title: Kv7 channels critically determine coronary artery reactivity: left-right differences and down-regulation by hyperglycaemia.
abstract: OBJECTIVE
  Voltage-gated potassium channels encoded by KCNQ genes (Kv7 channels) are emerging as important regulators of vascular tone. In this study, we analysed the contribution of Kv7 channels to the vasodilation induced by hypoxia and the cyclic AMP pathway in the coronary circulation. We also assessed their regional distribution and possible impairment by diabetes.
  
  
  RESULTS
  We examined the effects of Kv7 channel modulators on K+ currents and vascular reactivity in rat left and right coronary arteries (LCAs and RCAs, respectively). Currents from LCA were more sensitive to Kv7 channel inhibitors (XE991, linopirdine) and activators (flupirtine, retigabine) than those from RCA. Accordingly, LCAs were more sensitive than RCAs to the relaxation induced by Kv7 channel enhancers. Likewise, relaxation induced by the adenylyl cyclase activator forskolin and hypoxia, which were mediated through Kv7 channel activation, were greater in LCA than in RCA. KCNQ1 and KCNQ5 expression was markedly higher in LCA than in RCA. After incubation with high glucose (HG, 30 mmol/L), myocytes from LCA, but not from RCA, were more depolarized and showed reduced Kv7 currents. In HG-incubated LCA, the effects of Kv7 channel modulators and forskolin were diminished, and the expression of KCNQ1 and KCNQ5 was reduced. Finally, vascular responses induced by Kv7 channel modulators were impaired in LCA, but not in RCA, from type 1 diabetic rats.
  
  
  CONCLUSIONS
  Our results reveal that the high expression and function of Kv7 channels in the LCA and their down-regulation by diabetes critically determine the sensitivity to key regulators of coronary tone.
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morales-Cano
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Bianca
authors.initials: B
authors.lastname: Barreira
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Rachele
authors.initials: R
authors.lastname: Pandolfi
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Chamorro
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Granada 18071, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Jimenez
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC+), Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Villamor
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, Granada 18071, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Perez-Vizcaino
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciudad Universitaria S/N, Madrid 28040, Spain Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain acogolludo@med.ucm.es.
authors.forename: Angel
authors.initials: A
authors.lastname: Cogolludo
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology; D051656:KCNQ Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin / Q000009:adverse effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C501028:Kcnq5 protein, rat; D013311:Streptozocin; D000242:Cyclic AMP; D005947:Glucose
keywords: Diabetes mellitus; Hypoxia; Ion channels; Potassium channels; Vascular