Abstract 3394: Beta-adrenergic Receptor Blockade Reduces Sympathetic Overactivation in Heart Failure and Restores Adrenal GRK2-alfa2-adrenergic Receptor-cathecolamine Production Axis
β-adrenergic receptor (AR) blockade has been proven to exert several beneficial effects on the cardiovascular system and to reduce heart failure (HF)-related morbidity and mortality. Sympathetic nervous system (SNS) hyperactivity is a hallmark of chronic HF and significantly worsens the prognosis in HF patients. Thus, the success of β-AR blockade in HF therapy is mainly attributed to its ability to protect the heart from the noxious effects of augmented catecholamine (CA) levels. β-blocker treatment has also been proven to reduce SNS hyperactivity in HF but the underlying molecular mechanisms for this effect are still incompletely understood. Recently, we reported that adrenal G-protein coupled receptor kinase-2 (GRK2) is up-regulated in the adrenal medulla during HF and, by decreasing the function of the sympatho-inhibitory α2-ARs, contributes to the elevated CA levels. In the present study, we investigated whether β-blocker treatment can affect the adrenal GRK2-α2-AR-CA production axis in HF. Four weeks after surgically-induced myocardial infarction, adult male Sprague-Dawley rats were randomized to vehicle (HF/control [C]) or β1-selective blocker bisoprolol (B) treatment (HF/B). Sham-operated rats served as controls. After the 10-week treatment period, β-blocker therapy resulted in significant amelioration of HF-related adverse cardiac remodeling. The positive effects of B on cardiac maladaptive remodeling were also visible at the molecular level, since Collagen-1, TGF-β, ANF and, BNP mRNA levels, whose expression was increased in HF/C hearts, were significantly lowered in HF/B hearts. Plasma circulating CA levels were found increased in HF/C rats compared to sham, while β-AR blockade was capable of significantly reducing plasma CA levels when compared to HF/C rats. B was also able to significantly attenuate adrenal GRK2 overexpression observed in HF/C rats compared to sham. Finally, α2-AR density in the plasma membranes obtained from the adrenal glands of HF/B rats was markedly augmented. Taken together these results suggest that β-AR blockade normalizes the adrenal GRK2-α2-AR-CA production axis, and this might be (part of) the mechanism whereby this therapy counteracts sympathetic overdrive and halts worsening of the failing heart.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).