New developments in cardiovascular adrenergic receptor pharmacology: Molecular mechanisms and clinical relevance

A DRENERGIC receptors (ARs) (classically (Xa, e~2, [31, [32) are plasma membrane-bound proteins involved in many aspects of general physiology and cardiovascular function? ARs are important in physiologic functions, such as myocardial rate and contractility, systemic and pulmonary vascular tone and blood flow, sedation/hypnosis, platelet aggregation, insulin secretion, and gut motility, as well as diseases such as congestive heart failure (CHF), hypertension, pheochromocytoma, benign prostatic hyperplasia, and possibly diabetes. ARs interact with the endogenous catecholamines norepinephrine (NE) and epinephrine (EPI), and several classes of drugs (predominantly adrenergic agonists and antagonists). 2,3 When occupied by agonists, these receptors couple to specific effector molecules via intermediary heterotrimeric guanine-nucleotide regulatory proteins (G proteins) (Fig 1). Specifically, [31-ARs and [32-ARs couple to the stimulatory G protein Gs, which activates the enzyme adenylyl cyclase (AC), resulting in increases in intracellular cyclic adenosine 3',5'-monophosphate (cAMP) (Fig 2). Alpha2-ARs inhibit AC via coupling to the inhibitory G protein, Gi, and also activate a Na+/H + exchanger, resulting in ion fluxes in the cell. Alphal-AR agonist occupancy activates Gq, ultimately activating phospholipase C-13 isozymes, which hydrolyze membrane phosphoinositides into inositol trisphosphate (IP3) and diacyl glycerol (DAG). IP3 binds to IP3 receptors on the sarcoplasmic reticulum, resulting in increases in free cytosolic Ca ++ and ultimately in smooth muscle contraction (Fig 2). In cardiac myocytes, production of cAMP causes activation of protein kinase A (PKA), which phosphorylates calcium channels, causing them to open. Increased intracellular calcium with depolarization binds to the catalytic site on troponin C, resulting in freeing of actin from the actin/ tropomyosin complex; the net result is the ability of actin to form cross-bridges with myosin leading to myocyte contraction.