Role of K + Channels in the Pathophysiology of Primary Aldosteronism

Abstract

See related article, pp 587–591 Primary aldosteronism (PA) is defined as a group of endocrine disorders in which aldosterone production is inappropriately high, relatively autonomous, and independent of the renin-angiotensin system and extracellular potassium (K+), the major normal aldosterone stimulators, and in which aldosterone secretion is not suppressed by sodium loading. Patients with PA exhibit hypertension, high plasma aldosterone concentration, low plasma renin activity, and varying degrees of hypokalemia and metabolic alkalosis.1 The 2 most common causes of PA are unilateral aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) with bilateral adrenal hyperplasia. PA is the most common cause of secondary (remediable) hypertension, estimated to occur in ≈8% of the general hypertensive population and in ≈20% of patients with pharmacologically resistant hypertension. Because the cardiovascular morbidity and mortality rates are much higher in PA than in primary (essential) hypertension, intense research efforts have focused on understanding the pathophysiology of these disorders. Although APA, estimated to account for ≤50% of PA, is potentially curable with unilateral laparoscopic adrenalectomy, IHA must be treated with lifelong mineralocorticoid receptor blockers and other antihypertensive agents. For both APA and IHA, an important unresolved question has been, “What drives autonomous adrenal zona glomerulosa (ZG) cell proliferation and the production of aldosterone in these most common forms of PA?” For IHA, this question is now beginning to be addressed by studies in knockout mice, several of which have been reported as models of PA with bilaterally increased aldosterone production. The first approach has been using TWIK-related acid sensitive K (TASK) channel knockouts. TASK channels are members of the KCNK family of 2-pore domain/4 transmembrane K+ channels. The channel subunits expressed in the adrenal, TASK-1 and TASK-3, form homodimeric and heterodimeric “leak” …