Endothelin-1 and ET receptors impair left ventricular function by mediated coronary arteries dysfunction in chronic intermittent hypoxia rats

Physiol Rep. 2017 Jan;5(1):e13050. doi: 10.14814/phy2.13050.

Abstract

Obstructive sleep apnea (OSA) results in cardiac dysfunction and vascular endothelium injury. Chronic intermittent hypoxia (CIH), the main characteristic of OSAS, is considered to be mainly responsible for cardiovascular system impairment. This study is aimed to evaluate the role of endothelin-1(ET-1) system in coronary injury and cardiac dysfunction in CIH rats. In our study, Sprague-Dawley rats were exposed to CIH (FiO2 9% for 1.5 min, repeated every 3 min for 8 h/d, 7 days/week for 3 weeks). After 3 weeks, the left ventricular developed pressure (LVDP) and coronary resistance (CR) were measured with the langendorff mode in isolated hearts. Meanwhile, expressions of ET-1 and ET receptors were detected by immunohistochemical and western blot, histological changes were also observed to determine effects of CIH on coronary endothelial cells. Results suggested that decreased LVDP level combined with augmented coronary resistance was exist in CIH rats. CIH could induce endothelial injury and endothelium-dependent vasodilatation dysfunction in the coronary arteries. Furthermore, ET-1 and ETA receptor expressions in coronary vessels were increased after CIH exposure, whereas ETB receptors expression was decreased. Coronary contractile response to ET-1 in both normoxia and CIH rats was inhibited by ETA receptor antagonist BQ123. However, ETB receptor antagonist BQ788 enhanced ET-1-induced contractile in normoxia group, but had no significant effects on CIH group. These results indicate that CIH-induced cardiac dysfunction may be associated with coronary injury. ET-1 plays an important role in coronary pathogenesis of CIH through ETA receptor by mediating a potent vasoconstrictor response. Moreover, decreased ETB receptor expression that leads to endothelium-dependent vasodilatation decline, might be also participated in coronary and cardiac dysfunction.

Keywords: Cardiac function; chronic intermittent hypoxia; coronary resistance; endothelial receptors; endothelin‐1.

MeSH terms

  • Animals
  • Coronary Vessels / metabolism
  • Coronary Vessels / pathology
  • Coronary Vessels / physiopathology*
  • Endothelin Receptor Antagonists / administration & dosage
  • Endothelin Receptor Antagonists / pharmacology*
  • Endothelin-1 / administration & dosage
  • Endothelin-1 / metabolism
  • Endothelin-1 / pharmacology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology*
  • Hypoxia / complications
  • Hypoxia / metabolism*
  • Hypoxia / physiopathology
  • Hypoxia / veterinary
  • Male
  • Myocardial Contraction / drug effects
  • Myocardial Contraction / immunology
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology
  • Peptides, Cyclic / administration & dosage
  • Peptides, Cyclic / pharmacology
  • Piperidines / administration & dosage
  • Piperidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Endothelin / metabolism*
  • Sleep Apnea, Obstructive / complications
  • Sleep Apnea, Obstructive / metabolism
  • Sleep Apnea, Obstructive / physiopathology
  • Vasodilation / drug effects
  • Vasodilation / physiology
  • Ventricular Dysfunction, Left / chemically induced*
  • Ventricular Dysfunction, Left / pathology
  • Ventricular Dysfunction, Left / physiopathology

Substances

  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Oligopeptides
  • Peptides, Cyclic
  • Piperidines
  • Receptors, Endothelin
  • BQ 788
  • cyclo(Trp-Asp-Pro-Val-Leu)