Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants

Abstract

Background: We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. Methods: Sixteen healthy male participants (32±5 y, 26±2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWP). Results: IH increased circulating ET-1, epinephrine, and FFA (p<0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH mediated increases in FFA (p<0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (p>0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. Conclusions: IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

The Role of Endothelin Receptors in the Regulation of Kidney Function and Blood Pressure

“…Действия эндотелина вне почек, несомненно, могут способствовать развитию гипертонии, но внутрипочечные действия также, вероятно, играют более важную роль. Повышенная почечная мРНК ET-1 и повышенная экскреция ET-1 с мочой [40,41] при гипертензивных состояниях являются убедительными доказательствами того, что почечная продукция ET-1 увеличивается при гипертонии. Также было обнаружено повышенное содержание пептида ET-1 в самой почке при артериальной гипертензии  НАУЧНОЕ ОБОЗРЕНИЕ № 3, 2022   БИОЛОГИЧЕСКИЕ НАУКИ  [42].…”