Published online before print May 12, 2008, doi: 10.1161/HYPERTENSIONAHA.108.110296
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(Hypertension. 2008;52:156.)
© 2008 American Heart Association, Inc.
Original Articles |
Postnatal Intermittent Hypoxia and Developmental Programming of Hypertension in Spontaneously Hypertensive Rats
The Role of Reactive Oxygen Species and L-Ca2+ Channels
From the Kosair Children’s Hospital Research Institute (G.K.S-O., D.G.), Department of Pediatrics, Institute of Molecular Cardiology (R.V.O., Y.G., S.D.P.), Department of Medicine, and Department of Pharmacology and Toxicology (D.G.), University of Louisville, Ky; Department of General Physiology (G.K.S-O., A.D.N.), St Petersburg State University, St Petersburg, Russia; Medical Service (S.D.P.), and the Louisville Veterans’ Affairs Medical Center, Louisville, Ky.
Correspondence to David Gozal, University of Louisville, Department of Pediatrics, KCHRI, 570 S Preston St, Ste 204, Louisville, KY 40202. E-mail david.gozal{at}louisville.edu
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Abstract |
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Obstructive and central apneas during sleep are associated with chronic intermittent hypoxia (CIH) and increased cardiovascular morbidity. Spontaneously hypertensive rats exposed to CIH during postnatal days 4 to 30 develop exaggerated hypertension as adults. We hypothesized that reactive oxygen species and altered L-Ca2+ channel activity may underlie the postnatal programming of exaggerated blood pressure and cardiac remodeling. Newborn male spontaneously hypertensive rats were exposed to CIH (10% and 21% O2 alternating every 90 seconds, 12 h/d, for postnatal days 4 to 30) or normoxia (room air). In each condition, spontaneously hypertensive rats received daily (SC) 1 of 3 treatments: L-calcium channel blocker nifedipine (5 mg/kg), superoxide dismutase mimetic MnTMPyP pentachloride (10 mg/kg), or vehicle (polyethylene glycol). Blood pressure was evaluated monthly for 6 months after birth, and echocardiographic assessments were conducted at 6 months of age. CIH vehicle-treated rats presented higher systolic blood pressure (187±5 mm Hg) as compared with normoxic vehicle treated controls (163±2 mm Hg; P<0.001). Postnatal CIH elicited marked increases in left ventricular wall thickness in a pattern of concentric hypertrophy with augmented systolic contractility. The treatment with nifedipine in the CIH group attenuated blood pressure (159±2 mm Hg; P<0.001) and normalized left ventricular wall thickness and systolic function, whereas the treatment with SOD mimetic decreased blood pressure (165±2 mm Hg; P<0.001) and reduced left ventricular wall thickness without changes in the systolic function. We conclude that Ca2+ and reactive oxygen species–mediated signaling during intermittent hypoxia are critical mechanisms underlying postnatal programming of an increased severity of hypertension and hypertrophic cardiac remodeling in a genetically susceptible rodent model.
Key Words: intermittent hypoxia • calcium channels • oxidative stress • sleep apnea • hypertension
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Introduction |
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Intermittent hypoxia (IH) during sleep is one of the characteristics of sleep apnea that is associated with substantial cardiovascular (CV) morbidity, such as hypertension and heart failure. Sleep-disordered breathing with apneic episodes and intermittent hypoxemia are frequently encountered in young children1; however, the potential consequences of postnatal IH on adult CV dysfunction are not clear. There is accumulating evidence that IH is associated with an increased oxidative stress2–6 and that redox signaling during this condition has been extensively implicated in CV pathophysiology, including some forms of hypertension and cardiac function.2,7–9 Perinatal L-arginine and antioxidant supplements were shown to reduce blood pressure (BP) in adult spontaneously hypertensive rats (SHRs), suggesting a critical role of oxidative status during perinatal development in programming BP later in life.10 In previous work from our laboratory, we demonstrated that SHRs exposed for the first 30 days of postnatal life to a chronic intermittent hypoxia (CIH) regimen that mimics sleep apnea will develop much more severe hypertension as adults when compared with normoxic controls.11 The long-term effects of CIH were most likely mediated by the interaction between genetic predisposition for hypertension, as seen in SHRs, and the persistent blunting of baroreflex functions, as elicited by CIH. Interestingly, normotensive Sprague-Dawley rats exposed to perinatal chronic IH for the same time frame will not develop elevated BPs as young adults, despite persistently blunted baroreceptor function. This may suggest activation of redundant mechanisms aiming to preserve normal BPs.11,12
