Evidence suggests that beta-Adrenergic receptor signaling increases heart rate and force through not just cyclic AMP but also the Ca2+-releasing second messengers NAADP (nicotinic acid adenine dinucleotide phosphate) and cADPR (cyclic ADP-ribose). Nevertheless, proof of the physiological relevance of these messengers requires direct measurements of their levels in response to receptor stimulation. Here we report that in intact Langendorff-perfused hearts beta-adrenergic stimulation increased both messengers, with NAADP being transient and cADPR being sustained. Both NAADP and cADPR have physiological and therefore pathological relevance by providing alternative drug targets in the beta-adrenergic receptor signaling pathway. (C) 2012 Elsevier Inc. All rights reserved.