Background; The 棺-adrenergic receptor (棺AR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca²⁺ homeostasis. Objective and Methods; We investigated the role of 棺AR stimulation in augmenting cardiac function and its role in the activation of Ca²⁺/calmodulin-dependent kinase II (CaMKII) using various 棺AR knockouts (KO) including 棺1ARKO, 棺2ARKO and 棺1/棺2AR double KO (DKO) mice. We employed a murine model of left anterior descending coronary ligation to examine the differential contributions of specific 棺AR subtypes in the activation of CaMKII in vivo in failing myocardium. Results; Cardiac inotropy, chronotropy and CaMKII activity following short term ISO stimulation was significant attenuated in 棺1ARKO and DKO compared to either the 棺2ARKO or WT mice indicating that 棺1ARs are required for catecholamine induced increases in contractility and CaMKll activity. Eight weeks post MI, 棺1ARKO and DKO mice showed a significant attenuation in fractional shortening compared to either the 棺2ARKO or WT mice. CaMKII activity after MI was significantly increased only in the 棺2ARKO and WT hearts and not in the 棺1ARKO and DKO hearts. The border zone of the infarct in the 棺2ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared to the 棺1ARKO and DKO hearts. Conclusion; Taken together, these data show that cardiac function and CaMKII activity is mediated almost exclusively by the 棺1AR. Moreover, it appears that 棺1AR signaling is detrimental to cardiac function following myocardial infarction, possibly through activation of CaMKII.