Targeting Cardiac Myocyte Na⁺-K⁺ Pump Function With β3 Adrenergic Agonist in Rabbit Model of Severe Congestive Heart Failure

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).

Indices for HF were lung-, heart-, and liver: body weight ratios and ascites after circumflex coronary artery ligation in rabbits. Na⁺-K⁺ pump current, I_p, 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.

Coronary ligation caused ascites in most rabbits, significantly increased lung-, heart-, and liver: body weight ratios, and decreased I_p 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 I_p 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.

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.