Does endothelin play a role in chemoreception during acute hypoxia in normal men?
BACKGROUND
The peripheral chemoreceptors are the dominant reflex mechanism responsible for the rise in ventilation and muscle sympathetic nerve activity (MSNA) in response to hypoxia. Animal studies have suggested that endothelin (ET) plays an important role in chemosensitivity. Moreover, several human clinical conditions in which circulating ET levels are increased are accompanied by enhanced chemoreflex sensitivity. Whether ET plays a role in normal human chemosensitivity is unknown.


METHODS
We determined whether bosentan, a nonspecific ET receptor antagonist, would decrease chemoreflex sensitivity in 14 healthy subjects. We assessed the effects of bosentan on the response to isocapnic hypoxia, using a randomized, crossover, double-blinded study design.


RESULTS
Bosentan increased mean (+/- SEM) plasma ET levels from 1.97 +/- 0.28 to 2.53 +/- 0.23 pg/mL (p = 0.01). Hypoxia increased mean minute ventilation from 6.7 +/- 0.3 to 8+/0.4 L/min (p < 0.01), mean MSNA from 100 to 111 +/- 5% (p < 0.01), mean heart rate from 67 +/- 3 to 86 +/- 3 beats/min (p < 0.01), and mean systolic BP from 116 +/- 3 to 122 +/- 3 mm Hg (p < 0.01). However, none of these responses differed between therapy with bosentan and therapy with placebo (p = 0.26). Bosentan did not affect the mean MSNA responses to the apneas, during normoxia (change from baseline: placebo, 259 +/- 58%; bosentan, 201 +/- 28%; p = 0.17) or during hypoxia (change from baseline: placebo, 469 +/- 139%; bosentan, 329 +/- 46%; p = 0.24). The durations of the voluntary end-expiratory apneas in normoxia and hypoxia, and the subsequent reductions in oxygen saturation, were also similar with therapy using bosentan and placebo (p = 0.42).


CONCLUSIONS
In healthy men, ET does not play an important role in peripheral chemoreceptor activation by acute hypoxia.
Gujic
Marko
M
Department of Cardiology, Erasme University Hospital, 808 Lennik Road, B-1070 Brussels, Belgium. marko.gujic@ulb.ac.be
Houssière
Anne
A
Xhaët
Olivier
O
Argacha
Jean-François
JF
Denewet
Nathalie
N
Noseda
André
A
Jespers
Pascale
P
Melot
Christian
C
Naeije
Robert
R
van de Borne
Philippe
P
D000208:Acute Disease; D000328:Adult; D001049:Apnea / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D000077300:Bosentan; D002628:Chemoreceptor Cells / Q000502:physiology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009132:Muscles / Q000294:innervation; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan