beta(1)-Receptors increase cAMP and induce abnormal Ca(i) cycling in the German shepherd sudden death model.
We studied the role of beta-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 beta(1)-receptors (not beta(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 beta(1)-receptor agonists, and 3) beta(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 beta(1)- and beta(2)-receptor pathways with differing requirements for cAMP. The propensity to develop arrhythmias is not induced by beta(2)-receptors (or a rise in calcium alone), but rather occurs in the context of beta(1)-receptor activation of the cAMP-dependent pathway.
Steinberg
Susan F
SF
Center for Molecular Therapeutics, Departments of Pharmacology, Medicine and Pediatrics, College of Physicians and Surgeons of Columbia University, New York 10032, USA.
Alcott
Sasha
S
Pak
Elena
E
Hu
Donglei
D
Protas
Lev
L
Möise
N Sydney
NS
Robinson
Richard B
RB
Rosen
Michael R
MR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002395:Catecholamines / Q000633:toxicity; D002454:Cell Differentiation; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D000242:Cyclic AMP / Q000378:metabolism*; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000662:veterinary*; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000209:etiology* / Q000503:physiopathology; D004285:Dogs; D004558:Electric Stimulation; D004983:Ethanolamines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D012016:Reference Values; D014661:Vasoconstriction
D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D004983:Ethanolamines; D018342:Receptors, Adrenergic, beta-1; C002904:zinterol; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium