β1-Adrenergic antagonist monotherapy of male rabbits with ischemic HFrEF reverses sarcolemmal Na+-K+ pump inhibition and reduces lung congestion.

Cotreatment with angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor antagonists was obligatory, and an aldosterone antagonist was optional, in trials that established the efficacy of β1-adrenergic receptor (β1AR) antagonists in heart failure with reduced ejection fraction (HFrEF). However, with worsening HFrEF, combination treatment is often not tolerated, and patients receive β1AR antagonists only. It cannot be assumed that monotherapy is efficacious and might even be harmful because a raised myocardial cytosolic Na+ concentration ([Na+c]) in HFrEF reduces myocardial contractility, while β1AR-coupled signaling has been widely reported to activate myocyte Na+-K+ pump-mediated Na+c export in previous studies. We ligated the circumflex coronary artery of rabbits or performed sham thoracotomy. Rabbits with left ventricular ejection fraction <25% 7 days after coronary ligation were treated with the β1AR antagonist metoprolol or vehicle. Metoprolol reduced heart rate of sham-operated rabbits but not of rabbits that had coronary ligation. Metoprolol had no effect on systolic, diastolic, or mean blood pressures in either group. The primary index for heart failure, lung:body weight ratios, was ∼89% higher after coronary ligation than after sham thoracotomy, and metoprolol significantly reduced this to a ∼46% difference. The index for Na+-K+ pump function, electrogenic pump current (Ip), increased for myocytes from sham-operated rabbits. For myocytes from rabbits that had coronary ligation, metoprolol reversed a 63% decrease in Ip. Results are consistent with enhanced Na+-K+ pump-mediated Na+c export in HFrEF contributing to efficacy of β1AR antagonist monotherapy independent of heart rate and afterload but do not support β1AR-coupled cyclic adenosine monophosphate (cAMP) signaling increasing cardiac Na+-K+ pump activity.NEW & NOTEWORTHY β1AR antagonists are frequently the only guideline-directed treatment tolerated in heart failure with reduced ejection fraction (HFrEF), and they might be deleterious because raised cytosolic [Na+] is harmful in HFrEF and β1AR agonists reportedly enhance myocyte Na+ export. Here, an antagonist reversed reduced Na+-K+ pump function of myocytes from noninfarcted myocardium in an ischemic model of HFrEF and improved pulmonary congestion, consistent with benefit of Na+ export but not with widely reported β1AR agonist-induced export.