Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat

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Abstract

We recently developed a model of chronic intermittent hypoxia (CIH) (FiO2 5%, 8 h/day, 35 days) in the rat that was associated with an increased infarction in isolated heart. The aim of the present study was to characterize its functional consequences on vasoreactivity.

Aorta and carotid artery were studied using organ bath technique while mesenteric vascular bed was perfused.

In the three vascular beds, relaxation to acetylcholine was similar in CIH and control normoxic (NX) rats. Contractions to noradrenaline and angiotensin II were similar between CIH and NX rats. In contrast, contraction to endothelin-1 was increased by 17% (P < 0.05) in carotid artery from CIH rats. Indomethacin pre-treatment reduced by 24% (P < 0.001) contraction to endothelin-1 in carotid artery from CIH rats only.

These data suggested that 35-day CIH-exposure induced no change in endothelial function of aorta, carotid artery and mesenteric bed. In contrast, CIH-exposure induced an increased contractile response to endothelin-1 in carotid artery, presumably owing to the release of constrictor cyclooxygenase-derived products.

Introduction

Obstructive sleep apnea (OSA) syndrome is a common disorder affecting 4% of men and 2% of women in the general population (Young et al., 1993). This breathing disorder is strongly associated with cardiovascular diseases. Actually, sleep apnea represents a major independent risk factor for hypertension, coronary heart disease and cardiac arrhythmias. Sleep apnea is also strongly associated with heart failure and stroke (Wolk et al., 2003, Lavie, 2004).

Repetitive hypoxemic stress occurring during sleep induces reflex sympathetic activation and leads to an increase in blood pressure both acutely and chronically. Thus, hypoxemia, sympathetic activation, increased arterial pressure (Shamsuzzaman et al., 2003) as well as insulin resistance (Vgontzas et al., 2003) and increased oxidant stress (Lavie, 2003) may contribute to the onset of abnormal vascular function in OSA syndrome. Indeed, in OSA patients, numerous clinical studies have demonstrated reduced flow-mediated dilation (Imadojemu et al., 2002, Ip et al., 2004) and blunted vasodilatation in response to acetylcholine (Carlson et al., 1996, Kato et al., 2000) or bradykinin (Duchna et al., 2000), suggesting that OSA syndrome may be associated with endothelial dysfunction. Furthermore, an increased sensitivity to angiotensin II-induced vasoconstrictor response has also been reported in OSA patients (Kraiczi et al., 2000).

Although alterations of vascular function have been found in patients with OSA syndrome, the mechanisms underlying the association between OSA and cardiovascular diseases are not fully understood. In this regard, several animal models have been developed to address the effect of chronic intermittent hypoxia (CIH) on the cardiovascular system (Fletcher et al., 1992, Brooks et al., 1997, Kanagy et al., 2001, Tahawi et al., 2001, Julien et al., 2003, Thomas and Wanstall, 2003, Phillips et al., 2004, Joyeux-Faure et al., 2005). Experimental protocols vary greatly in cycle length, severity of hypoxia, number of hypoxic episodes per day and number of exposure days. However, CIH studies in rodents represent a unique opportunity to explore the mechanisms of vascular changes related to one of the major consequences of sleep apnea, i.e. intermittent hypoxia (for review, see (Neubauer, 2001)).

We recently developed a model of CIH in the rat that was associated with an increased infarction in isolated heart (Joyeux-Faure et al., 2005). The aim of the present study was to characterize the functional consequences of this model of CIH on vascular reactivity. To date, there are no studies that have investigated the vascular function of three vascular beds of the systemic circulation with the same experimental model of CIH. Therefore, the present study assessed the functional reactivity of aorta, carotid artery and vascular mesenteric bed. Aorta and carotid artery were studied in order to investigate the reactivity of conductance vessels while mesenteric bed was chosen in order to investigate the reactivity of resistance vessels.

Section snippets

Methods

This investigation conformed to the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996) and with French law and local ethical committee guidelines for animal research. Experiments were conducted on 40 adult male Wistar rats (weight range 220–240 g) from Elevage Janvier (France) housed in controlled conditions and provided with standard rat chow. Food and water were available ad libitum.

Relaxant responses

Acetylcholine evoked endothelium-dependent relaxations in aorta and carotid artery from CIH and NX rats. In terms of efficacy and potency, these relaxations were similar in aorta and carotid artery from both rat groups (Table 1).

Similarly, SNP evoked concentration-dependent relaxations that were similar in aorta from both rat groups (Table 1).

Contractile responses

KCl, noradrenaline, endothelin-1 and angiotensin II-induced concentration-dependent contractions in aorta and carotid artery from all rat groups. The

Discussion

To our knowledge, this is the first study evaluating the consequences of CIH-exposure on the function of three vessels from the systemic circulation in rats. Aorta and carotid artery were studied in order to investigate the reactivity of conductance vessels while mesenteric bed was chosen in order to investigate the reactivity of resistance vessels.

Several mediators have been suggested as contributors to sleep apnea associated cardiovascular morbidity. Sleep apnea patients exhibit decreased

Acknowledgements

The authors thank Christophe Ribuot, Sandrine Launois-Rollinat, Julia Tonini and Pauline Béguin for their help with the experimental model of CIH. This study was supported by a grant from ANTADIR.

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