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Centrally acting agents stimulate α2 receptors and/or imadozoline receptors on adrenergic neurons situated within the rostral ventrolateral medulla and, in so doing, sympathetic outflow is reduced. Centrally acting agents also stimulate peripheral α2 receptors, which, for the most part, is of marginal clinical significance. Central a agonists have had a lengthy history of use, starting with α-methyldopa, which has had a dramatic decline in use, in part, because of bothersome side effects. Patients who require multidrug therapy with otherwise resistant hypertension, such as diabetic and/or renal failure patients, are typically responsive to these drugs, as are patients with sympathetically driven forms of hypertension. Perioperative forms of hypertension respond well to clonidine, a circumstance where the additional anesthesia- and analgesia-sparing effects of this drug may offer additional clinical benefits. Clonidine can be used adjunctively with other more traditional therapies in heart failure, particularly when hypertension is present. Sustained-release moxonidine, however, is associated with early mortality and morbidity when used in patients with heart failure. Escalating doses of drugs in this class often give rise to salt and water retention, in which case diuretic therapy becomes a valuable adjunctive therapy.