Natasha A S Fry1, Chia-Chi Liu2, Alvaro Garcia3, Elisha J Hamilton1, Keyvan Karimi Galougahi2, Yeon Jae Kim1,2, David W Whalley2,4, Henning Bundgaard5, Helge H Rasmussen1,2,4. 1. North Shore Heart Research Group, Kolling Medical Research Institute, University of Sydney, Australia (N.A.S.F., E.J.H., Y.J.K., H.H.R.). 2. University of Sydney, Australia (C.-C.L., K.K.G., Y.J.K., D.W.W., H.H.R.). 3. University of Technology Sydney, Australia (A.G.). 4. Department of Cardiology, Royal North Shore Hospital, Sydney, Australia (D.W.W., H.H.R.). 5. Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark (H.B.).
Abstract
BACKGROUND: Abnormally high cytosolic Na+ concentrations in advanced heart failure impair myocardial contractility. Stimulation of the membrane Na+-K+ pump should lower Na+ concentrations, and the β3 adrenoceptor (β3 AR) mediates pump stimulation in myocytes. We examined if β3 AR-selective agonists given in vivo increase myocyte Na+-K+ pump activity and reverse organ congestion in severe heart failure (HF). METHODS: Indices for HF were lung-, heart-, and liver: body weight ratios and ascites after circumflex coronary artery ligation in rabbits. Na+-K+ pump current, Ip, was measured in voltage-clamped myocytes from noninfarct myocardium. Rabbits were treated with the β3 AR agonists CL316,243 or ASP9531, starting 2 weeks after coronary ligation. RESULTS: Coronary ligation caused ascites in most rabbits, significantly increased lung-, heart-, and liver: body weight ratios, and decreased Ip relative to that for 10 sham-operated rabbits. Treatment with CL316,243 for 3 days significantly reduced lung-, heart-, and liver: body weight ratios and prevalence of ascites in 8 rabbits with HF relative to indices for 13 untreated rabbits with HF. It also increased Ip significantly to levels of myocytes from sham-operated rabbits. Treatment with ASP9531 for 14 days significantly reduced indices of organ congestion in 6 rabbits with HF relative to indices of 6 untreated rabbits, and it eliminated ascites. β3 AR agonists did not significantly change heart rates or blood pressures. CONCLUSIONS: Parallel β3 AR agonists-induced reversal of Na+-K+ pump inhibition and indices of congestion suggest pump inhibition is a useful target for treatment with β3 AR agonists in congestive HF.
BACKGROUND: Abnormally high cytosolic Na+ concentrations in advanced heart failure impair myocardial contractility. Stimulation of the membrane Na+-K+ pump should lower Na+ concentrations, and the β3 adrenoceptor (β3 AR) mediates pump stimulation in myocytes. We examined if β3 AR-selective agonists given in vivo increase myocyte Na+-K+ pump activity and reverse organ congestion in severe heart failure (HF). METHODS: Indices for HF were lung-, heart-, and liver: body weight ratios and ascites after circumflex coronary artery ligation in rabbits. Na+-K+ pump current, Ip, was measured in voltage-clamped myocytes from noninfarct myocardium. Rabbits were treated with the β3 AR agonists CL316,243 or ASP9531, starting 2 weeks after coronary ligation. RESULTS: Coronary ligation caused ascites in most rabbits, significantly increased lung-, heart-, and liver: body weight ratios, and decreased Ip relative to that for 10 sham-operated rabbits. Treatment with CL316,243 for 3 days significantly reduced lung-, heart-, and liver: body weight ratios and prevalence of ascites in 8 rabbits with HF relative to indices for 13 untreated rabbits with HF. It also increased Ip significantly to levels of myocytes from sham-operated rabbits. Treatment with ASP9531 for 14 days significantly reduced indices of organ congestion in 6 rabbits with HF relative to indices of 6 untreated rabbits, and it eliminated ascites. β3 AR agonists did not significantly change heart rates or blood pressures. CONCLUSIONS: Parallel β3 AR agonists-induced reversal of Na+-K+ pump inhibition and indices of congestion suggest pump inhibition is a useful target for treatment with β3 AR agonists in congestive HF.