Previous studies have shown that SHRs experience oxidative stress because of enhanced production of reactive oxygen species (ROS) by increased reduced nicotinamide-adenine dinucleotide phosphate oxidase13 and xanthine oxidase14 activity and also through dysfunctional endothelial NO synthase (uncoupled).15 Impaired endothelium-mediated vasodilation in hypertension has been linked to decreased NO synthesis or to increased NO degradation because of its interaction with O2– to form ONOO–.16 ROS also lead to apoptosis of endothelial cells, loss of microvessels in SHR,17 and promote leukocyte adhesion to the endothelium resulting in further ROS release.18 Inhibition of ROS generation with apocynin (a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor) or allopurinol (a xanthine oxidase inhibitor) and radical scavenging with antioxidants or SOD mimetics decreased systemic BP and prevented development of hypertension in most animal models of hypertension. The beneficial effects of these antioxidant strategies have been attributed to the following: (1) normalization of endothelial function, (2) regression of vascular remodeling, (3) reduced vascular inflammation, and (4) improved renal function.15
One of the instant early responses to hypoxia in various cell types is an increase in intracellular Ca2+ ([Ca2+]i) that could be implicated in ROS-mediated CV effects. ROS increase the cytosolic Ca2+ level through mobilization of intracellular Ca2+ stores and/or through the influx of extracellular Ca2+.19–22 A direct modulation of Ca2+ channels by ROS and ROS-dependent increases in vascular intracellular Ca2+ primarily via extracellular Ca2+ influx have been conclusively demonstrated.19,23,24 In cardiac and vascular tissues, 2 types of Ca2+ channels (L- and T-type) are present,25 and high voltage-gated L-Ca2+ channels play a critical role in excitation-contraction coupling in cardiac, skeletal, and smooth muscle tissue.
We examined the hypothesis that ROS and L-Ca2+ channels are involved in long-term alterations of CV function observed in adult SHRs after postnatal exposures to CIH. We, therefore, evaluated the protective roles of antioxidant treatment with the superoxide dismutase mimetic MnTMPyP pentachloride and with the L-type Ca2+ channel blocker nifedipine in preventing the more severe hypertensive phenotype and cardiac remodeling induced by postnatal CIH in SHRs.
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Materials and Methods |
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All of the experimental protocols were approved by the University of Louisville Institutional Animal Use and Care Committee and were in accordance with National Institutes of Health requirements for the care and use of laboratory animals.
Experimental Groups
Pregnant SHRs were purchased from Charles River Laboratories (Wilmington, MA). Litters were randomly assigned into 1 of 6 groups. Rats of the first 3 groups were exposed to chronic IH as described previously11,12 from postnatal days 4 to 30 (pups exposed at day 1 had a poor survival rate). During this time they received daily SC injections of the following: (1) ROS scavenger SOD mimetic MnTMPyP pentachloride (manganese [III] tetrakis [1-methyl-4-pyridyl] porphyrin pentachloride; 10 mg/kg per day; Alexis Biochemical Corp); (2) L-type Ca2+ channel blocker nifedipine (5 mg/kg per day in 0.02 mL of polyethylene glycol 400; Sigma); (3) vehicle (polyethylene glycol and polyethylene glycol 400, 0.02 mL/d; Sigma). Three other groups of SHRs received similar treatments but were exposed to room air (RA) as normoxic controls. Accordingly, the groups were labeled as IH/RA-SODm, IH/RA-Nif, and IH/RA. All of the pups undergoing IH exposures were returned to normoxic conditions after postnatal day 30. For the present experiments, measurements were conducted only in male rats (n=8 per experimental group) to circumvent potential hormonal confounders on BP. Systemic BP was evaluated every 30 days until 6 months of age, at which time echocardiographic assessment of left ventricular (LV) function was performed.
Lipid Peroxidation
Total lipid peroxides were measured as the sum of malonaldehyde and 4-hydroxyalkenals using a commercially available kit (Bioxytech LPO-586; Oxisresearch, OXIS International, Inc) using cardiac tissue homogenates from rat pups exposed to IH from day 4 for 2 weeks and treated with either vehicle or the SOD mimetic. Protein concentration was determined using a Protein Assay kit (Bio-Rad Laboratories).
