Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity

Snow, Jessica; Kitzis, Vanessa; Norton, Charles E.; Torres, Samantha N.; Johnson, Kimberly D.; Kanagy, Nancy L.; Walker, Benjimen R.; Resta, Thomas C.

doi:10.1152/japplphysiol.00698.2005

Cited by 62 publications

(85 citation statements)

References 44 publications

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“…Although several studies report that intermittent hypoxia induces modest-to-severe LV and RV hypertrophy in rodents (2,8,22,23,58), our study is in agreement with other reports showing that intermittent hypoxia with or without CO 2 supplementation does not induce cardiac hypertrophy (5,17,56). It is possible that LV hypertrophy did not develop in our mouse model because of CO 2 supplementation or that the elevation in systemic blood pressure was below the threshold for activation of the cardiac hypertrophy gene program.…”

Section: Discussionsupporting

confidence: 92%

“…Polycythemia is not consistently observed in SA animal models, with or without CO 2 supplementation, and SA patients (2,9,12,16,23,30,35,42,43,56). In the present study, H-IH did not induce significant polycythemia in mice.…”

Section: Discussioncontrasting

confidence: 60%

“…During the normal sleep period, air in the cage was cycled between a low (5%) O2-high (5%) CO2 environment and room air. In rats, this protocol causes hypoxia but maintains constant plasma CO2 levels, while exposure to 5% O2 alone induces profound hypocapnia (56). The mice were exposed to 20 H-IH episodes per hour for 7 h/day for 2, 7, or 21 days.…”

Section: Methodsmentioning

confidence: 99%

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NFATc3 is required for intermittent hypoxia-induced hypertension

Garcı́a¹,

Duling²,

Alò³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Sleep apnea, defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension and peripheral vascular disease. Exposure of rodents to brief periods of intermittent hypercarbia/hypoxia (H-IH) during sleep mimics the cyclical hypoxia-normoxia of sleep apnea. Endothelin-1, an upstream activator of nuclear factor of activated T cells (NFAT), is increased during H-IH. Therefore, we hypothesized that NFATc3 is activated by H-IH and is required for H-IH-induced hypertension. Consistent with this hypothesis, we found that H-IH (20 brief exposures per hour to 5% O2-5% CO2 for 7 h/day) induces systemic hypertension in mice [mean arterial pressure (MAP) ϭ 97 Ϯ 2 vs. 124 Ϯ 2 mmHg, P Ͻ 0.05, n ϭ 5] and increases NFATc3 transcriptional activity in aorta and mesenteric arteries. Cyclosporin A, an NFAT inhibitor, and genetic ablation of NFATc3 [NFATc3 knockout (KO)] prevented NFAT activation. More importantly, H-IHinduced hypertension was attenuated in cyclosporin A-treated mice and prevented in NFATc3 KO mice. MAP was significantly elevated in wild-type mice (⌬ ϭ 23.5 Ϯ 6.1 mmHg), but not in KO mice (⌬ ϭ Ϫ3.9 Ϯ 5.7). These results indicate that H-IH-induced increases in MAP require NFATc3 and that NFATc3 may contribute to the vascular changes associated with H-IH-induced hypertension.nuclear factor of activated T cells; hypercarbic; mouse; endothelin-1; sleep apnea SLEEP APNEA (SA), defined as intermittent respiratory arrest during sleep, affects up to 20% of the adult population. Among the major consequences of SA are decreased O 2 saturation (hypoxia) and increased CO 2 saturation (hypercapnia). In SA patients, incidence of hypertension, peripheral vascular disease, stroke, and sudden cardiac death is increased (for review see Refs. 21 and 44). Thus SA appears to directly initiate vascular changes that predispose individuals to cardiovascular disease.Recently, it was demonstrated that exposure of rodents to periods of intermittent hypoxia with CO 2 supplementation [intermittent hypercarbia/hypoxia (H-IH)] during sleep mimics the cyclical hypoxia-normoxia of SA. In rats exposed to H-IH, blood pressure (34, 35) and circulating endothelin-1 (ET-1) are elevated (35), vasoconstrictor sensitivity to ET-1 is increased (2), and blood pressure is normalized with ET antagonists (35). These studies, together with clinical studies showing increased circulating ET-1 in SA (10, 55), suggest that augmented ET-1 vasoconstriction contributes to SA hypertension. The sustained increased blood pressure observed in SA patients and animal models also appears to involve activation of the sympathetic nervous and renin-angiotensin systems and diminished activity of nitric oxide synthase (for review see Refs. 44 and 52).ET-1 acts through G␣ q -coupled receptors as a Ca 2ϩ -mobilizing agent and as a potent activator of the nuclear factor of activated T cells (NFAT) (1, 25, 57). ANG II, glucose through UTP release, and ␣ 1 -adrenergic agonists are also potent stimuli of NFAT activation (1,25,27,46,57).NFAT...

