Abstract Chronic exposure to intermittent hypoxia (CIH) increases carotid sinus nerve activity in normoxia and in response to acute hypoxia. We hypothesized that CIH augments basal and ...chemoreflex-stimulated sympathetic outflow through an angiotensin receptor-dependent mechanism. Rats were exposed to CIH for 28 days: a subset was treated with losartan. Then, lumbar sympathetic activity was recorded under anesthesia during 20-s apneas, isocapnic hypoxia, and potassium cyanide. We measured carotid body superoxide production and expression of angiotensin II type-1 receptor, neuronal nitric oxide synthase, and NADPH oxidase. Sympathetic activity was higher in CIH vs. control rats at baseline, during apneas and isocapnic hypoxia, but not cyanide. Carotid body superoxide production and expression of angiotensin II type 1 receptor and gp91phox subunit of NADPH oxidase were elevated in CIH rats, whereas expression of neuronal nitric oxide synthase was reduced. None of these differences were evident in animals treated with losartan. CIH-induced augmentation of chemoreflex sensitivity occurs, at least in part, via the renin–angiotensin system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Xanthine oxidase is a major source of superoxide in the vascular endothelium. Previous work in humans demonstrated improved conduit artery function following xanthine oxidase inhibition in patients ...with obstructive sleep apnea.
To determine whether impairments in endothelium-dependent vasodilation produced by exposure to chronic intermittent hypoxia are prevented by in vivo treatment with allopurinol, a xanthine oxidase inhibitor.
Sprague-Dawley rats received allopurinol (65 mg/kg/day) or vehicle via oral gavage. Half of each group was exposed to intermittent hypoxia (FIO(2) = 0.10 for 1 min, 15×/h, 12 h/day) and the other half to normoxia. After 14 days, gracilis arteries were isolated, cannulated with micropipettes, and perfused and superfused with physiological salt solution. Diameters were measured before and after exposure to acetylcholine (10(-6)M) and nitroprusside (10(-4)M).
In vehicle-treated rats, intermittent hypoxia impaired acetylcholine-induced vasodilation compared to normoxia (+4 ± 4 vs. +21 ± 6 μm, p = 0.01). Allopurinol attenuated this impairment (+26 ± 6 vs. +34 ± 9 μm for intermittent hypoxia and normoxia groups treated with allopurinol, p = 0.55). In contrast, nitroprusside-induced vasodilation was similar in all rats (p = 0.43). Neither allopurinol nor intermittent hypoxia affected vessel morphometry or systemic markers of oxidative stress. Urinary uric acid concentrations were reduced in allopurinol- versus vehicle-treated rats (p = 0.02).
These data confirm previous findings that exposure to intermittent hypoxia impairs endothelium-dependent vasodilation in skeletal muscle resistance arteries and extend them by demonstrating that this impairment can be prevented with allopurinol. Thus, xanthine oxidase appears to play a key role in mediating intermittent hypoxia-induced vascular dysfunction.
Abstract We previously demonstrated that chronic exposure to intermittent hypoxia (CIH) impairs endothelium-dependent vasodilation in rats. To determine the time course of this response, rats were ...exposed to CIH for 3, 14, 28, or 56 days. Then, we measured acetylcholine- and nitroprusside-induced vasodilation in isolated gracilis arteries. Also, we measured endothelial and inducible nitric oxide synthase, nitrotyrosine, and collagen in the arterial wall and urinary isoprostanes. Endothelium-dependent vasodilation was impaired after 2 weeks of CIH. Three days of CIH was not sufficient to produce this impairment and longer exposures ( i.e . 4 and 8 weeks) did not exacerbate it. Impaired vasodilation was accompanied by increased collagen deposition. CIH elevated urinary isoprostane excretion, whereas there was no consistent effect on either isoform of nitric oxide synthase or nitrotyrosine. Exposure to CIH produces functional and structural deficits in skeletal muscle resistance arteries. These impairments develop within 2 weeks after initiation of exposure and they are accompanied by systemic evidence of oxidant stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract In rats, acute exposure to hypoxia causes a decrease in mean arterial pressure (MAP) caused by a predominance of hypoxic vasodilation over chemoreflex-induced vasoconstriction. We previously ...demonstrated that exposure to chronic intermittent hypoxia (CIH) impairs hypoxic vasodilation in isolated