A key feature of heart failure is the chronic elevation of circulating catecholamines which desensitizes the β-adrenergic receptor signaling pathway, rendering patients incapable of increasing cardiac output in response to acute stress (eg. exercise). β-adrenergic receptor blockers (β-blockers) are commonly used to treat this condition, but precisely how they work is still controversial and poorly understood. Two opposing theories are that β-blockers work by 1) blocking the harmful consequences of chronic signaling or 2) paradoxically increasing receptor sensitivity. To investigate whether β-blockers function by increasing receptor sensitivity, we extended a published computational model of the β
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-adrenergic receptor signaling pathway developed in our lab by using a ternary complex receptor module. This receptor model includes the spontaneous switching between the active and inactive conformations of the receptor that is crucial for accurate representation of β-blockers. Parameter values were determined from literature to model 11 agonists and 10 β-blockers. The new receptor model was validated against ligand binding studies and adenylyl cyclase assays from literature. Chronic and acute stresses were modeled as low and high (100X greater) concentrations of the agonist isoproterenol. Simulations indicate that when the β-blocker propranolol is present during chronic stress, cAMP levels are increased upon application of an acute stress, elevating intracellular calcium levels and contractility. This suggests that in addition to blocking the harmful consequences of chronic signaling, β-blockers may sensitize the response to acute stress. Preliminary data from calcium imaging experiments in isolated cardiac ventricular cells confirm this prediction. Simulations with a range of commonly used β-blockers indicate that individual drugs differ significantly in their ability to enhance receptor sensitivity. In addition, simulation of the Gly389Arg polymorphism suggests that the Arg389 variant has reduced sensitization to acute stress in the presence of propranolol. These simulations are a first step towards evaluating personalized β-blocker therapies with computational models.
Combination Therapy With VELCADE and Tissue Plasminogen Activator Is Neuroprotective in Aged Rats After Stroke and Targets MicroRNA-146a and the Toll-Like Receptor Signaling Pathway
