AT1R Blockade and Periodic Breathing During Sleep in Hypoxia
Condition: Sleep Disordered Breathing; Hypoxia; Respiration; Sleep Disorder; Chemoreceptor Apnea
MeSH terms: Respiratory Aspiration; Sleep Apnea Syndromes; Sleep Wake Disorders; Hypoxia
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Hyperoxic Hypercapnic Ventilatory Response Test; Hypoxic Hypercapnic Ventilatory Response Test; Repeated Hypoxic Apneas; Hypoxic Sleep Study; Losartan; Placebo
Intervention type(s): Other; Other; Other; Other; Drug; Drug
Intervention description(s): End-tidal PO2 will be clamped at 300 mmHg while end-tidal PCO2 will be increased in three minutes stages from baseline to +2, +4, and +6 mmHg.; End-tidal PO2 will be clamped at normoxic levels while end-tidal PCO2 will be increased in three minutes stages from baseline to +2, +4, and +6 mmHg.; Six hypoxic apnea cycles will be performed. One apneic cycle involves breathing 2-3 breaths of 100% Nitrogen and breath-holding for 20s followed by room air breathing.; Participants will be instrumented with a sleep monitoring system and will sleep in a normobaric hypoxic chamber with a fraction of inspired oxygen of 13.5%.; Losartan, 50mg, BID; Placebo, 50mg, BID
Other intervention name(s): Cozaar; microcrystalline cellulose
Intervention MeSH terms: Losartan
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Angiotensin receptor blockade; control of breathing; breath-holding