Abstract 17142: Treatment With a Beta3 Adrenergic Receptor Agonist in Heart Failure Reverses an Oxidative Modification and Inhibition of the Na+-K+ Pump in Cardiac Myocytes and Improves Pulmonary Congestion
An abnormally high cytosolic Na+ concentration in cardiac myocytes is a nodal point of multiple interacting abnormalities that perpetuate the heart failure (HF) syndrome, and, since activation of the beta3 adrenergic receptor (beta3-AR) stimulates the only export route for Na+, the Na+-K+ pump, we tested the hypothesis that treatment with a beta3-AR agonist is useful in HF. We induced HF in rabbits by ligating the circumflex coronary artery. HF was identified by serum brain natriuretic peptide levels, increased lung/body weight ratios and the presence of ascites and congestive hepatopathy. Electrogenic Na+-K+ pump current (Ip, arising from 3:2 Na+:K+ exchange ratio and normalized for cell capacitance) was identified as the ouabain-sensitive membrane current of voltage clamped myocytes. Glutathionylation of the β1 Na+-K+ pump subunit, a reversible oxidative modification that inhibits pump activity, was identified by coimmuno-precipitation and immuno-blotting techniques of cardiac myocyte lysate. Ip was significantly reduced in myocytes from 5 rabbits with HF compared with myocytes from 5 sham rabbits (0.17 ± 0.02 pA/pF vs. 0.33 ± 0.04 pA/pF) while β1 pump subunit glutathyonylation measured with either of two independent techniques was significantly increased by 1.3-3 fold. Treatment following HF with the beta3-AR agonist CL316,243 (CL) via osmotic mini-pumps for 3 days (duration limited by expense of CL) completely reversed inhibition of Ip (0.41 ± 0.04 pA/pF vs. 0.17 ± 0.02 pA/pF), significantly decreased lung/body weight ratios (6.42 ± 0.34 g/Kg vs. 4.93 ± 0.07 g/Kg) and decreased β1 pump subunit glutathionylation ~1.5-fold. Treatment had no effect on blood pressure or heart rate. We conclude that CL reverses a key pathophysiological abnormality in HF and improves pulmonary congestion, a clinically relevant index of the syndrome. A beta3-AR agonist is now approved for treatment of overactive bladder syndrome in Japan, the USA and the EU. Our study suggests a HF indication should be explored for beta3-AR agonists.
- © 2013 by American Heart Association, Inc.