Role of (3)-AR dysregulation, as either cardio-conserving or cardio-disrupting mediator, remains unknown yet. Therefore, we examined the molecular mechanism of (3)-AR activation in depressed myocardial contractility using a specific agonist CL316243 or using (3)-AR overexpressed cardiomyocytes. Since it has been previously shown a possible correlation between increased cellular free Zn2+ ([Zn2+](i)) and depressed cardiac contractility, we first demonstrated a relation between (3)-AR activation and increased [Zn2+](i), parallel to the significant depolarization in mitochondrial membrane potential in rat ventricular cardiomyocytes. Furthermore, the increased [Zn2+](i) induced a significant increase in messenger RNA (mRNA) level of (3)-AR in cardiomyocytes. Either (3)-AR activation or its overexpression could increase cellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels, in line with significant changes in nitric oxide (NO)-pathway, including increases in the ratios of pNOS3/NOS3 and pGSK-3/GSK-3, and PKG expression level in cardiomyocytes. Although (3)-AR activation induced depression in both Na+- and Ca2+-currents, the prolonged action potential (AP) seems to be associated with a marked depression in K+-currents. The (3)-AR activation caused a negative inotropic effect on the mechanical activity of the heart, through affecting the cellular Ca2+-handling, including its effect on Ca2+-leakage from sarcoplasmic reticulum (SR). Our cellular level data with (3)-AR agonism were supported with the data on high [Zn2+](i) and (3)-AR protein-level in metabolic syndrome (MetS)-rat heart. Overall, our present data can emphasize the important deleterious effect of (3)-AR activation in cardiac remodeling under pathological condition, at least, through a cross-link between (3)-AR activation, NO-signaling, and [Zn2+](i) pathways. Moreover, it is interesting to note that the recovery in ER-stress markers with (3)-AR agonism in hyperglycemic cardiomyocytes is favored. Therefore, how long and to which level the (3)-AR agonism would be friend or become foe remains to be mystery, yet.