resistance arteries; therefore, we hypothesized that the acute systemic hemodynamic responses to hypoxia would be altered by exposure to CIH. To test this hypothesis, rats were exposed to CIH for 14 days. Heart rate (HR) and MAP were monitored by telemetry. On the first day of CIH exposure, acute episodes of hypoxia caused a decrease in MAP (−9 ± 5 mmHg) and an increase in HR (+45 ± 4 beats/min). On the 14th day of CIH exposure the depressor response was attenuated (−4 ± 1 mmHg; 44% of the day 1 response) and the tachycardia was enhanced (+68 ± 2 beats/min; 151% of the day 1 response). The observed time-dependent modulation of the acute hemodynamic responses to hypoxia may reflect important changes in neurocirculatory regulation that contribute to CIH-induced hypertension.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Highlights ► CIH increases arterial pressure and causes vascular endothelial dysfunction. ► Blockade of the angiotensin II type I receptor with losartan prevents increases in arterial pressure and ...endothelial dysfunction associated with CIH. ► CIH was not associated with increased superoxide levels in saphenous arteries. ► The AT1/AT2 receptor ratio in saphenous arteries was increased by CIH but unaffected by losartan.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Using a transgenic cross, we evaluated features of preeclampsia, renal injury and the sFlt1/VEGF changes. Transgenic hAGT and hREN, or wild-type (WT) C57Bl/6 mice were cross-bred: female hAGT × male ...hREN for preeclampsia (PRE) model and female WT × male WT for pregnant controls (WTP). Samples were collected for plasma VEGF, sFlt1, and urine albumin. Blood pressures (BP) were monitored by telemetry. Vascular reactivity was investigated by wire myography. Kidneys and placenta were immunostained for sFlt1 and VEGF. Eleven PRE and 9 WTP mice were compared. PRE more frequently demonstrated albuminuria, glomerular endotheliosis (80% vs. 11%;
= 0.02), and placental necrosis (60% vs. 0%;
< 0.01). PRE group demonstrated declining BPs with advancing gestation. Plasma sFlt1 increased across pregnancy in PRE; VEGF did not vary. IHC demonstrated the presence of sFlt1 in glomeruli, lymphatics, and collecting tubules of PRE kidneys, suggesting excretion. VEGF immunostaining was increased specifically in the glomeruli of PRE kidneys. Placenta in PRE showed marked immunostaining for sFlt1. We conclude that this transgenic model of preeclampsia recapitulates human preeclamptic state with high fidelity, and that, vascular adaptation to pregnancy is suggested by declining BPs and reduced vascular response to PE and increased response to acetylcholine. Placental damage with resultant increased release of sFlt1, proteinuria, deficient spiral artery remodeling, and glomerular endotheliosis were observed in this model of PRE. Increased VEGF binding to glomerular endothelial cells in this model of PRE is similar to human PRE and leads us to hypothesize that renal injury in preeclampsia may be mediated through local VEGF.
Exposure of rats to chronic intermittent hypoxia (CIH) impairs vasodilator responsiveness and raises arterial pressure. CIH‐induced increases in arterial pressure are prevented by blockade of the ...angiotensin type 1 receptor (AT1R); however, it is unknown if renin‐angiotensin system (RAS) activity plays a role in CIH‐induced vascular dysfunction. Sprague Dawley rats were exposed to CIH, while control rats (NORM) were housed under normoxic conditions. A subset of animals from each group was treated with an AT1R blocker, losartan (Los), during the exposure period. Arterial pressure was monitored by telemetry. After 4 weeks, gracilis arteries (GA) were isolated and cannulated with glass micropipettes, and pressurized to 80 mmHg. Diameters were measured using video microscopy before and after exposure to acetylcholine (10−6 M) or sodium nitroprusside (10−4 M) in the superfusate. CIH caused elevations in arterial pressure when intermittent hypoxia cycles were administered and also when the animals were unperturbed. Los attenuated both increases. Acetylcholine‐induced vasodilation was blunted in CIH vs. NORM, and this was prevented by Los treatment. Responses to nitroprusside were not different between CIH‐exposed and control animals. These results suggest that vascular dysfunction associated with CIH is dependent in part on RAS signaling through the AT1R. Funded by #HL074072.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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