RT Journal Article
SR Electronic
T1 Modeling the Effects of β1-adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca2+ Handling
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.090951
DO 10.1124/mol.113.090951
A1 Robert K. Amanfu
A1 Jeffrey J. Saucerman
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/05/27/mol.113.090951.abstract
AB β-adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biological mechanisms governing their efficacy are still poorly understood. The complexity of β-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuitively predict the effect of β-blockers on cardiac physiology. While some studies indicate that β-blockers are efficacious by inhibiting β-adrenergic signaling, other studies suggest that they work by maintaining β-adrenergic responsiveness. Here we use a systems pharmacology approach to test the hypothesis that in ventricular myocytes, these two apparently conflicting mechanisms for β-blocker efficacy can occur concurrently. We extended a computational model of the β1-adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca2+ and FRET imaging of adult rat ventricular myocytes, surprisingly suggest that β-blockers can both inhibit and maintain signaling depending on the magnitude of receptor stimulation. The balance of inhibition and maintenance of β1-adrenergic signaling is predicted to depend on the specific β-blocker (with greater responsiveness for metoprolol than carvedilol) and β1-adrenergic receptor Arg389Gly polymorphisms.