Modeling the Effects ofβ₁-Adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca²⁺Handling

Abstract

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 of b-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 b 1 -adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca 21 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 b 1 -adrenergic signaling is predicted to depend on the specific b-blocker (with greater responsiveness for metoprolol than carvedilol) and b 1 -adrenergic receptor Arg389Gly polymorphisms.

Recent developments in using mechanistic cardiac modelling for drug safety evaluation

“…These include more detail on metabolic changes underlying forms of arrhythmia and more detail on the feedbacks by which electrical and ionic changes might be involved longer-term in controlling gene expression (electrotranscription coupling). These alternative mechanisms have been attempted elsewhere, for instance inclusion of binding kinetics [52] , gene expression [109] , safety pharmacology [110] , influence of beta-adrenergic activity [111] and cell signalling 112 , 113 . Because we are already faced with problems of under-determination in the more-complex models, how can these additional demands be compatible with the need for mathematical reduction to simpler models?…”

Combination Treatment With Antihypertensive Agents Enhances the Effect of Qiliqiangxin on Chronic Pressure Overload–induced Cardiac Hypertrophy and Remodeling in Male Mice

“…Metoprolol, one of the most commonly prescribed beta-blockers, exerts its pharmacological effects through the inhibition of adrenergic receptors. 35 Many large-scale clinical trials, including the CIBISII, the MERIT-HF, and the COPERNICUS trial, have demonstrated that the long-term use of a BB in patients with heart failure reduces overall mortality, cardiovascular mortality, and the risk of sudden cardiac death. 36 …”

Correlation of ADRB1 rs1801253 Polymorphism with Analgesic Effect of Fentanyl After Cancer Surgeries

“…Recent studies mainly focused on the role of ADRB1 gene in the pathogenesis of disease, and it has been found that ADRB1 polymorphisms are related to various diseases [ 34 – 39 ]. Researches also found that the rs1801253 polymorphism was related with beta-blocker response [ 40 – 43 ]. This suggested to us that the rs1801253 has become increasingly important in the reaction to pain, and might be associated with analgesic effect.…”