title: Interaction of angiotensin II with the angiotensin type 2 receptor inhibits the cardiac transient outward potassium current.
abstract: OBJECTIVE
  The Ca2+ -independent transient outward K+ current (Ito) plays a crucial role in shaping the cardiac action potential. In the present study, we examined whether angiotensin II (AngII) regulated the Ito as well as the putative intracellular cascade responsible for the effects.
  
  
  METHODS
  Ito was recorded in rat ventricular myocytes using the nystatin-perforated patch-clamp configuration.
  
  
  RESULTS
  AngII (0.1 microM) inhibited Ito (21.9+/-4.8% at +40 mV), but not the IK1, in a voltage- and time-independent manner. The inhibition decreased at concentrations higher than 1 microM resulting in a bell-shaped dose-response curve (IC50 = 3.1+/-1.5 microM). The blocking effects were abolished in the presence of the type 2 AngII receptor (AT2R) antagonist PD123319, but not in the presence of the selective type 1 AngII receptor (AT1R) antagonist candesartan. Moreover, the selective AT2R agonist CGP42112A completely reproduced the effects of AngII (20.5+/-2.4% of block at +40 mV), indicating that AngII-induced Ito block was mediated via stimulation of AT2R. Furthermore, selective stimulation of AT2R by CGP42112A significantly prolonged the rat atrial action potentials recorded using conventional microelectrode techniques. The AngII-induced inhibition of I(to) was not modified by either Npi-nitro-L-arginine-methyl ester (L-NAME) or eicosatetrayonic acid (ETYA), indicating that neither the nitric oxide (NO)-guanosine 3',5'-cyclic monophosphate (cGMP) system nor the arachidonic acid cascade was implicated in the effects of AngII on Ito. However, the AngII-induced Ito inhibition was completely abolished by the serine/threonine phosphatase type 2A (PP2A) inhibitors, okadaic acid and cantharidin, but not by the inactive analog of okadaic acid, 1-norokadaone. Intracellular application of PP2A decreased Kv4.2 currents recorded in transiently transfected Chinese hamster ovary cells (CHO).
  
  
  CONCLUSIONS
  These results indicate that AngII activates PP2A through the stimulation of the AT2R, resulting in a decrease of the Ito amplitude.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense, 28040, Madrid, Spain. rcaballero@ift.csic.es
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caballero
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gómez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moreno
authors.forename: Lucía
authors.initials: L
authors.lastname: Nuñez
authors.forename: Teresa
authors.initials: T
authors.lastname: González
authors.forename: Cristina
authors.initials: C
authors.lastname: Arias
authors.forename: Miriam
authors.initials: M
authors.lastname: Guizy
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*
chemical_list: D015221:Potassium Channels; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II