thromboxane-a2 and Sleep-Apnea--Obstructive

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of intermittent hypoxia. This disease is associated with premature atherosclerosis and consequently with increased cardiovascular morbidity and mortality. Atherosclerosis is a chronic inflammatory disease characterized by the activation of some components of the cyclooxygenase pathway. In particular, OSA is associated with activation of the thromboxane A2 (TXA2)-pathway, in which obesity seems to be a major confounding factor. Moreover, TXA2-pathway activation is related to the vascular remodeling associated with OSA. In view of the modest effect of the conventional treatment of OSA by continuous positive airway pressure on the cardiovascular risk in obese OSA patients, the identification of new therapeutic targets to treat OSA-induced atherosclerosis seems essential. As disruption of the TXA2-pathway has been suggested to be of potential interest to prevent atherosclerosis progression, we have reviewed the recent findings on the intricate interaction between the TXA2-pathway, chronic intermittent hypoxia and atherosclerosis and suggest promising therapeutic strategies to treat OSA-related atherogenesis, including pharmacological and/or nutritional approaches.

Topics: Animals; Atherosclerosis; Humans; Hypoxia; Molecular Targeted Therapy; Sleep Apnea, Obstructive; Thromboxane A2

Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)-induced inflammation. Cyclooxygenase (COX)-formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH.. Twelve healthy, male participants underwent three, 6-hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex(®) (selective COX-2 inhibitor) in a double-blind, randomized, crossover study design. Pre- and post-IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre-IH blood pressure (P ≤ 0.04) and decreased pre-IH CBF (P=0.04) while neither physiological variable was affected by COX-2 inhibition (P ≥ 0.90). Post-IH, MAP was elevated (P ≤ 0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX-2 inhibition abrogated the IH-induced MAP increase (P=0.19), but resulted in lower post-IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P ≤ 0.4) and COX-1 formed thromboxane A2 concentrations (P=0.02).. COX-2 and COX-1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX-1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA.. www.clinicaltrials.gov. Unique identifier: NCT01280006.

Topics: Adult; Blood Pressure; Celecoxib; Cerebrovascular Circulation; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Double-Blind Method; Epoprostenol; Female; Heart Rate; Humans; Hypoxia; Indomethacin; Male; Middle Aged; Pyrazoles; Sleep Apnea, Obstructive; Sulfonamides; Thromboxane A2