BP Measurements
Automated occlusion plethysmography (tail cuff method) was used and involved an analog-to-digital signal converter and a digital acquisition and analysis system (Kent Scientific Corp), as recommended. At least 8 to 10 BP readings were obtained from each rat; these values were then averaged to yield the mean BP for that time point for each rat. Systolic and diastolic pressure and heart rate were measured every 4 weeks, starting at week 4 of postnatal life through week 24.
Echocardiographic Assessment of LV Function
M-mode, 2D, and spectral Doppler echocardiography were performed as described previously.26,27 Imaging was performed under light anesthesia with ketamine (22 mg/kg, IM) and xylazine (2.7 mg/kg, IM), using a Toshiba 380 PowerVision machine and a pediatric broad-band transducer operating at 10-MHz frequency and 120-Hz frame rate. At the age of 6 to 7 months, the following variables were measured: LV end-diastolic and end-systolic diameter (LVEDD and LVESD), anterior wall thickness (AWT) and posterior wall thickness (PWT) at end diastole, and ejection time from the aortic Doppler trace. LV hypertrophy was indexed by relative wall thickness at end diastole (RWT=[AWT+PWT]/LVEDD) and LV systolic function by fractional shortening (FS=[LVEDD–LVESD]/LVEDD) and the mean velocity of circumferential fiber shortening (Vcf=FS/ejection time).
Data Analysis
Data were tabulated, and responses were compared using 1- or 2-way ANOVA or Student t tests, followed by Newman-Keuls posthoc tests. A P<0.05 was considered to achieve statistical significance. The results are expressed as means±SEMs.
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Results |
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Body Weight
Body weights were significantly reduced among 6-month–old IH-exposed rats compared with corresponding RA controls receiving vehicle, SOD mimetic, or nifedipine (by 13.6%, 13.3%, and 14.6%, respectively; P<0.001). There were no differences between the weights of IH-vehicle SHR and those of IH-exposed rats receiving SOD mimetic or nifedipine treatment (Figure 1).
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IH-SODm, 
IH-Nif and the corresponding baseline (RA groups receiving similar treatment).
Lipid Peroxide Measurements
In 6 rat pups treated from day 5 of life with IH and SOD mimetic, cardiac lipid peroxide levels were 376±34 µmol/L per milligram of protein compared with 895±43 µmol/L per milligram of protein in 5 rat pups treated with IH and vehicle (P<0.05).
Changes in BP and Heart Rate
Eight male SHRs completed the experimental protocol for each of the 6 treatment groups. BP measurements at ages 1 and 6 months are summarized in Figure 2. By 6 months of age, IH-exposed SHRs developed significantly higher systolic and diastolic pressures than RA SHRs (187±5 and 163±2 mm Hg, P<0.001; and 139±6 and 87±3 mm Hg, P<0.01, respectively). Treatment of IH-exposed rats with the SOD mimetic MnTMPyP pentachloride or with the L-calcium channel blocker nifedipine abrogated the IH-induced BP increases (Figure 2A and 2B), such that both systolic and diastolic BPs were similar to corresponding treatment RA-exposed controls. There were no differences in either systolic or diastolic BPs among the 3 groups of RA-exposed rats (P>0.05; Figure 2A and 2B). No differences in HR occurred at 6 months of age among all of the experimental groups (Figure 2C).
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Echocardiographic Examination of LV Function
Representative LV M-mode echocardiograms from each experimental group are shown in Figure 3. Cardiac structure and function were significantly affected in IH-exposed SHRs as compared with RA vehicle controls. The phenotype observed was that of concentric LV hypertrophy, with IH-exposed animals exhibiting smaller LV chamber size (decreased LVEDD and LVESD; P<0.001; Figure 4), increased wall thickness (AWT, PWT, and RWT; P<0.05; Figure 4), and augmented systolic function (FS, P<0.001, and Vcf, P<0.05; Figure 4) in IH vehicle-treated rats compared with normoxic rats.
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P<0.05 vs RA; #P<0.05 vs RA; P<0.01 vs RA-SODm. C, Fractional shortening of the left ventricle in 6-month-old SHR measured by Doppler echocardiography. *P<0.001 vs RA; Treatment with nifedipine (Table and Figure 4) significantly attenuated IH-induced concentric hypertrophy resulting in smaller RWT (P<0.05 versus IH vehicle; P value not significant versus RA nifedipine), increased LV chamber size (LVEDD, P<0.05 versus IH-vehicle; P value not significant versus RA nifedipine), and normalization of systolic function (Vcf, P<0.001 versus IH vehicle; P value not significant versus RA nifedipine). Moreover, although the effects were not as uniformly striking, treatment with an SOD mimetic also resulted in similar responses, with smaller increases in RWT (P<0.05) and strong trends toward normalization of both systolic function (FS, P=0.054, and Vcf, P=0.095) and LV chamber size (LVESD, P=0.073) as compared with IH vehicle–exposed rats.
