PT - JOURNAL ARTICLE AU - Robert K. Amanfu AU - Jeffrey J. Saucerman TI - Modeling the Effects of <em>β</em><sub>1</sub>-Adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca<sup>2+</sup> Handling AID - 10.1124/mol.113.090951 DP - 2014 Aug 01 TA - Molecular Pharmacology PG - 222--230 VI - 86 IP - 2 4099 - http://molpharm.aspetjournals.org/content/86/2/222.short 4100 - http://molpharm.aspetjournals.org/content/86/2/222.full SO - Mol Pharmacol2014 Aug 01; 86 AB - β-Adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biologic 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 intuit 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 Förster resonance energy transfer 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.