Carvedilol induces biased β1 adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility

Cardiovasc Res. 2021 Aug 29;117(10):2237-2251. doi: 10.1093/cvr/cvaa266.

Abstract

Aims: β-blockers are widely used in therapy for heart failure and hypertension. β-blockers are also known to evoke additional diversified pharmacological and physiological effects in patients. We aim to characterize the underlying molecular signalling and effects on cardiac inotropy induced by β-blockers in animal hearts.

Methods and results: Wild-type mice fed high-fat diet (HFD) were treated with carvedilol, metoprolol, or vehicle and echocardiogram analysis was performed. Heart tissues were used for biochemical and histological analyses. Cardiomyocytes were isolated from normal and HFD mice and rats for analysis of adrenergic signalling, calcium handling, contraction, and western blot. Biosensors were used to measure β-blocker-induced cyclic guanosine monophosphate (cGMP) signal and protein kinase A activity in myocytes. Acute stimulation of myocytes with carvedilol promotes β1 adrenergic receptor (β1AR)- and protein kinase G (PKG)-dependent inotropic cardiac contractility with minimal increases in calcium amplitude. Carvedilol acts as a biased ligand to promote β1AR coupling to a Gi-PI3K-Akt-nitric oxide synthase 3 (NOS3) cascade and induces robust β1AR-cGMP-PKG signal. Deletion of NOS3 selectively blocks carvedilol, but not isoproterenol-induced β1AR-dependent cGMP signal and inotropic contractility. Moreover, therapy with carvedilol restores inotropic contractility and sensitizes cardiac adrenergic reserves in diabetic mice with minimal impact in calcium signal, as well as reduced cell apoptosis and hypertrophy in diabetic hearts.

Conclusion: These observations present a novel β1AR-NOS3 signalling pathway to promote cardiac inotropy in the heart, indicating that this signalling paradigm may be targeted in therapy of heart diseases with reduced ejection fraction.

Keywords: Carvedilol; Contractility; Cyclic guanosine monophosphate; Heart dysfunction; β adrenergic receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / pharmacology*
  • Animals
  • Cardiotonic Agents / pharmacology*
  • Carvedilol / pharmacology*
  • Cells, Cultured
  • Cyclic GMP / metabolism*
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Heart Diseases / drug therapy*
  • Heart Diseases / enzymology
  • Heart Diseases / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Contraction / drug effects*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism*
  • Rats
  • Receptors, Adrenergic, beta-1 / drug effects*
  • Receptors, Adrenergic, beta-1 / metabolism
  • Second Messenger Systems

Substances

  • Adrb1 protein, mouse
  • Adrenergic alpha-1 Receptor Antagonists
  • Cardiotonic Agents
  • Receptors, Adrenergic, beta-1
  • Carvedilol
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic GMP