig. 6). These observations suggest that impaired vasodilator responses in resistance arteries are due to altered mechanisms of endothelium-dependent vascular relaxation after exposure to intermittent hypoxia rather than altered sensitivity to NO or structural impairments in the arterial wall that restrict the vessels' ability to increase their diameter in response to dilator stimuli. This impairment of endothelial function was evident before the development of hypertension in this experimental model (known to raise blood pressure), because mean arterial pressures were nearly identical in the hypoxia- and normoxia-exposed rats (Table 1).

Previous studies of animal models indicate that the primary prohypertensive component of CIH is transient blood oxygen desaturation (4, 9, 26, 31) rather than the hypercapnia and sleep disruption that occurs during sleep-disordered breathing (3, 4). The present findings, obtained in a model that produces hypocapnic hypoxia, suggest that hypoxia is also the primary stimulus that impairs endothelial function, because rats exposed to the same noise and cage environment during normoxia did not demonstrate similar alterations in their responses to dilator stimuli.

The sensitivity of blood vessels to vasoactive stimuli has been extensively studied during hypertension and sleep-disordered breathing (2, 16, 22, 28). For example, a previous study by Tahawi et al. (30) reported impaired responses to ACh in cremasteric arterioles of rats exposed to chronic episodic hypoxia, concomitant with a significant elevation in blood pressure. However, virtually no studies to date have determined the effect of systemic exposure to intermittent hypoxia on vascular reactivity in the absence of hypertension. Thus the present study is the first to document the effects of exposure to CIH per se on responses of isolated skeletal muscle and cerebral resistance arteries to vasodilator stimuli and to demonstrate that CIH can lead to impaired vascular reactivity in the absence of elevated arterial pressure.

Effect of intermittent hypoxia on NO-dependent vasodilation. As noted above, previous studies have demonstrated impaired responses to ACh in arterioles of Sprague-Dawley rats treated with intermittent hypoxia for 35 days (30). ACh-induced dilation is normally mediated via NO but also may involve the release of several different vasoactive compounds (1, 6, 15, 17, 18), depending on the specific vessel studied. Previous studies in our laboratory have determined that the vascular response to ACh is mediated by NO released from the endothelium in rat skeletal muscle and cerebral resistance arteries (29) and that ACh-induced vascular relaxation in both of these arteries is impaired in hypertension (12, 20). In the present study, skeletal muscle and cerebral resistance arteries of rats administered normoxia for 14 days exhibited a significant dilator response to ACh (10^–7–10^–4 M), similar to previous reports in this laboratory (10) (Figs. 2 and 3). However, vasodilator responses to the same doses of ACh were significantly impaired in arteries of rats exposed to intermittent hypoxia (Figs. 2 and 3). These findings suggest that vasodilation to ACh is impaired in CIH due to reductions in the synthesis and/or release of NO by the endothelium, because the responses of the vessels to sodium nitroprusside, an endothelium-independent, NO-mediated dilator, were unaltered by CIH (Fig. 4, A and B).

Effect of CIH on maximal relaxation of skeletal muscle and cerebral resistance arteries. In the present study, there was no difference in the maximal relaxation occurring in response to Ca²⁺-free PSS in CIH versus control rats (Fig. 6). The latter observation demonstrates that 14 days of CIH exposure does not cause structural narrowing of the vessels and that the diminished ability of these arteries to respond to vasodilator stimuli is not due to constraints resulting from structural alterations in the vessel wall, which can contribute to the impaired ability of arteries to respond to vasodilator stimuli in hypertension.

Effect of CIH on acute hypoxia-induced dilation in skeletal muscle and cerebral resistance arteries. In the present study, isolated cerebral and skeletal muscle resistance arteries from normoxic rats demonstrated a significant increase in diameter in response to a simultaneous reduction in superfusion and perfusion PO₂ (Fig. 5A), similar to observations reported in previous studies (10, 20). However, dilator responses to acute hypoxia were completely abolished in arteries from rats subjected to CIH (Fig. 5B). This alteration in the ability of arteries to dilate in response to hypoxia may be important in the development and progression of hypertension caused by sleep-disordered breathing. The finding that gracilis arteries and MCA fail to dilate during acute exposure to hypoxia is important because it demonstrates that short-term exposure to intermittent hypoxia can lead to alterations in the signaling mechanisms that mediate hypoxic dilation of resistance arteries, independent of elevations in arterial blood pressure.

Although the mechanism by which intermittent hypoxia causes impairments in the ability of resistance arteries to respond to endothelium-dependent vasodilator stimuli is unknown, other investigators have determined that elevated levels of reactive oxygen species deplete vascular NO during hypertension and exposure to sustained hypoxia (11, 19, 27, 31). Coupled with studies suggesting that patients with obstructive sleep apnea have increased superoxide generation (24), additional studies investigating the role of reactive oxygen species in the vasculature of this model of sleep-disordered breathing seem to be warranted. Future studies of the effect of CIH on vascular control mechanisms may be important in determining factors that cause individuals to develop hypertension as a consequence of sleep-disordered breathing. It is possible that endothelial dysfunction arising from CIH may impair blood flow regulation and compromise tissue perfusion and oxygen delivery during stresses such as hemorrhage, exercise, and episodes of hypoxemia caused by sleep-disordered breathing, even in the absence of a significant elevation of arterial blood pressure.

