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

Abstract

New findings: What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensin II and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation. Losartan and allopurinol are effective therapies for achieving blood pressure control in sleep apnoea.

Abstract: Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensin II type 1 receptor (AT1 R) blockade. Both AT1 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-1 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 O2 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.

Keywords: chemoreflex; renin-angiotensin system; sympathetic nervous system.

Conflict of interest statement

Competing interests

None of the authors have competing interests to report.

© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.

Figures

Figure 1

Numbers of subjects allocated to the three treatment groups from the randomization strata. Assignment into a stratum was based on average number of hours of nightly CPAP in the month prior to study enrollment.

Figure 2

CONSORT diagram showing flow of participants through the study.

Figure 3

Observed changes in baseline values for primary and secondary outcome measures (mean, 95% CI) in the 3 treatment groups. Mean arterial pressure (MAP) was reduced, relative to placebo, with allopurinol and losartan treatments. The reduction produced by allopurinol was smaller than that caused by losartan. No statistically significant differences in other variables were observed. FVC and CVC values were multiplied by 100 and VE values were multiplied by 10 so that the data points are discernable on these axes. MSNA, muscle sympathetic nerve activity; MAP, mean arterial pressure; CVC, cerebral vascular conductance; FVC, forearm vascular conductance *pxp<0.05, allopurinol vs. losartan; yp<0.05, allopurinol vs. placebo; zp<0.05, losartan vs. placebo

Figure 4

Brief hyperoxic exposure decreased muscle sympathetic activity (MSNA) in all treatment groups. Within the losartan group, the amount of hyperoxic inhibition of total MSNA activity was diminished significantly after 6 weeks of treatment, but this change wasn’t statistically different from changes in the allopurinol or placebo group (RM-ANOVA p>0.05). Data shown are mean±SEM.

Figure 5

Tidal volume (VT) and muscle sympathetic nerve activity (MSNA) during normoxia, hypoxia (SaO2, 80%), and when subjects voluntarily mimicked, in normoxia, the same levels of VT and breathing frequency elicited by the hypoxic exposure. MSNA was comparable during normoxic eupnea and normoxic hyperpnoea, indicating that increased ventilatory volumes and rates (not shown), per se, have no effect on MSNA. Data shown are mean±SEM. *p

Figure 6

Upper panel shows initial and final values for normoxic forearm vascular conductance (FVC), separated by sex, in the three treatment groups. In female subjects, baseline FVC was significantly increased by allopurinol, but was unaffected by losartan and placebo treatments (RM-ANOVA p=0.009). Baseline FVC did not change with any treatment in male subjects. Lower panel shows initial and final values for normoxic cerebral vascular conductance (CVC), separated by sex, in the three treatment groups. CVC did not change with any treatment and subgroup analysis revealed no sex differences. Data shown are mean±SEM.