Cardiac α1-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 alpha(1A)- and alpha(1B)-, and beta(1)- and beta(2)-AR subtypes, which are all members of the G-protein-coupled receptor superfamily that signal via interaction with heterotrimeric G-proteins. Cardiac function - both inotropy and chronotropy - is regulated predominantly by beta(1)-AR. Activation of alpha(1)-ARs also results in increased contractility, as well as changes in the electrophysiotogical properties and metabolic responses of the heart. Nonetheless, there is little evidence that cardiac alpha(1)-ARs play a major functional rote under normal physiological conditions. In pathological settings, alpha(1)-ARs may function in a compensatory fashion to maintain cardiac inotropy when the beta-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 a,alpha(1)-ARs are importantly involved in both developmental cardiomyocyte growth, as welt as pathological hypertrophy. In the presence of pressure overload or with myocardial infarction, activation of alpha(1)-ARs, particularly the alpha(1A)-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.