Role of β
3-AR dysregulation, as either cardio-conserving or cardio-disrupting mediator, remains unknown yet. Therefore, we examined the molecular mechanism of β
3-AR activation in depressed myocardial contractility using a specific agonist CL316243 or using β
3-AR overexpressed cardiomyocytes. Since it has been previously shown a possible correlation between increased cellular free Zn
2+ ([Zn
2+]
i) and depressed cardiac contractility, we first demonstrated a relation between β
3-AR activation and increased [Zn
2+]
i, parallel to the significant depolarization in mitochondrial membrane potential in rat ventricular cardiomyocytes. Furthermore, the increased [Zn
2+]
i induced a significant increase in messenger RNA (mRNA) level of β
3-AR in cardiomyocytes. Either β
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-3β/GSK-3β, and PKG expression level in cardiomyocytes. Although β
3-AR activation induced depression in both Na
+- and Ca
2+-currents, the prolonged action potential (AP) seems to be associated with a marked depression in K
+-currents. The β
3-AR activation caused a negative inotropic effect on the mechanical activity of the heart, through affecting the cellular Ca
2+-handling, including its effect on Ca
2+-leakage from sarcoplasmic reticulum (SR). Our cellular level data with β
3-AR agonism were supported with the data on high [Zn
2+]
i and β
3-AR protein-level in metabolic syndrome (MetS)-rat heart. Overall, our present data can emphasize the important deleterious effect of β
3-AR activation in cardiac remodeling under pathological condition, at least, through a cross-link between β
3-AR activation, NO-signaling, and [Zn
2+]
i pathways. Moreover, it is interesting to note that the recovery in ER-stress markers with β
3-AR agonism in hyperglycemic cardiomyocytes is favored. Therefore, how long and to which level the β
3-AR agonism would be friend or become foe remains to be mystery, yet.
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