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

Co-treatment with ACE inhibitors/angiotensin II receptor antagonists was obligatory and an aldosterone antagonist optional in trials that established 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 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% seven 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 (I p ), increased for myocytes from sham-operated rabbits. For myocytes from rabbits that had coronary ligation, metoprolol reversed a 63% decrease of 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 does not support β1AR-coupled cAMP signaling increasing cardiac Na + -K + pump activity.