Figure 1. Acute dobutamine application induces positive inotropy; chronic dobutamine application deteriorates cardiac function.

Dobutamine activates β₁‐ and β₂‐adrenergic receptors (β₁AR and β₂AR). Activated βARs increase contractility and relaxation of cardiomyocytes via the activation of stimulatory G‐proteins (G_s), which in turn activate protein kinase A and Ca²⁺/calmodulin‐dependent protein kinase II. These kinases increase Ca²⁺ cycling: upon phosphorylation, phospholamban (PLN) dissociates from sarco‐/endoplasmatic reticulum Ca²⁺‐ATPase (SERCA2a). This leads to increased SERCA2a‐mediated Ca²⁺ re‐uptake into the sarcoplasmatic reticulum and cardiomyocyte contractility. Phosphorylation of troponin I (TnI) decreases Ca²⁺ sensitivity and thereby increases cardiomyocyte relaxation. However, G‐protein‐coupled receptor kinase (GRK) phosphorylates activated G‐protein‐coupled receptors (GPCR) as for example β₁AR and β₂AR, which induces receptor desensitization and internalization. This blunts βAR signalling and the initial increase in cardiomyocyte contractility upon dobutamine application. Further, chronic βAR stimulation induces apoptosis, fibrosis and arrhythmia, in particular via hyperphosphorylation of the ryanodine receptor 2 (RyR2) and L‐type Ca²⁺ channels (LTCC), thereby leading to increased diastolic Ca²⁺ leak.