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Discussion |
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This study shows the critical role of ROS and L-Ca2+ channels in the metaplasticity of BP control mechanisms as induced by IH exposures during the early postnatal period. Indeed, whereas nonhypertensive rat strains, such as Sprague-Dawley rats, display lifelong alterations in baroreflex, genetically hypertensive rats, such as SHRs, will manifest markedly higher BP compared with normoxic controls when subjected to IH postnatally. Thus, treatment of neonatal SHR male pups with either the SOD mimetic MnTMPyP pentachloride or with the L- Ca2+ channel blocker nifedipine prevented the exaggerated increases in BP and, to varying degrees, attenuated long-term concentric hypertrophic LV remodeling. In SHR-IH, the developmental changes in BP were accelerated with the prehypertensive period composed of 2 months versus 3 months in other groups (Figure 2A and 2B). The more severe hypertension and LV remodeling in the CIH-vehicle group at 6 months could be ascribed because of a variety of mechanisms initiated by exposure to CIH.4,11,12,17,26,27 ROS and L-Ca2+ channel mechanisms might not necessarily be the only standing mechanisms for the exaggerated CV dysfunction at 6 months in the SHR, although they appear to be critical for the initiation and progression of the developmental programming of long-term CV morbidity after CIH in neonatal SHRs.
Body Weight
All of the IH-exposed rats, both those receiving vehicle as well as those receiving treatment, had lower body weights at 6 months of age compared with corresponding RA-exposed rats. Because the duration of IH was only during the first month of postnatal life, one might have predicted catch-up growth in the subsequent 5 months of normoxia. Epidemiological studies indicate that the low birth weight or alternatively the accelerated somatic growth that occurs after birth are major determinants in the risk for developing hypertension in adulthood.28–30 However, such were not the growth characteristics of the animals included in our experiments. In fact, SHRs exposed to IH had the same birth weight as those slated to RA exposures, and, as mentioned, IH-exposed SHRs did not sustain periods of marked accelerated growth after discontinuation of IH. Therefore, it is very unlikely that factors such as birth weight or somatic growth patterns may account for the disparities in BP temporal trajectories in IH-vehicle SHRs. CIH in SHRs may reduce nutrient intake. In addition to low weight gain, protein deficiency could cause impairment in the redox status, decrease antioxidant defense mechanisms, and increase markers of oxidative stress.31,32 Antioxidant therapy was shown to normalize adult hypertension, vascular dysfunction, microvascular rarefaction,10,33 and LV hypertrophy34 associated with in utero exposure to a low-protein diet.
Blood Pressure
The perinatal period is a critical stage in development, whereby perturbations such as IH can lead to lifelong alterations in organ structure and function, a phenomenon that has been termed "metaplasticity."35,36 For example, postnatal hyperoxia and either prenatal or postnatal IH induce lifelong modification of respiratory control networks.37,38 Analogous to such findings, we have reported previously on the anatomic and functional changes in baroreceptor-related networks in Sprague-Dawley rats after early postnatal IH.12 Interestingly, prenatal IH was not associated with such alterations.12 Furthermore, in this normotensive rodent strain, the persistent modification of baroreflex functions was not accompanied by changes in BP. Considering the postnatal IH-induced potentiation of the underlying systemic hypertension in the SHR model as found in the current experiments, we assume that redundant mechanisms aiming to preserve the normotensive status may have been effectively operational in the IH-exposed Sprague-Dawley rats.39 However, in a genetically predisposed hypertensive animal model such as the SHR, those mechanisms will be either ineffective or already fully activated, such that any additional "prohypertensive burden," such as that induced by postnatal IH, will entail an increment in the severity of the underlying hypertension.
