title: Upregulation of SK3 and IK1 channels contributes to the enhanced endothelial calcium signaling and the preserved coronary relaxation in obese Zucker rats.
abstract: OBJECTIVE
  Endothelial small- and intermediate-conductance KCa channels, SK3 and IK1, are key mediators in the endothelium-derived hyperpolarization and relaxation of vascular smooth muscle and also in the modulation of endothelial Ca2+ signaling and nitric oxide (NO) release. Obesity is associated with endothelial dysfunction and impaired relaxation, although how obesity influences endothelial SK3/IK1 function is unclear. Therefore we assessed whether the role of these channels in the coronary circulation is altered in obese animals.
  
  
  RESULTS
  In coronary arteries mounted in microvascular myographs, selective blockade of SK3/IK1 channels unmasked an increased contribution of these channels to the ACh- and to the exogenous NO- induced relaxations in arteries of Obese Zucker Rats (OZR) compared to Lean Zucker Rats (LZR). Relaxant responses induced by the SK3/IK1 channel activator NS309 were enhanced in OZR and NO- endothelium-dependent in LZR, whereas an additional endothelium-independent relaxant component was found in OZR. Fura2-AM fluorescence revealed a larger ACh-induced intracellular Ca2+ mobilization in the endothelium of coronary arteries from OZR, which was inhibited by blockade of SK3/IK1 channels in both LZR and OZR. Western blot analysis showed an increased expression of SK3/IK1 channels in coronary arteries of OZR and immunohistochemistry suggested that it takes place predominantly in the endothelial layer.
  
  
  CONCLUSIONS
  Obesity may induce activation of adaptive vascular mechanisms to preserve the dilator function in coronary arteries. Increased function and expression of SK3/IK1 channels by influencing endothelial Ca2+ dynamics might contribute to the unaltered endothelium-dependent coronary relaxation in the early stages of obesity.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Climent
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martínez
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Contreras
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Albino
authors.initials: A
authors.lastname: García-Sacristán
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rivera
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Prieto
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009213:Myography; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D007211:Indoles; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496901:Kcnn3 protein, rat; D010091:Oximes; D051640:Small-Conductance Calcium-Activated Potassium Channels