Distinct actions of intermittent and sustained β-adrenoceptor stimulation on cardiac remodeling

Heart disease is associated with increased sympathetic nerve activity and elevated levels of circulating catecholamines, resulting in chronic stimulation of the β-adrenergic receptors (β-AR) and consequent pathological cardiac remodeling. Experimentally, chronic administration of the β-AR agonist isoproterenol (ISO) has been most commonly used to model β-AR-induced cardiac remodeling. However, it remains unclear whether β-AR-mediated cardiac remodeling and dysfunction differs between sustained versus pulsatile (intermittent) exposure to a β-agonist. Here, we compare the effects of intermittent versus sustained administration of ISO on cardiac remodeling and function in mice. Animals were administered 5 mg (kg d)(-1) ISO for 2 weeks either by daily subcutaneous injection, or continuous infusion via an implanted osmotic minipump. Cardiac function and remodeling were determined by echocardiography, micromanometry and histology. Moreover, Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were utilized to define the proteins and genes involved. Both sustained and intermittent administration of ISO resulted in a similar degree of cardiac hypertrophy (16% and 19%, respectively). However, mice receiving ISO by daily injection developed more severe ventricular systolic and diastolic dysfunction and myocardial fibrosis compared with mice receiving ISO via the osmotic minipump. The disparity in results between the delivery methods is suggested to be due, at least in part, to increased expression of fibrogenic factors, including connective tissue growth factor (CTGF) and NADPH oxidase (NOX4), in mice receiving intermittent application of ISO. In summary, compared with sustained exposure to a β-AR agonist, intermittent β-AR stimulation leads to more severe cardiac dysfunction and fibrosis. These findings not only further our understanding of β-AR function in the setting of cardiac pathophysiology, but also highlight that significant differences can result dependent upon the mode of experimental β-AR stimulation in inducing cardiomyopathy.