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Udgivet

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

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  • Natasha A S Fry
  • Chia-Chi Liu
  • Alvaro Garcia
  • Elisha J Hamilton
  • Keyvan Karimi Galougahi
  • Yeon Jae Kim
  • David W Whalley
  • Henning Bundgaard
  • Helge H Rasmussen
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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.

OriginalsprogEngelsk
TidsskriftCirculation. Heart failure
Vol/bind13
Udgave nummer9
Sider (fra-til)e006753
ISSN1941-3289
DOI
StatusUdgivet - sep. 2020

ID: 62093120