β(2)-Adrenergic and M(2)-muscarinic receptors decrease basal t-tubular L-type Ca2+ channel activity and suppress...

Area of Science:

• Cardiology
• Molecular Pharmacology
• Cell Physiology

Background:

• L-type Ca(2+) channels (LTCC) are vital for cardiac excitation-contraction coupling.
• Previous studies showed altered LTCC activity in failing myocytes due to protein phosphatase (PP) imbalances.
• Pertussis toxin normalized LTCC densities and contractility in failing hearts.

Purpose of the Study:

• To identify specific Gi/o protein-coupled receptors responsible for LTCC abnormalities in heart failure.
• To investigate the role of β2-adrenergic, M2-muscarinic, and A1-adenosine receptors in cardiac dysfunction.

Main Methods:

• Mice with heart failure were treated with isoproterenol and selective antagonists for β2-adrenergic (ICI118,551), M2-muscarinic (atropine), or A1-adenosine (DPCPX) receptors.
• Cardiac function was assessed by measuring lung weight/tibial length, fractional shortening, and pressure-volume loops (dP/dtmax, dP/dtmin).
• LTCC current densities in t-tubular (TT) and sarcolemmal (SS) membranes of ventricular myocytes were measured.

Main Results:

• Treatment with ICI118,551 or atropine, but not DPCPX, improved cardiac function and contractility markers compared to isoproterenol alone.
• Ventricular myocytes from mice treated with ICI118,551 or atropine showed normalized TT LTCC current density and reduced SS LTCC current density.
• These changes were associated with the normalization of protein phosphatase (PP) activities.

Conclusions:

• β2-adrenergic and M2-muscarinic receptors, but not A1-adenosine receptors, contribute to reduced ventricular contractility in heart failure.
• These receptors impair cardiac function partly by decreasing basal t-tubular LTCC activity.
• Antagonists of β2-adrenergic and/or M2-muscarinic receptors could be beneficial adjunct therapies for heart failure.