Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea

Abstract

Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensin II type 1 receptor (AT R) blockade. Both AT R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25 events h and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6 weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure.

The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia

“…The present analysis is based on data collected during a previously reported randomized clinical trial (NCT01637623) of the effects of allopurinol, losartan and placebo on chemoreflex sensitivity in hypertensive patients with OSA (Morgan et al . 2018). The majority of data reported herein were obtained at the initial (pre‐randomization, prior to drug treatment) visit to the laboratory.…”

“…Assessment of carotid chemoreflex sensitivity has received recent attention in clinical conditions such as hypertension (Tafil-Klawe et al 1985), heart failure (Schultz et al 2007) and obstructive sleep apnoea (OSA) (Narkiewicz et al 1999a), and also in the context of acclimatization to high altitude hypoxia (Dempsey et al 2014). A variety of transient and steady-state stimulatory and inhibitory interventions (Narkiewicz et al 1999a;Leuenberger et al 2001;Steinback et al 2009;Sinski et al 2014;Morgan et al 2018;Phillips et al 2018;Keir et al 2019) have been employed to provoke measurable increases and decreases in ventilation and sympathetic outflow; however, limited information is available on whether ventilatory and neurocirculatory responses to carotid chemoreceptor stimulation and inhibition are associated in human subjects.…”

Angiotensin II-Type I Receptor Antagonism Does Not Influence the Chemoreceptor Reflex or Hypoxia-Induced Central Sleep Apnea in Men

“…The exaggerated lumbar sympathetic and MAP responses to breath hold following chronic intermittent hypoxia were attenuated by losartan, an effect likely mediated by blunted upregulation of AT 1 R expression on the carotid body (Marcus et al, 2010). In contrast, losartan does not influence the ventilatory response to step changes in normocapnic hypoxia in patients with OSA (Morgan et al, 2018). In agreement with our findings, this indicates an alternative mechanism involved in chemoreceptor sensitization that is independent of the AT 1 R. For example, heart failure models suggest a reduction in carotid body blood flow is necessary to reduce neural nitric oxide synthase expression while elevating carotid body AT 1 R expression and ANG-II concentration (Li and Schultz, 2006).…”

G-Protein-Coupled Receptor (GPCR) Signaling in the Carotid Body: Roles in Hypoxia and Cardiovascular and Respiratory Disease

“…Translational findings in humans are currently limited. However, in a recent clinical trial, it was observed that losartan reduced systolic and diastolic blood pressure in OSA patients without modifying muscle-sympathetic outflow or ventilation during hypoxia [ 102 ]. OSA was fairly well established in these patients and as such, there may have been irreversible epigenetic remodeling of CB function [ 103 ], accounting for the apparent lack of impact of losartan on CB function.…”