title: Abnormal cardiac repolarization and impulse initiation in German shepherd dogs with inherited ventricular arrhythmias and sudden death.
abstract: OBJECTIVE
  We tested the hypothesis that delayed afterdepolarization (DAD)-associated rhythms in German shepherd dogs with reduced anteroseptal left ventricular (LV) sympathetic innervation derive from abnormal beta-adrenergic receptor effector coupling.
  
  
  RESULTS
  In anteroseptal LV midmyocardium of afflicted dogs, beta-receptor density was greater than that in normal dogs (P < .05), with affinity being equal in both groups. Basal and maximum isoproterenol (ISO) stimulated adenylyl cyclase activity of anteroseptal LV of afflicted dogs was greater than that in normal dogs (P < .05). Isolated anteroseptal M cell preparations of afflicted dogs studied with microelectrodes showed abnormal lengthening, rather than shortening of action potential duration in response to ISO, as well as a 61% incidence of 10(-7) mol/l ISO-induced triggered activity as compared to 12% in normals (P < .05). In contrast, there was no difference between afflicted and control dogs in triggered activity, beta-receptors or adenylyl cyclase activity in a normally innervated region of the ventricles.
  
  
  CONCLUSIONS
  In this model there is an increase in beta-receptor density and beta-adrenergic stimulation of adenylyl cyclase and of triggered activity in anteroseptal myocardium but not in a normally innervated region of the heart. Hence, abnormal beta-adrenergic signal transduction appears associated with the neural abnormality identified in dogs with inherited VT.
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Sosunov
authors.forename: E P
authors.initials: EP
authors.lastname: Anyukhovsky
authors.forename: A
authors.initials: A
authors.lastname: Shvilkin
authors.forename: M
authors.initials: M
authors.lastname: Hara
authors.forename: S F
authors.initials: SF
authors.lastname: Steinberg
authors.forename: P
authors.initials: P
authors.lastname: Danilo
authors.forename: M R
authors.initials: MR
authors.lastname: Rosen
authors.forename: N S
authors.initials: NS
authors.lastname: Möise
authors.forename: J
authors.initials: J
authors.lastname: Mérot
authors.forename: V
authors.initials: V
authors.lastname: Probst
authors.forename: F
authors.initials: F
authors.lastname: Charpentier
authors.forename: Y
authors.initials: Y
authors.lastname: Legeay
authors.forename: H
authors.initials: H
authors.lastname: Le Marec
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000503:physiopathology*; D002478:Cells, Cultured; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004285:Dogs; D004562:Electrocardiography; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008954:Models, Biological; D010656:Phenylephrine / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000503:physiopathology*
chemical_list: D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D000262:Adenylyl Cyclases; D007545:Isoproterenol