Therefore, the changes in BP and cardiac function after postnatal IH could result not only from intracellular but also from extracardiac neural and humoral mechanisms that control the heart. In our preceding studies, we found increased sympathetic chemoreflexes, decreased baroreflex control of HR and sympathetic activity, and decreased heart rate variability in normotensive Sprague-Dawley rats subjected to the same IH protocol.11,12,40 We and others have also shown that IH induces oxidative stress, which induces apoptotic cell losses within the central nervous system in adult and newborn animals, including CV control nuclei.3,5,6,41–43 Interestingly, when adult rats are exposed to an IH protocol, LV dysfunction occurs and appears to be mediated, at least in part, by increased oxidative stress.2 Perinatal IH exposures are also associated with plasticity and metaplasticity of neural responses, more specifically as they are related to chemoreceptor, sympathetic, and somatic nerves, all of which may reflect the principal mechanisms underlying the long-term changes in CV control.44–46
It is now well established that increases in BP are determined by corresponding increases in peripheral vascular resistance. In the present study, BP returned to control levels when IH-exposed SHRs received an SOD mimetic, further confirming the role of ROS in the IH-induced exacerbation of BP elevation in SHRs. It is likely that scavenging of the excessive production of ROS associated with IH may have prevented ROS-related suppression of vasodilation because of decreasing NO availability in endothelial cells and formation of toxic ONOO–.16 Of note, endothelial NO synthase is extensively present at birth with a distribution similar to the pattern found in mature animals,47 and such processes are altered in SHRs with reduced bioavailability of uncoupled NO synthase.15 The role of Ca2+ channels in vascular dysfunction is not only supported by the beneficial responses to nifedipine in our experiments but is also supported by the fact that ROS can modulate the permeability of Ca2+ channels in the vascular smooth muscle cells and in the myocardium.19,23
LV Function
Vehicle-treated IH SHRs exhibited concentric LV hypertrophy and augmented systolic function that paralleled the exaggerated hypertensive response. These structural changes most likely reflected the effects of chronically increased afterload on the heart and compensatory LV hypertrophy. Recent evidence from human studies shows that normotensive patients with obstructive sleep apnea (OSA) present an increase of LV mass of similar magnitude to patients with hypertension but no OSA and that both conditions operate in an additive fashion.48 Similar findings were reported for LV wall thickness. The increased ventricular afterload was correlated with increased large arterial stiffness and heart remodeling in both OSA and hypertension.48
Although blockade of L-type calcium channels with nifedipine and amelioration of oxidative stress with an SOD mimetic both prevented the IH-induced rise in BP and, thus, reduced afterload equally, nifedipine imparted a much greater effect in attenuating the concentric remodeling phenotype. There is a possibility of an interplay between the effects of nifedipine and SOD. SOD increases the bioavailability of NO to dilate resistance vessels; however, NO-mediated vasodilator responses in SHRs were markedly diminished after the blockade of Ca2+ channels with nifedipine. This could suggest that NO dilates resistance arteries via direct and/or hyperpolarization-induced closure of L-Ca2+ channels.49 Also, nifedipine increases NO bioavailability by antioxidative mechanisms50 and by upregulating SOD expression in endothelial and vascular smooth muscle cells.51,52 In our experiments, both SOD mimetic and nifedipine decreased BP, although only nifedipine decreased systolic function. This may suggest that SOD mostly affected peripheral vascular resistance, whereas nifedipine affected both vascular resistance and heart contractility. These observations indicate that, in addition to IH-mediated hypertension and the indirect effects of augmented load on the heart, IH may also induce direct myocardial effects related to L-type calcium channel function that contribute to long-term LV remodeling. Indeed, because nifedipine appeared more efficient than the SOD mimetic in preventing pathological LV remodeling, L-type Ca2+ channels may potentially represent a target for ROS in the neonatal myocardium, and in the context of oxidative stress, some degree of irreversibility may occur. It is also possible that the higher doses of the SOD mimetic may be needed for more complete protection of cardiac structure and function, over and above the levels required for lowering BP and for recovery of the vascular response. In agreement with our results, transfer of human extracellular SOD gene into SHRs did not reduce cardiac output, such that the reduction of systemic BP in SHRs is likely the result of a decrease in systemic vascular resistance.53
Limitations of the Study
Although IH is a hallmark of OSA, our model do not replicate all of the OSA-related features, which also include hypercapnia, sleep fragmentation, and reduced sleep hours. However, the latter features of OSA are more likely to occur at later ages, and IH is by far the most common perturbation in young infants suffering from apnea of prematurity. An additional limitation would have been the desirable inclusion of a combined SOD mimetic and nifedipine group, which would allow for examination of the relative contributions of each of the putative separate mechanisms potentially underlying the potentiation of the CV phenotype after postnatal chronic IH.