	ACKNOWLEDGMENTS

 
GRANTS

This study was supported by National Heart, Lung, and Blood Grants HL-65289, HL-29857, and HL-72920.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. H. Lombard, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: jlombard{at}mcw.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Amezcua JL, Dusting GJ, Palmer RM, and Moncada S. Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator. Br J Pharmacol 95: 830–834, 1988.[Web of Science][Medline]
2. Auch-Schwelk W and Vanhoutte PM. Endothelium-derived contracting factor released by serotonin in the aorta of the spontaneously hypertensive rat. Am J Hypertens 4: 769–772, 1991.[Web of Science][Medline]
3. Bao G, Metreveli N, and Fletcher EC. Acute and chronic blood pressure response to recurrent acoustic arousal in rats. Am J Hypertens 12: 504–510, 1999.[CrossRef][Web of Science][Medline]
4. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, and Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 99: 106–109, 1997.[Web of Science][Medline]
5. Carlson JT, Rangemark C, and Hedner JA. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. J Hypertens 14: 577–584, 1996.[CrossRef][Web of Science][Medline]
6. Chen G, Suzuki H, and Weston AH. Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels. Br J Pharmacol 95: 1165–1174, 1988.[Web of Science][Medline]
7. Dart RA, Gregoire JR, Gutterman DD, and Woolf SH. The association of hypertension and secondary cardiovascular disease with sleep-disordered breathing. Chest 123: 244–260, 2003.[CrossRef][Web of Science][Medline]
8. Fletcher EC and Bao G. The rat as a model of chronic recurrent episodic hypoxia and effect upon systemic blood pressure. Sleep 19: S210–S212, 1996.[Web of Science][Medline]
9. Fletcher EC, Bao G, and Miller CC III. Effect of recurrent episodic hypocapnic, eucapnic, and hypercapnic hypoxia on systemic blood pressure. J Appl Physiol 78: 1516–1521, 1995.[Abstract/Free Full Text]
10. Fredricks KT, Liu Y, and Lombard JH. Response of extraparenchymal resistance arteries of rat skeletal muscle to reduced PO₂. Am J Physiol Heart Circ Physiol 267: H706–H715, 1994.[Abstract/Free Full Text]
11. Frisbee JC. Impaired dilation of skeletal muscle microvessels to reduced oxygen tension in diabetic obese Zucker rats. Am J Physiol Heart Circ Physiol 281: H1568–H1574, 2001.[Abstract/Free Full Text]
12. Frisbee JC and Lombard JH. Development and reversibility of altered skeletal muscle arteriolar structure and reactivity with high salt diet and reduced renal mass hypertension. Microcirculation 6: 215–225, 1999.[CrossRef][Web of Science][Medline]
13. Frisbee JC, Roman RJ, Falck JR, Linderman JR, and Lombard JH. Impairment of flow-induced dilation of skeletal muscle arterioles with elevated oxygen in normotensive and hypertensive rats. Microvasc Res 60: 37–48, 2000.[CrossRef][Web of Science][Medline]
14. Frisbee JC, Roman RJ, Krishna UM, Falck JR, and Lombard JH. Altered mechanisms underlying hypoxic dilation of skeletal muscle resistance arteries of hypertensive versus normotensive Dahl rats. Microcirculation 8: 115–127, 2001.[CrossRef][Web of Science][Medline]
15. Jaiswal N and Malik KU. Prostacyclin synthesis elicited by cholinergic agonists is linked to activation of M2 alpha and M2 beta muscarinic receptors in the rabbit aorta. Prostaglandins 39: 267–280, 1990.[CrossRef][Web of Science][Medline]
16. Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, and Somers VK. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102: 2607–2610, 2000.[Abstract/Free Full Text]
17. Keef KD and Bowen SM. Effect of ACh on electrical and mechanical activity in guinea pig coronary arteries. Am J Physiol Heart Circ Physiol 257: H1096–H1103, 1989.[Abstract/Free Full Text]
18. Komori K and Suzuki H. Heterogeneous distribution of muscarinic receptors in the rabbit saphenous artery. Br J Pharmacol 92: 657–664, 1987.[Web of Science][Medline]
19. Lenda DM, Sauls BA, and Boegehold MA. Reactive oxygen species may contribute to reduced endothelium-dependent dilation in rats fed high salt. Am J Physiol Heart Circ Physiol 279: H7–H14, 2000.[Abstract/Free Full Text]
20. Liu Y, Fredricks KT, Roman RJ, and Lombard JH. Response of resistance arteries to reduced PO₂ and vasodilators during hypertension and elevated salt intake. Am J Physiol Heart Circ Physiol 273: H869–H877, 1997.[Abstract/Free Full Text]
21. Lombard JH, Liu Y, Fredricks KT, Bizub DM, Roman RJ, and Rusch NJ. Electrical and mechanical responses of rat middle cerebral arteries to reduced PO₂ and prostacyclin. Am J Physiol Heart Circ Physiol 276: H509–H516, 1999.[Abstract/Free Full Text]
22. Panza JA, Casino PR, Badar DM, and Quyyumi AA. Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 87: 1475–1481, 1993.[Abstract/Free Full Text]
23. Peppard PE, Young T, Palta M, and Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342: 1378–1384, 2000.[Abstract/Free Full Text]
24. Schulz R, Schmidt D, Blum A, Lopes-Ribeiro X, Lucke C, Mayer K, Olschewski H, Seeger W, and Grimminger F. Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy. Thorax 55: 1046–1051, 2000.[Abstract/Free Full Text]
25. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier NF, O'Connor GT, Boland LL, Schwartz JE, and Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 163: 19–25, 2001.[Abstract/Free Full Text]
26. Sica AL, Greenberg HE, Ruggiero DA, and Scharf SM. Chronic-intermittent hypoxia: a model of sympathetic activation in the rat. Respir Physiol 121: 173–184, 2000.[CrossRef][Web of Science][Medline]
27. Steiner DR, Gonzalez NC, and Wood JG. Interaction between reactive oxygen species and nitric oxide in the microvascular response to systemic hypoxia. J Appl Physiol 93: 1411–1418, 2002.[Abstract/Free Full Text]
28. Suzuki H, Ikezaki H, Hong D, and Rubinstein I. PGH₂-TxA₂ receptor blockade restores vasoreactivity in a new rodent model of genetic hypertension. J Appl Physiol 88: 1983–1988, 2000.[Abstract/Free Full Text]
29. Sylvester FA, Stepp DW, Frisbee JC, and Lombard JH. High-salt diet depresses acetylcholine reactivity proximal to NOS activation in cerebral arteries. Am J Physiol Heart Circ Physiol 283: H353–H363, 2002.[Abstract/Free Full Text]
30. Tahawi Z, Orolinova N, Joshua IG, Bader M, and Fletcher EC. Altered vascular reactivity in arterioles of chronic intermittent hypoxic rats. J Appl Physiol 90: 2007–2013, 2001.[Abstract/Free Full Text]
31. Vaziri ND and Wang ZQ. Sustained systemic arterial hypertension induced by extended hypobaric hypoxia. Kidney Int 49: 1457–1463, 1996.[Web of Science][Medline]
32. Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, and Skatrud J. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 157: 1746–1752, 1997.[Abstract/Free Full Text]

