Inhibiting GRK2 to improve β-AR signaling in HF or aging appears counter-intuitive since β-blockers are effective in HF, however, GRK2 inhibition chronically up-regulates receptors in addition to resensitizing them, restoring normal β-AR contractile and metabolic signaling that essentially reestablishes the fight-or-flight response and studies have shown this to be true with βARKct and paroxetine lowering Ca2+ levels and SNS over-activity in HF models (Rengo et al., 2009b; Raake et al., 2013; Schumacher et al., 2015). This evidence concerns the gene ADRB2 and hydrops fetalis.