Perspectives
Postnatal IH, as might occur in premature infants, not only induces long-lasting alterations of baroreflex circuitry12 but is further associated with aggravated systemic hypertension in genetically predisposed animals. We propose that interactions between genetic susceptibility to hypertension, as in SHRs, and mechanisms that disrupt baroreceptor function and elicit increased oxidative stress, such as postnatal IH, could provide realistically possible clinical settings for the perinatal programming of CV pathology in adults and their altered phenotypic expression. Early intervention during postnatal ontogenesis using traditional antihypertensive drugs, such as nifedipine or a SOD mimetic, effectively prevented the incremental hypertensive effects of neonatal IH and, therefore, suggests potential therapeutic measures. However, additional studies will be required for delineation of the exact mechanisms within the vascular bed and the myocardium that underlie the long-term cardiac remodeling induced by postnatal IH.
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Acknowledgments |
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Sources of Funding
This study was supported by National Institutes of Health grants HL69932, HL65270, and 2P50HL60296 (to D.G.), F32HL70494/NRSA (to G.K.S.), a Veterans’ Affairs Merit Grant and National Institutes of Health grants ES11860 and HL078825 (to S.D.P.), and the Commonwealth of Kentucky Research Challenge for Excellence Trust Fund and Children’s Foundation Endowment for Sleep Research (to D.G.).
Disclosures
None.
Received January 14, 2008; first decision February 11, 2008; accepted April 14, 2008.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Marcus CL. Pathophysiology of childhood obstructive sleep apnea: current concepts. Respir Physiol. 2000; 119: 143–154.[CrossRef][Medline] [Order article via Infotrieve]
2. Chen L, Einbinder E, Zhang Q, Hasday J, Balke CW, Scharf SM. Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med. 2005; 172: 915–920.
3. Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med. 2003; 167: 1548–1553.
4. Troncoso Brindeiro CM, da Silva AQ, Allahdadi KJ, Youngblood V, Kanagy NL. Reactive oxygen species contribute to sleep apnea-induced hypertension in rats. Am J Physiol Heart Circ Physiol. 2007; 293: H2971–H2976.
5. Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, Luo C, Kheirandish L, Gozal D, Liu R. Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience. 2004; 126: 313–323.[CrossRef][Medline] [Order article via Infotrieve]
6. Zhan G, Serrano F, Fenik P, Hsu R, Kong L, Pratico D, Klann E, Veasey SC. NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med. 2005; 172: 921–929.
7. Landmesser U, Harrison DG. Oxidative stress and vascular damage in hypertension. Coronary Artery Dis. 2001; 12: 455–461.[CrossRef][Medline] [Order article via Infotrieve]
8. Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Failure. 2002; 8: 132–140.[CrossRef]
9. Wilcox CS. Reactive oxygen species: roles in blood pressure and kidney function. Curr Hypertens Rep. 2002; 4: 160–166.[Medline] [Order article via Infotrieve]
10. Racasan S, Braam B, van der Giezen DM, Goldschmeding R, Boer P, Koomans HA, Joles JA. Perinatal L-arginine and antioxidant supplements reduce adult blood pressure in spontaneously hypertensive rats. Hypertension. 2004; 44: 83–88.
11. Soukhova GK, Gozal D. Long-lasting plasticity of baroreceptor function following postnatal intermittent hypoxia in normotensive and hypertensive rats. 33rd Annual Meeting of the Society for Neuroscience; New Orleans, LA, Nov 8–12, 2003; No. 341:2. Abstract.
12. Soukhova-O'Hare GK, Cheng Z, Roberts AM, Gozal D. Postnatal intermittent hypoxia alters baroreflex function in adult rats. Am J Physiol Heart Circ Physiol. 2006; 290: 1157–1164.
13. Wu R, Millette E, Wu L, de Champlain J. Enhanced superoxide anion formation in vascular tissues from spontaneously hypertensive and desoxicorticosterone acetate-salt hypertensive rats. J Hypertens. 2001; 19: 741–748.[CrossRef][Medline] [Order article via Infotrieve]
14. Suzuki H, DeLano FA, Parks DA, Jamshidi N, Granger DN, Ishii H, Suematsu M, Zweifach BW, Schmid-Schönbein GW. Xanthine oxidase associated with arterial blood pressure in spontaneously hypertensive rats. Proc Natl Acad Sci U S A. 1998; 95: 4754–4759.
15. Touyz RM. Reactive oxygen species, vascular oxydative stress, and redox signaling in hypertension. What is clinical significance? Hypertension. 2004; 44: 248–252.
