Chronic hypercapnia inhibits hypoxic pulmonary  vascular remodeling

Ooi, Henry; Cadogan, Elaine; Sweeney, Michele; Howell, Katherine; O’Regan, R. G.; McLoughlin, Paul

doi:10.1152/ajpheart.2000.278.2.h331

Cited by 65 publications

(76 citation statements)

References 31 publications

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“…The effects of chronic intermittent hypoxia or hypercapnic hypoxia on pulmonary arterial pressure have not been previously investigated. It is well known that chronic continuous hypoxia has a significant effect on pulmonary arterial pressure and pulmonary vascular remodelling in animals [13,27]. However, OOI et al [13] have shown that hypercapnia combined with hypoxia markedly reduced the pulmonary hypertension and right ventricular hypertrophy observed in rats after chronic continuous hypoxia alone, and inhibited to some degree the pulmonary vascular remodelling that is associated with continuous hypoxia alone.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic continuous hypoxia has been shown to impair normal weight gain in rats [17]. Whereas chronic continuous hypoxia alone and continuous hypercapnia alone impair weight gain, a combination of continuous hypoxia and hypercapnia causes weight loss [13]. For chronic intermittent hypercapnic hypoxia, FLETCHER et al [16] showed that the body weights of the treated rats at the end of 5 weeks were not significantly different from controls, but the actual weight gain was somewhat impaired.…”

Section: Discussionmentioning

confidence: 99%

“…A tracheal cannula was inserted. The pulmonary arterial pressure was measured using the isolated-perfused lung technique [13,15]. This technique has certain advantages over in vivo measurement, in that it is technically easier to use and yields results which are independent of cardiovascular and respiratory changes or reflex effects.…”

Section: Chronic Intermittent Hypercapnic Hypoxia Treatmentmentioning

confidence: 99%

“…However, apnoeas are accompanied by hypercapnia as well as hypoxia [12], but the effects of this combination of chronic intermittent blood gas changes on pulmonary arterial pressure are unknown. It is known that chronic continuous hypercapnia protects against the effects of continuous hypoxia on right ventricular weight and pulmonary arterial pressure [13]. Therefore, it is not clear whether prolonged intermittent hypercapnia in association with prolonged intermittent hypoxia would affect right ventricular weight or pulmonary arterial pressure.…”

mentioning

confidence: 99%

“…It has previously been shown that chronic intermittent hypocapnic hypoxia increases the haematocrit in rats [11]. A combination of chronic continuous hypoxia and hypercapnia greatly reduces the increase in haematocrit caused by chronic continuous hypoxia alone [13], but the effects of chronic intermittent hypoxia and hypercapnia on haematocrit have not been studied. As with pulmonary hypertension, the presence of increased haematocrit is variable in OSA patients.…”

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Chronic intermittent hypercapnic hypoxia increases pulmonary arterial pressure and haematocrit in rats