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Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 60%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

NFATc3 is required for intermittent hypoxia-induced hypertension

Garcı́a¹,

Duling²,

Alò³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The common approach to model the hypoxia of chronic lung disease is a 23 -24 hour exposure to hypoxia for 2 -3 weeks. One recent study compared steady state constant to intermittent exposures, there is a differential effect on pulmonary vasculature which is at least partially modulated by the presence or absence of hypercapnia [20]. Neither of these paradigms however, simulate hypoxia in pulmonary disorders that results from the normal physiology of sleep [21].…”

Section: Discussionmentioning

confidence: 99%

Constant daily hypoxia leads to different degrees of pulmonary hypertension in two different rat strains

Bouserhal¹,

Lunteren²,

Jacono³

2012

OJMIP

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Pulmonary diseases associated with diurnal hypoxemia are known to be associated with pulmonary hypertension in some patients. In this study we examined the effects of daily hypoxia (10% oxygen; 8h/day for 14 days) on two strains of rats to simulate sleep related hypoxia in pulmonary diseases expecting to find differences in vascular responses, the development of right ventricular hypertrophy and pulmonary hypertension according to genetic background. In response to daily hypoxia, Sprague Dawley rats developed right ventricular hypertrophy while Brown Norway rats did not. Both strains developed pulmonary hypertension (elevated right ventricular pressure) although the increase was significantly greater in the Sprague Dawley strain. Pulmonary artery (first branch) vasoconstrictive responses to potassium chloride were increased equally in both strains and the subsequent vasodilation with acetylcholine were reduced equally with daily hypoxia in both strains. Taken together, these findings suggest that the genetic makeup of the rats contributed significantly to the development of right ventricular hypertrophy and the degree of pulmonary hypertension. Moreover, this response is not secondary to differences in the intralobar pulmonary vascular reactivity. Genetic background could explain why certain patients do worse with hypoxia inducing pulmonary vascular diseases.

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“…It is the central link of the pathogenesis of pulmonary heart disease, which is a serious threat to human health. [1][2][3] The morbidity and mortality of HPH caused by chronic obstructive pulmonary disease (COPD) are high, which can bring a heavy burden to families and society. So far, there is no effective treatment.…”

mentioning

confidence: 99%

Expressions of G2A and OGR1 in peripheral blood cells of patients with hypoxia-induced pulmonary hypertension

Yang

et al. 2017

DCC

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Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypoxia-induced pulmonary hypertension (HPH). Methods: Thirty-one patients with HPH were enrolled for IPH group, 16 males and 15 females, aged (65.19 ± 5.86) years; and 30 healthy people were enrolled for control group (NC group), 15 males and 15 females, aged (63.47 ± 6.16) years. The peripheral blood samples were collected and the mRNA expressions of G2A and OGR1 were determined by using real-time fluorescent quantitative PCR. The pulmonary arterial pressure (PAP) of HPH group was detected with echocardiography for the analysis of blood gas and pulmonary function testing. Human peripheral blood was collected to detect the mRNA levels of G2A, OGR1 and the serum levels of tumor necrosis factor-α (TNF-α). Results: PaCO2 was increased significantly in HPH group than that in NC group (p < .05). The percentage of forced expiratory volume in 1 s in predicted value (FEV1 pro%) and the ratio of FEV1/forced vital capacity (FVC) in HPH group were significant lower than those in NC group (p < .05). The expressions of peripheral blood G2A mRNA and TNF-α in HPH group were increased dramatically than those in NC group (p < .05). The expressions of OGR1 mRNA in peripheral blood had no difference between HPH group and NC group. The expressions of G2A mRNA and TNF-α in HPH group were positively related to pulmonary artery pressure significantly. Conclusions: The expression of proton-sensing receptor G2A and the level of TNF-α were increased in peripheral blood cells of patients with pulmonary hypertension. The expressions of TNF-α and G2A had positive correlations with pulmonary artery pressure.

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Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity

Cited by 62 publications

References 44 publications

NFATc3 is required for intermittent hypoxia-induced hypertension

NFATc3 is required for intermittent hypoxia-induced hypertension

Constant daily hypoxia leads to different degrees of pulmonary hypertension in two different rat strains

Expressions of G2A and OGR1 in peripheral blood cells of patients with hypoxia-induced pulmonary hypertension

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