Review Cardiac a1-adrenergic drive in pathological remodelling

The heart is richly innervated by sympathetic nerves, and both acute and chronic regulation of cardiac function via sympathetically released catecholamines acting on cardiomyocyte adrenergic receptors (ARs), is critical for circulatory homeostasis. Cardiomyocytes express a1A- and a1B-, and b1- and b2-AR subtypes, which are all members of the G-protein-coupled receptor superfamily that signal via inter-action with heterotrimeric G-proteins. Cardiac function – both inotropy and chronotropy – is regulated predominantly by b1-AR. Activation of a1-ARs also results in increased contractility, as well as changes in the electrophysiological properties and metabolic responses of the heart. Nonetheless, there is little evidence that cardiac a1-ARs play a major functional role under normal physiological conditions. In pathological settings, a1-ARs may function in a compensatory fashion to maintain cardiac inotropy when the b-AR system is downregulated and uncoupled from G-proteins and effectors. In addition, as we consider here, recent evidence from clinical studies and from genetically engineered animal models indicates that a1-ARs are importantly involved in both developmental cardiomyocyte growth, as well as pathological hypertrophy. In the presence of pressure overload or with myocardial infarction, activation of a1-ARs, particularly the a1A-subtype, also appears to produce important pro-survival effects at the level of the cardiomyocyte, and to protect against maladaptive cardiac remodelling and decompensation to heart failure