McGuire

Bradford

2001

Eur Respir J

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Chronic intermittent hypercapnic hypoxia increases pulmonary arterial pressure and haematocrit in rats. M. McGuire, A. Bradford. #ERS Journals Ltd 2001. ABSTRACT: Sleep-disordered breathing is associated with pulmonary hypertension and raised haematocrit. The multiple episodes of apnoea in this condition cause chronic intermittent hypoxia and hypercapnia but the effects of such blood gas changes on pulmonary pressure or haematocrit are unknown. The present investigation tests the hypothesis that chronic intermittent hypercapnic hypoxia causes increased pulmonary arterial pressure and erythropoiesis.Rats were treated with alternating periods of normoxia and hypercapnic hypoxia every 30 s for 8 h per day for 5 days per week for 5 weeks, as a model of the intermittent blood gas changes which occur in sleep-disordered breathing in humans. Haematocrit, red blood cell count and haemoglobin concentration were measured each week and systemic and pulmonary arterial blood pressure and heart weight were measured after 5 weeks.In relation to control, chronic intermittent hypercapnic hypoxia caused a significant increase in systemic (104.3¡4.7 mmHg versus 121.0¡10.4 mmHg) and pulmonary arterial pressure (20.7¡6.8 mmHg versus 31.3¡7.2 mmHg), right ventricular weight (expressed as ratios) and haematocrit (45.2¡1.0% versus 51.5¡1.5%).It is concluded that the pulmonary hypertension and elevated haematocrit associated with sleep-disordered breathing is caused by chronic intermittent hypercapnic hypoxia. Sleep disordered breathing affects 1-4% of adults [1]. It is associated with multiple episodes of hypoxia and hypercapnia due to hypopnoea or apnoea, which are either caused by intermittent collapse of the upper airway (UA), termed obstructive sleep apnoea (OSA; the most common form of sleep disordered breathing), or a reduced drive to breath, termed central apnoea [2]. The condition is associated with a number of cardiovascular changes, including increased pulmonary and systemic arterial blood pressure, right ventricular hypertrophy, cardiac arrhythmias and increased haematocrit. Diurnal pulmonary hypertension is present in 17-42% of OSA patients [3][4][5][6][7] and represents a serious threat to long-term outcome in these patients [8]. The cause of pulmonary hypertension in these patients is unknown. During an apnoeic event, pulmonary arterial pressure is acutely increased [9], presumably due to hypoxic pulmonary vasoconstriction, so that repetitive episodes of increased pressure may ultimately give rise to daytime pulmonary hypertension [10]. In support of this, it has recently been shown that chronic intermittent hypocapnic hypoxia in rats causes right ventricular hypertrophy, suggesting that pulmonary arterial pressure is increased [11]. However, apnoeas are accompanied by hypercapnia as well as hypoxia [12], but the effects of this combination of chronic intermittent blood gas changes on pulmonary arterial pressure are unknown. It is known that chronic continuous hypercapnia protects against the effects of continuous hypoxia...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chronic Intermittent Hypercapnic Hypoxia Treatmentmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic intermittent hypercapnic hypoxia increases pulmonary arterial pressure and haematocrit in rats

McGuire

Bradford

2001

Eur Respir J

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Impaired iNOS–sGC–cGMP signalling contributes to chronic hypoxic and hypercapnic pulmonary hypertension in rat

Xia

et al. 2012

Cell Biochemistry & Function

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Nitric oxide (NO) is an important vascular modulator in the development of pulmonary hypertension. NO exerts its regulatory effect mainly by activating soluble guanylate cyclase (sGC) to synthesize cyclic guanosine monophosphate (cGMP). Exposure to hypoxia causes pulmonary hypertension. But in lung disease, hypoxia is commonly accompanied by hypercapnia. The aim of this study was to examine the changes of sGC enzyme activity and cGMP content in lung tissue, as well as the expression of inducible nitric oxide synthase (iNOS) and sGC in rat pulmonary artery after exposure to hypoxia and hypercapnia, and assess the role of iNOS-sGC-cGMP signal pathway in the development of hypoxic and hypercapnic pulmonary hypertension. Male Sprague-Dawley rats were exposed to hypoxia and hypercapnia for 4 weeks to establish model of chronic pulmonary hypertension. Weight-matched rats exposed to normoxia served as control. After exposure to hypoxia and hypercapnia, mean pulmonary artery pressure, the ratio of right ventricle/left ventricle+septum, and the ratio of right ventricle/body weight were significantly increased. iNOS mRNA and protein levels were significantly increased, but sGC α(1) mRNA and protein levels were significantly decreased in small pulmonary arteries of hypoxic and hypercapnic exposed rat. In addition, basal and stimulated sGC enzyme activity and cGMP content in lung tissue were significantly lower after exposure to hypoxia and hypercapnia. These results demonstrate that hypoxia and hypercapnia lead to the upregulation of iNOS expression, downregulation of sGC expression and activity, which then contribute to the development of pulmonary hypertension.

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