Effect of episodic hypoxia on sympathetic activity and blood pressure

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Abstract

One of the major manifestations of obstructive sleep apnea (OSA) is profound and repeated (episodic) hypoxia during sleep. Acute hypoxia leads to stimulation of the peripheral chemoreceptors, which in turn directly increase sympathetic outflow. It is believed that this increase in sympathetic outflow is directly responsible, at least in part, for the acute blood pressure (BP) changes seen in OSA. It is difficult however, to study the chronic effects of repeated episodic hypoxia (EH) in humans since the chronic cardiovascular changes may take many years to manifest. For this reason, we developed a method of providing recurrent short periods of hypoxia (resembling the episodic desaturation in humans with OSA) to rats for 35 days, stimulating the chemoreceptors and the sympathetic nervous system, allowing examination of the chronic cardiovascular response to EH. The result of EH in rats is a 10–14 mmHg increase in resting (unstimulated) mean BP that lasts for several weeks after cessation of the daily EH. This BP increase is blocked by carotid body denervation, sympathetic nerve ablation, renal sympathectomy, adrenal medullectomy, and the angiotensin-1 receptor blocker losartan. Thus, it appears that adrenergic and renin–angiotensin system over-activity contribute to the early chronic elevated BP in EH and perhaps in human hypertension associated with OSA.

Introduction

Repetitive obstructive sleep apnea (OSA) in humans as well as animals results in elevation of systemic blood pressure (BP) with each apnea as well as a more prolonged elevation extend beyond the period of apneas (Shepard, 1985). This, along with epidemiologic data, supports the hypothesis that repetitive airway obstructive with desaturation can lead to secondary hypertension. Indeed, snoring and repetitive sleep apnea may be major causes of hypertension in patients previously labeled with essential hypertension.

Animal preparations of acute apnea in the dog, pig, and lamb have provided the opportunity to study in depth, acute hemodynamic and cardiovascular response to apnea (Kimoff et al., 1994, Brooks et al., 1997). But it may take many years for nightly, repetitive apnea to lead to sustained daytime systemic hypertension, making prospective studies of hypertension in these models or humans difficult or impossible. Currently, the majority of hypertension research is conducted in rodents because of the many similarities of BP control and cardiovascular response between these animals and humans. The technology of knockout and transgenic mice have made rodents even more important in such research. Given the short life span of rodents, many of the models of chronic renal and endocrine hypertension paralleling human clinical disease can be studied in greater depth than is possible in humans. Thus, several groups are now working on animal preparations in which recurrent events during sleep can be induced over a period of weeks or months to test the hypothesis that apnea/hypoxia leads to chronic hypertension. This monograph will discuss the use of an episodic hypoxia rat (EHR) preparation in which rats are exposed to recurrent periods of episodic hypoxia (EH) mimicking the recurrent desaturation of OSA. EH is continued for eight hours per day for 35 days, inducing sustained elevation of BP.

Section snippets

The chronic episodic hypoxia model

We constructed 25 chambers where rodents could be exposed to rapid swings in ambient oxygen concentration (FiO2), inducing changes in oxygen saturation (SaO2) similar to that seen in humans with sleep apnea (Fig. 1). These cylindrical Plexiglas chambers are 28 cm in length with a diameter 10 cm and volume of 2.4 L. The ends are covered with a snug fitting lid in which holes are drilled that can be plugged with perforated rubber stoppers. A timed solenoid valve distributes pure nitrogen to each

Plasma renin in the EHR

Plasma renin activity (PRA) is regulated by sympathetic nerves and can affect diurnal BP through the renin–angiotensin system. Thus, PRA could be instrumental in chronic BP elevation in the EHR. To this end PRA was examined in 24 Sprague Dawley rats after 35 days of EH. Half of the group was treated with losartan [an angiotensin 1 (AT1) receptor blocker] 15 mg/kg per day by gastric gavage. The other half were treated with vehicle (Fletcher et al., 1999). The groups were divided as follows: five

Uncited references

Bao and Fletcher, 1997, Fletcher et al., 1999.

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