Vol. 282, Issue 4, H1181-H1188, April 2002
1-Receptors increase cAMP and induce abnormal
Cai cycling in the German shepherd sudden death
model
Susan F.
Steinberg1,
Sasha
Alcott1,
Elena
Pak1,
Donglei
Hu1,
Lev
Protas1,
N. Sydney
Möise2,
Richard B.
Robinson1, and
Michael R.
Rosen1
1 Center for Molecular Therapeutics, Departments of
Pharmacology, Medicine and Pediatrics, College of Physicians and
Surgeons of Columbia University, New York 10032;
and 2 Cornell University, College of Veterinary
Medicine, Ithaca, New York 14853-6401
We studied the role of 
-adrenergic
receptor subtype signaling to cAMP and calcium in the genesis of
catecholamine-dependent arrhythmias in German shepherd dogs that
develop lethal arrhythmias at ~5 mo of age. There were three major
findings in this study: 1) isoproterenol induces similar
increases in cAMP in afflicted and control dogs exclusively through
1-receptors (not 2), 2) cells
from afflicted dogs display prolonged relaxation kinetics at long cycle
lengths and large frequent spontaneous calcium oscillations (and
aftercontractions) with little increase in calcium transient amplitude
in response to 1-receptor agonists, and 3)
2-receptor agonists induce a similar marked increases in
calcium transient and twitch amplitude, with only rare spontaneous
calcium oscillations in afflicted and control cells. These results
indicate that catecholamines provide inotropic support to canine
cardiomyocytes through distinct 1- and
2-receptor pathways with differing requirements for
cAMP. The propensity to develop arrhythmias is not induced by
2-receptors (or a rise in calcium alone), but rather
occurs in the context of 1-receptor activation of the
cAMP-dependent pathway.
cardiac arrhythmia; -adrenergic receptors; afterdepolarization; aftercontractions; calcium
