Effect of Angiotensin Receptor Blockers on Periodic Breathing During Sleep in Hypoxia
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- apnea-hypopnea index
研究概览
简要总结
Sleep disordered breathing (SDB) is characterized by regular periods of no breathing (apnea) or low levels of breathing (hypopnea) and leads to repeated periods of low oxygenation, termed intermittent hypoxia that causes fluctuations in blood oxygen levels. This leads to increased peripheral chemoreflex sensitivity that is thought to occur through the stimulation of angiotensin-II, type-I receptors (AT1R) that are expressed primarily on glomus cells within the peripheral chemoreflex and ultimately results in long lasting hypertension. The goal of this study is to determine if AT1R receptor blockade can prevent the increase in chemoreflex sensitivity following one night of hypoxia and improve the severity of SDB.
详细描述
Objective: To determine the effects of angiotensin-II, type-I receptor (AT1R) blockade on the relationship between ventilatory control and sleep disordered breathing (SDB) following a night of hypoxic sleep in healthy humans.
Justification: Ventilatory adaptation to hypoxia is one of two major adaptations permitting humans to acclimatize successfully to high altitude. As the partial pressure of oxygen falls with ascent, the peripheral chemoreceptors are stimulated resulting in an increase in ventilation. The initial hypoxic ventilatory response is aimed at augmenting alveolar PO2 and subsequently arterial PO2, but results in a respiratory alkalosis that can only be compensated for by the reduction of renal excretion of bicarbonate. Despite metabolic compensation, both basal respiratory drive and peripheral chemoreceptor responsiveness remain elevated. Both of these elements of respiratory control have contrasting implications for breathing stability during sleep. The increase in basal ventilation at high altitude attenuates plant gain, a term describing how effectively a change in ventilation changes blood gases. Plant gain is determined by positioning the chemoreflex response on the isometabolic hyperbola. When arterial PCO2 is reduced during acclimatization to high altitude, the point of equilibrium is shifted to a steeper portion of the isometabolic hyperbola where a larger change in ventilation is necessary to evoke a given change in arterial PCO2. This feature is protective in nature and acts to stabilize breathing. However, the slope of the relationship between ventilation and arterial PCO2, termed controller gain, is greatly enhanced at high altitude and this may outweigh the effect on plant gain, destabilizing breathing and predisposing to central sleep apnea. Treatments that reduce controller gain without impacting plant gain might stabilize breathing and reduce the severity of central sleep apnea at high altitude without negatively impacting successful acclimatization.
The carotid body chemoreceptors serve an important regulatory role in controlling alveolar ventilation and their sensitivity is augmented at high altitude. Recent studies have established that the carotid body possesses a local angiotensin system, which contributes to the sensitization of the chemoreflex function in patients with heart failure, sleep apnea, and following exposure to intermittent hypoxia. Indeed, the over-activity of the carotid body contributes to breathing instability and increases the incidence of central apneas. Angiotensin II activates the carotid body and leads to afferent activity. The Type I cells within the carotid body act as a chemical sensor and they express both angiotensinogen and express two angiotensin receptors, AT1R and AT2R. Interestingly, pharmacological blockade of the AT1R has little functional significance at sea level in the normal state. But if chemoreceptor activity is augmented in conditions such as chronic, and intermittent hypoxia, and congestive heart failure, then blockade of the AT1R partially reverses this activity. Whether or not AT1R blockade at high altitude can attenuate the rise in chemoreceptor sensitivity and reduce the severity of sleep apnea in humans is unknown.
Purpose: To determine if blockade of the AT1R can attenuate the ventilatory response to CO2 and reduce the severity of sleep disordered breathing in healthy humans.
Hypothesis: Blockade of the AT1R will reduce the ventilatory sensitivity to CO2 and the severity of SDB in healthy humans following one night of hypoxia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •normotensive
- •forced expiratory volume in 1s : forced vital capacity ratio > 0.75
- •no medical history of cardiovascular and respiratory disease
- •not taking medications other than oral contraceptives
- •free from sleep apnea
- •body mass index less than 30 kg/m2
排除标准
- •history of hypertension
- •known impaired renal function
- •liver disease
- •heart failure
- •myocardial infarction
- •coronary artery disease
- •smoked within the past year
- •apnea hypopnea index > 5 events per hour
研究组 & 干预措施
Placebo
Participants will ingest microcrystalline cellulose by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Hyperoxic Hypercapnic Ventilatory Response Test (Other)
Placebo
Participants will ingest microcrystalline cellulose by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Hypoxic Hypercapnic Ventilatory Response Test (Other)
Placebo
Participants will ingest microcrystalline cellulose by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Repeated Hypoxic Apneas (Other)
Placebo
Participants will ingest microcrystalline cellulose by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Hypoxic Sleep Study (Other)
Placebo
Participants will ingest microcrystalline cellulose by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Placebo (Drug)
Losartan
Participants will ingest 50 mg of losartan, an angiotensin receptor blocker, by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Hyperoxic Hypercapnic Ventilatory Response Test (Other)
Losartan
Participants will ingest 50 mg of losartan, an angiotensin receptor blocker, by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Hypoxic Hypercapnic Ventilatory Response Test (Other)
Losartan
Participants will ingest 50 mg of losartan, an angiotensin receptor blocker, by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Repeated Hypoxic Apneas (Other)
Losartan
Participants will ingest 50 mg of losartan, an angiotensin receptor blocker, by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Hypoxic Sleep Study (Other)
Losartan
Participants will ingest 50 mg of losartan, an angiotensin receptor blocker, by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
干预措施: Losartan (Drug)
结局指标
主要结局
apnea-hypopnea index
时间窗: 8 hours
the number of apnea and hypopneas per hour during sleep in hypoxia
次要结局
- Average oxygen saturation(8 hours)
- Hyperoxic Hypercapnic Ventilatory Response(0 and 8 hours)
- Hyperoxic Hypercapnic Cerebral Blood Flow Response(0 and 8 hours)
- Hypoxic Hypercapnic Cerebral Blood Flow Response(0 and 8 hours)
- Hypoxic Hypercapnic Ventilatory Response(0 and 8 hours)
- Change in systolic and diastolic blood pressure during breath-hold(0 and 8 hours)
研究者
Glen Foster
Assistant Professor
University of British Columbia