Abnormal cardiac repolarization and impulse initiation in German shepherd dogs with inherited ventricular arrhythmias and sudden death.
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.
Sosunov
E A
EA
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Anyukhovsky
E P
EP
Shvilkin
A
A
Hara
M
M
Steinberg
S F
SF
Danilo
P
P
Rosen
M R
MR
Möise
N S
NS
Mérot
J
J
Probst
V
V
Charpentier
F
F
Legeay
Y
Y
Le Marec
H
H
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*
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D000262:Adenylyl Cyclases; D007545:Isoproterenol