Heart failure (HF) represents a significant health problem and one of its salient features is elevated Sympathetic Nervous System (SNS) activity and outflow, reflected by enhanced levels of circulating catecholamines in HF subjects, a significant aggravating factor for the disease. Epinephrine secretion from the adrenal medulla, along with Central norepinephrine release, represent the major catecholamines for SNS outflow and regulate a variety of key physiological events including the chronotropy and inotropy of the heart. Various G protein-coupled receptors (GPCRs) have been shown to regulate adrenal catecholamine release, some enhancing it (e.g. p-adrenergic receptors (pARs), while others inhibit it, most importantly a2ARs. Regulation of these receptors in the adrenal medulla and, specifically in chromaffin cells remains largely unknown, especially in HF. GPCR kinases (GRKs) play a prominent role in GPCR regulation in the heart during HF but their role in adrenal AR regulation is also un-studied. Since SNS activity is elevated in HF, increased adrenal catecholamine secretion would be expected to down-regulate GPCRs in the adrenal gland such as inhibitory a2ARs via the actions of GRKs. Thus, research focusing on GRK-mediated regulation of receptors that control adrenal secretion could reveal important mechanisms of enhanced catecholamine release and SNS activity in HF, and consequently produce novel therapeutic targets and molecular, diagnostic biomarkers of SNS activity in HF. Indeed, novel preliminary data from us show enhanced expression and activity of GRK2 in adrenal glands of multiple models of HF resulting in significant
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