16. Bauersachs J, Bouloumie A, Fraccarollo D, Hu K, Busse R, Ertl G. Endothelial dysfunction in chronic myocardial infarction despite increase vascular endothelial nitric oxide synthase and soluble guanilate cyclase expression: role of enhanced vascular superoxide production. Circulation. 1999; 100: 292–298.
17. Kobayashi N, DeLano F, Schmid-Schönbein GW. Oxidative stress promotes endothelial cells apoptosis and loss of microvessels in the spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 2005; 25: 2114–2121.
18. Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993; 92: 1866–1874.[Medline] [Order article via Infotrieve]
19. Tabet F, Savoia C, Schiffrin EL, Touyz RM. Differential calcium regulation by hydrogen peroxide and superoxide in vascular smooth muscle cells from spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2004; 44: 200–208.[CrossRef][Medline] [Order article via Infotrieve]
20. Yang ZW, Zheng T, Zhang A, Altura BT, Altura BM. Mechanisms of hydrogen peroxide-induced contraction of rat aorta. Eur J Pharmacol. 1998; 344: 169–181.[CrossRef][Medline] [Order article via Infotrieve]
21. Yang ZW, Zheng T, Wang J, Zhang A, Altura BT, Altura BM. Hydrogen peroxide induces contraction and raises [Ca2+]i in canine cerebral arterial smooth muscle: participation of cellular signaling pathways. Naunyn Schmiedebergs Arch Pharmacol. 1999; 360: 646–653.[CrossRef][Medline] [Order article via Infotrieve]
22. Lin MJ, Yang XR, Cao YN, Sham JS. Hydrogen peroxide-induced Ca2+ mobilization in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2007; 292: L1598–L1608.
23. Ermak G, Davies KJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol. 2002; 38: 713–721.[CrossRef][Medline] [Order article via Infotrieve]
24. Clapham DE. Calcium signaling. Cell. 1995; 80: 259–268.[CrossRef][Medline] [Order article via Infotrieve]
25. Perez-Reyes E. Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev. 2003; 83: 117–161.
26. Prabhu SD, Chandrasekar B, Murray DR, Freeman GL. β-Adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation. 2000; 101: 2103–2109.
27. Srivastava S, Chandrasekar B, Gu Y, Luo J, Hamid T, Hill BG, Prabhu SD. Downregulation of CuZn-superoxide dismutase contributes to β-adrenergic receptor-mediated oxidative stress in the heart. Cardiovasc Res. 2007; 74: 445–455.
28. Ashton N. Perinatal development and adult blood pressure. Braz J Med Biol Res. 2000; 33: 731–740.[Medline] [Order article via Infotrieve]
29. Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from systematic review of the literature. J Hypertens. 1996; 14: 935–941.[Medline] [Order article via Infotrieve]
30. Law CM, Shiell AW, Newsome CA, Syddall HE, Shinebourne EA, Fayers PM, Martyn CN, de Swiet M. Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age. Circulation. 2002; 105: 1088–1092.
31. Huang CJ, Fwu ML. Degree of protein deficiency affects the extent of the depression of the antioxidative enzyme activities and enhancement of tissue lipid peroxidation inrats. J Nutr. 1993; 123: 803–810.
32. Li J, Wang H, Stoner GD, Bray TM. Dietary supplementation with cysteine prodrugs selectively restores tissue glutathione levels and redox status in protein-malnourished mice. J Nutr Biochem. 2002; 13: 625–633.[CrossRef][Medline] [Order article via Infotrieve]
33. Cambonie G, Comte B, Yzydorczyk C, Ntimbane T, Germain N, Lê NL, Pladys P, Gauthier C, Lahaie I, Abran D, Lavoie JC, Nuyt AM. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet. Am J Physiol Regul Integr Comp Physiol. 2007; 292: R1236–R1245.
34. Xu Y, Williams SJ, O'Brien D, Davidge ST. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. FASEB J. 2006; 20: 1251–1253.
35. Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci. 2003; 26: 239–266.[CrossRef][Medline] [Order article via Infotrieve]
36. Reeves SR, Gozal D. Changes in ventilatory adaptations associated with long-term intermittent hypoxia across the age spectrum in the rat. Respir Physiol Neurobiol. 2006; 150: 135–143.[CrossRef][Medline] [Order article via Infotrieve]
37. Gozal D, Reeves SR, Row BW, Neville JJ, Guo SZ, Lipton AJ. Respiratory effects of gestational intermittent hypoxia in the developing rat. Am J Respir Crit Care Med. 2003; 167: 1540–1547.
