Mol090951 222..230

b-Adrenergic receptor blockers (b-blockers) are commonly used to treat heart failure, but the biologic mechanisms governing their efficacy are still poorly understood. The complexity ofb-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuit the effect of b-blockers on cardiac physiology. While some studies indicate that b-blockers are efficacious by inhibiting b-adrenergic signaling, other studies suggest that they work by maintaining b-adrenergic responsiveness. Here, we use a systems pharmacology approach to test the hypothesis that in ventricular myocytes, these two apparently conflicting mechanisms for b-blocker efficacy can occur concurrently. We extended a computational model of the b1-adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca and Förster resonance energy transfer imaging of adult rat ventricular myocytes, surprisingly suggest that b-blockers can both inhibit and maintain signaling depending on the magnitude of receptor stimulation. The balance of inhibition and maintenance of b1-adrenergic signaling is predicted to depend on the specific b-blocker (with greater responsiveness for metoprolol than carvedilol) and b1-adrenergic receptor Arg389Gly polymorphisms.