We studied the role of ß-adrenergic receptor subtype signaling to cAMP and calcium in the genesis of catecholamine-dependent arrhythmias at <~> 5 months of age. The major findings are that [1] Isoproterenol induces similar increases in cAMP in afflicted and control dogs exclusively through ß₁- (not ß₂-) receptors, [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 ß₁-receptor agonists, and [3] ß₂-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 ß₁- and ß₂-receptor pathways with differing requirements for cAMP. The propensity to develop arrhythmias is not induced by ß₂-receptors (or a rise in calcium alone), but rather occurs in the context of ß₁-receptor activation of the cAMP-dependent pathway.