38. Ling L, Olson EB Jr, Vidruk EH, Mitchell GS. Attenuation of the hypoxic ventilatory response in adult rats following one month of perinatal hyperoxia. J Physiol. 1996; 495: 561–571.
39. Thongboonkerd V, Gozal E, Sachleben LR Jr, Arthur JM, Pierce WM, Cai J, Chao J, Bader M, Pesquero JB, Gozal D, Klein JB. Proteomic analysis reveals alterations in the renal kallikrein pathway during hypoxia-induced hypertension. J Biol Chem. 2002; 277: 34708–34716.
40. Soukhova-O'Hare GK, Roberts AM, Gozal D. Impaired control of renal sympathetic nerve activity following neonatal intermittent hypoxia in rats. Neurosci Lett. 2006; 399: 181–185.[CrossRef][Medline] [Order article via Infotrieve]
41. Griffioen KJ, Kamendi HW, Gorini CJ, Bouairi E, Mendelowitz D. Reactive oxygen species mediate central cardiorespiratory network responses to acute intermittent hypoxia. J Neurophysiol. 2007; 97: 2059–2066.
42. Ramanathan L, Gozal D, Siegel JM. Antioxidant responses to chronic hypoxia in the rat cerebellum and pons. J Neurochem. 2005; 93: 47–52.[CrossRef][Medline] [Order article via Infotrieve]
43. Reeves SR, Guo SZ, Brittian KR, Row BW, Gozal D. Anatomical changes in selected cardio-respiratory brainstem nuclei following early post-natal chronic intermittent hypoxia. Neurosci Lett. 2006; 402: 233–237.[CrossRef][Medline] [Order article via Infotrieve]
44. Mitchell GS, Baker TL, Nanda SA, Fuller DD, Zabka AG, Hodgeman BA, Bavis RW, Mack KJ, Olson EB Jr. Intermittent hypoxia and respiratory plasticity. J Appl Physiol. 2001; 90: 2466–2475.
45. Prabhakar NR, Peng YJ, Jacono FJ, Kumar GK, Dick TE. Cardiovascular alterations by chronic intermittent hypoxia: importance of carotid body chemoreflexes. Clin Exp Pharm Physiol. 2005; 32: 447–449.[CrossRef][Medline] [Order article via Infotrieve]
46. Reeves SR, Mitchell GS, Gozal D. Early postnatal intermittent hypoxia modifies hypoxic ventilatory responses and long-term phrenic facilitation in adult rats. Am J Physiol Regul Integr Comp Physiol. 2006; 290: 1664–1671.
47. Ursell PC, Mayes M. Endothelial isoform of nitric oxide synthase in rat heart increases during development. Anat Rec. 1996; 246: 465–472.[CrossRef][Medline] [Order article via Infotrieve]
48. Drager LF, Bortolotto LA, Figueiredo AC, Silva BC, Krieger EM, Lorenzi-Filho G. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007; 131: 1379–1386.[CrossRef][Medline] [Order article via Infotrieve]
49. Lewis SJ, Bhopatkar MY, Walton TM, Bates JN. Role of voltage-sensitive calcium channels in nitric oxide-mediated vasodilation in spontaneously hypertensive rats. Eur J Pharmacol. 2005; 528: 144–149.[CrossRef][Medline] [Order article via Infotrieve]
50. Berkels R, Egink G, Marsen TA, Bartels H, Roesen R, Klaus W. Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms. Hypertension. 2001; 37: 240–245.
51. Fukuo K, Yang J, Yasuda O, Mogi M, Suhara T, Sato N, Suzuki T, Morimoto S, Ogihara T. Nifedipine indirectly upregulates superoxide dismutase expression in endothelial cells via vascular smooth muscle cell-dependent pathways. Circulation. 2002; 106: 356–361.
52. Fukuo K, Yang J, Suzuki T, Kaimoto T, Takemura Y, Yasuda O, Suhara T, Sato N, Ogihara T. Nifedipine upregulates manganese superoxide dismutase expression in muscular smooth muscle cells via endothelial cell-dependent pathways. Hypertens Res. 2003; 26: 503–508.[CrossRef][Medline] [Order article via Infotrieve]
53. Chu Y, Iida S, Lund DD, Weiss RM, DiBona GF, Watanabe Y, Faraci FM, Heistad DD. Gene transfer of extracellular superoxide dysmutase reduced arterial pressure in spontaneously hypertensive rats: role of heparin-binding domain. Circ Res. 2003; 92: 461–468.
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