The Role of Endothelin-1 in Obstructive Sleep Apnea Syndrome and Pulmonary Arterial Hypertension: Pathogenesis and Endothelin-1 Antagonists

Abstract

Obstructive Sleep Apnea Syndrome (OSAS) is a recognized risk factor for cardiovascular disorders and in some cases is complicated with Pulmonary Arterial Hypertension (PAH), as the endothelium is affected. Recent studies provide strong evidence for endothelial dysfunction in obstructive sleep apnea. The resultant vasoconstriction, abnormal cell proliferation and hyper-coagulability may lead to the initiation or progression of atherosclerotic cardiovascular and cerebrovascular disorders, which are frequently encountered in OSA patients. While the currently available therapies for OSAS, such as Continuous Positive Airway Pressure therapy (CPAP therapy), improve endothelial dysfunction, they are not well-tolerated by patients. CPAP therapy can reduce nocturnal hypoxemias and decrease noradrenaline circulating levels, but does not affect ET-1 plasma levels. Potent and selective Endothelin-1 receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure, and atherosclerosis. However, results are often contrasting and complicated because of the tissue-specific vasoconstrictor actions of Endothelin-B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo.

Use of Pulmonary Arterial Hypertension–Specific Therapy in Overweight or Obese Patients with Obstructive Sleep Apnea and Pulmonary Hypertension

“…28 Continuous PAP therapy can reduce nocturnal hypoxia but does not affect endothelin-1 plasma levels. 29 These studies also explain the favorable effect of PAH-specific therapy in our study and provide a rationale for considering such therapy in overweight or obese patients with OSA and PH. There were no adverse effects from the use of PAHspecific therapy.…”

Quantitative measurement of cysteinyl leukotrienes and leukotriene B4 in human sputum using ultra high pressure liquid chromatography–tandem mass spectrometry

“…In an additional study, increased levels of CysLTs have been reported in sputum from patients with aspirin-intolerant asthma [8] in the diagnosis of aspirin-intolerant asthma. It has been reported that LTB 4 is a potent inflammatory mediator and can be detected in sputum supernatants [9]. CysLTs, including LTE 4 and LTB 4 , have been detected in exhaled breath condensate [10,11], bronchoalveolar lavage fluid [12], and urine [13].…”

“…Several analytical methods for the quantification of CysLTs and/or LTB 4 in sputum have been reported, including HPLC/radioimmunoassay [14], radioimmunoassay [15], and enzyme immunoassay (EIA) [7,9,16,17]. LT concentrations in human sputum have been reported in wide ranges (from pg/mL to ng/mL) between labs and available technologies, which suggest a need for improved measurement of LTs in sputum.…”

Impact of Sleep Respiratory Disorders on Endothelial Function in Children

“…OSAS increases endothelin-1 plasma levels, which induce could increase arterial stiffness and blood pressure [33]. …”