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, 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.
Results:
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.
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.