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				N. Sakai, R. Mizuno, N. Ono, H. Kato, and T. Ohhashi High oxygen tension constricts epineurial arterioles of the rat sciatic nerve via reactive oxygen species Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1498 - H1507. [Abstract] [Full Text] [PDF]

				P. N. Ainslie, A. Barach, K. J. Cummings, C. Murrell, M. Hamlin, and J. Hellemans Cardiorespiratory and cerebrovascular responses to acute poikilocapnic hypoxia following intermittent and continuous exposure to hypoxia in humans J Appl Physiol, May 1, 2007; 102(5): 1953 - 1961. [Abstract] [Full Text] [PDF]

				G. E. Foster, P. J. Hanly, M. Ostrowski, and M. J. Poulin Effects of Continuous Positive Airway Pressure on Cerebral Vascular Response to Hypoxia in Patients with Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 720 - 725. [Abstract] [Full Text] [PDF]

				G. E. Foster, M. J. Poulin, and P. J. Hanly Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea Exp Physiol, January 1, 2007; 92(1): 51 - 65. [Abstract] [Full Text] [PDF]

				C. J. Lai, C. C. H. Yang, Y. Y. Hsu, Y. N. Lin, and T. B. J. Kuo Enhanced sympathetic outflow and decreased baroreflex sensitivity are associated with intermittent hypoxia-induced systemic hypertension in conscious rats J Appl Physiol, June 1, 2006; 100(6): 1974 - 1982. [Abstract] [Full Text] [PDF]

				E. B. Manukhina, H. F. Downey, and R. T. Mallet Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Experimental Biology and Medicine, April 1, 2006; 231(4): 343 - 365. [Abstract] [Full Text] [PDF]

				S. A. Phillips, E. B. Olson, J. H. Lombard, and B. J. Morgan Chronic intermittent hypoxia alters NE reactivity and mechanics of skeletal muscle resistance arteries J Appl Physiol, April 1, 2006; 100(4): 1117 - 1123. [Abstract] [Full Text] [PDF]

				C. Hinojosa-Laborde and S. W. Mifflin Sex Differences in Blood Pressure Response to Intermittent Hypoxia in Rats Hypertension, October 1, 2005; 46(4): 1016 - 1021. [Abstract] [Full Text] [PDF]

				G. E. Foster, D. C. McKenzie, W. K. Milsom, and A. W. Sheel Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia J. Physiol., September 1, 2005; 567(2): 689 - 699. [Abstract] [Full Text] [PDF]

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