Philadelphia, PA - What if a heart-failure drug could lessen the adrenal glands' deluge of catecholamines to a more normal ebb and flow, complementing the dam that beta blockers erect at the receptor level? A potential target for such a therapy might be the increased adrenal levels of a particular enzyme that helps mediate sympathetic activity, according to a laboratory study [1]. Inhibition of the enzyme in mouse and rat models of HF appeared to at least partially restore the normal metabolic feedback mechanisms controlling epinephrine and norepinephrine secretion that go out of control in patients with the syndrome.

The research suggests that the normal dampers on catecholamine release, which are mediated by ₂ adrenergic receptors, are impaired in HF by the upregulation of adrenal G protein-coupled receptor kinase 2 (GRK2) but can be restored by GRK2 inhibition, report the authors, Dr Anastasios Lymperopoulos (Jefferson Medical College, Philadelphia, PA) and associates. In their study, published online February 18, 2007 in Nature Medicine, GRK2 inhibition was accomplished chemically in vitro and by simulated gene therapy in vivo.

The group's findings suggest that the preservation of normal epinephrine and norepinephrine responses through GRK2 inhibition can to some extent reverse the adrenal and ventricular dysfunction characteristic of HF, according to coauthor Dr Walter J Koch (Jefferson Medical College). It makes more intuitive sense to restore a normal homeostatic balance of catecholamines than it does to block them at the cellular receptor level, he observed for heartwire.

Lymperopoulos et al "have uncovered a mechanism that may explain intra- and intercellular maladaptive changes that are involved in heart failure," writes Dr Stephen B Liggett (University of Maryland, Baltimore) in an accompanying editorial [2]. "The altered relationship between the heart and the adrenal gland that occurs during heart failure appears to be amenable to therapy aimed at adrenal gland GRK2." Liggett is director of his institution's cardiopulmonary genomics program.

Such adrenal-targeted sympatholytic therapy, added to beta blockade and other established HF treatments, would represent an entirely new approach to managing the syndrome, observed Koch, who heads his center's laboratory of cardiovascular gene therapy.

He and his group observed significantly increased levels of epinephrine and norepinephrine and depressed LV function in two heart-failure models: transgenic mice "programmed" to develop cardiomyopathy and rats with induced MI.

In a series of experiments with the animals and their isolated and cultured catecholamine-producing adrenal chromaffin cells, the group observed evidence for:

• Severe HF-related downregulation of adrenal ₂ receptors.
• Increased GRK2 levels in adrenal-gland extracts from the mice and rats with HF but not in control animals.
• GRK2-mediated alterations in ₂ receptor function that interfered with the receptors' inhibition of catecholamine secretion and consequent elevation in epinephrine and norepinephrine levels.
• Reversal of ₂ receptor dysfunction, reduced catecholamine levels, and improvements in the animals' myocardial contractility and LV function associated with GRK2 inhibition.
• Additive catecholamine-reducing effects from the combination of GRK2 inhibition and administration of the established ₂ receptor agonist moxonidine in the rats with induced HF.

The findings suggest that an inhibitor of GRK2 "would be a very nice synergistic drug" when administered with beta blockers and might potentiate the sympatholytic effects of ₂ agonists like moxonidine, a drug that had been abandoned as an HF therapy after it worsened clinical outcomes in randomized trials, according to Koch.

Moxonidine may not have worked, Koch said, because it targets receptors that the current data suggest are downregulated in HF. By the same reasoning, he added, the drug might show a positive effect in HF if it could be given with a drug that reverses the ₂ receptor impairment—such as a GRK2 inhibitor.