AT1R Blockade and Periodic Breathing During Sleep in Hypoxia
AT1R Blockade and Periodic Breathing During Sleep in Hypoxia
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.
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.

 Research Design General Procedures: Sleep studies will be conducted between 2100hrs and 0600
 hrs. Participants will arrive at the laboratory in the evening and will be allowed to sleep
 in the hypoxic chamber for 8 hours. Ventilatory responses will be assessed prior to entering
 the hypoxic chamber and immediately upon waking in the morning following sleep study. Either
 Losartan, an AT1R antagonist, (50 mg/dose; P.O.) or placebo will be administered three times
 throughout the protocol: the morning of the experimental day, the evening one hour prior to
 the ventilatory tests and finally the following morning after a night in the hypoxic chamber,
 one hour prior to the second battery of ventilatory tests. This protocol design is
 randomized, double blinded and placebo controlled and all participants will complete both
 experimental arms separated by at least 2 days (i.e. cross-over study design). During the
 ventilatory tests, participants will be studied in the supine position, 6 hours post-prandial
 & 24 hours post-caffeine, and breathing through a standard mouthpiece with a nose clamp.
 Non-invasive measures of heart rate (HR), blood pressure (BP), respiratory frequency (fB),
 tidal volume (VT), minute ventilation (V̇E), cerebral blood flow [assessed by transcranial
 Doppler (MCA and PCA)], end-tidal gases (PETCO2 and PETO2) and blood oxygen saturation (SpO2;
 finger pulse oximetry) will be monitored and recorded continuously. Venipuncture will be
 performed immediately prior to both ventilatory response tests and will be analyzed for
 plasma renin activity levels to confirm functional angiotensin receptor blockade.
Inclusion Criteria:

 -  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

 Exclusion Criteria:

 -  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