title: Adiponectin Receptor Agonist, AdipoRon, Causes Vasorelaxation Predominantly Via a Direct Smooth Muscle Action.
abstract: OBJECTIVE
  AdipoRon, an adiponectin receptor agonist, was recently proposed for treating insulin resistance and hyperglycemia. As adiponectin is vasoprotective via NO-mediated signaling, it was hypothesized that adipoRon similarly exerts potentially beneficial vasodilator effects. We therefore examined if adipoRon induces vasorelaxation and via what contributing mechanisms.
  
  
  METHODS
  Vascular function was assessed in skeletal muscle arteries from rats and cerebral/coronary arteries from mice using pressure and wire myography.
  
  
  RESULTS
  Using qPCR, mRNA for adiponectin receptors was demonstrated in skeletal muscle, cerebral and coronary arteries. AdipoRon-caused vasorelaxation was not abolished by compound C (10 μM; AMPK inhibitor). Inhibition of endothelium-dependent relaxation with combinations of l-NAME/indomethacin/apamin/TRAM-34 only slightly reduced adipoRon-mediated vasorelaxation in cerebral and coronary arteries. EC-denuded cremaster arteries showed similar relaxant responses to adipoRon as in intact vessels, suggesting adipoRon directly impacts VSMCs. K(+) currents measured in VSMCs isolated from mouse basilar and LAD arteries were not altered by adiopRon. In cremaster arteries, adipoRon induced vasorelaxation without a marked decrease in VSMC [Ca(2+)]i . Adiponectin, itself, caused vasodilation in intact cremaster arteries while failing to cause significant dilation in EC-denuded arteries, consistent with endothelium dependency of adiponectin.
  
  
  CONCLUSIONS
  AdipoRon exerts vasodilation by mechanisms distinct to adiponectin. The dominant mechanism for adipoRon-induced vasorelaxation occurs independently of endothelium-dependent relaxing factors, AMPK activation, K(+) efflux-mediated hyperpolarization and reductions in cytosolic [Ca(2+)]i .
authors.affiliation: Department of Medical Pharmacology & Physiology, University of Missouri-Columbia, Columbia, Missouri, USA.|Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, USA.
authors.forename: Kwangseok
authors.initials: K
authors.lastname: Hong
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, USA.|Division of Sport Science & Sport Science Institute, Incheon National University, Incheon, South Korea.
authors.forename: Sewon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, USA.|Drug Discovery Research Center, Luzhou Medical College, Luzhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, USA.
authors.forename: Miles A
authors.initials: MA
authors.lastname: Tanner
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, USA.|Drug Discovery Research Center, Luzhou Medical College, Luzhou, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medical Pharmacology & Physiology, University of Missouri-Columbia, Columbia, Missouri, USA.|Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hill
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000819:agonists* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C585113:AdipoRon; D010880:Piperidines; D054419:Receptors, Adiponectin
keywords: adiponectin; adiponectin receptors; endothelial independent; relaxation; vascular smooth muscle