How can the sustained production of aldosterone be regulated in what conventionally has been regarded as a nonexcitable cell if the membrane potential (Vm) of the cell rests close to the equilibrium potential for K + - a voltage that is not favorable for the opening of voltage-gated Ca 2+ channels and the enhanced entry of Ca 2+, the critical intracellular signal ( 9, 10)? Nevertheless, these studies have also raised fundamental questions about the physiological control of aldosterone production. Mouse models of PA have underscored the critical importance of K + channel activity in the control of aldosterone production ( 5– 7) indeed, genetic variation in the human KCNJ5 gene (encoding the inwardly rectifying K + channel) is found in a subset of patients with severe tumorigenic PA ( 8). Because intracellular Ca 2+ is the critical signal controlling aldosterone production, an understanding of the mechanisms underlying Ca 2+ entry is paramount to rational drug design. When aldosterone production is inappropriate for the level of salt, it is pathogenic, and hypertensive subjects with inappropriate levels have increased target organ damage and a greater odds ratio for cardiovascular disease than do patients with hypertension of unknown cause ( 3, 4). Aldosterone raises blood pressure and enhances renal Na reabsorption and K excretion. We conclude that native ZG cells are electrical oscillators, and that this behavior provides what we believe to be a new molecular explanation for the control of Ca 2+ entry in these steroidogenic cells.Īutonomous overproduction of aldosterone, termed primary hyperaldosteronism (PA), is the most common form of endocrine hypertension (13% incidence), but among patients with resistant hypertension, its incidence increases substantially to 20% ( 1, 2). This innate electrical excitability of ZG cells provides a platform for the production of a recurrent Ca 2+ signal that can be controlled by Ang II and extracellular potassium, the 2 major regulators of aldosterone production. Here, we show that mouse ZG cells within adrenal slices spontaneously generate membrane potential oscillations of low periodicity. Although sustained production of aldosterone requires persistent Ca 2+ entry through low-voltage activated Ca 2+ channels, isolated ZG cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca 2+ entry. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and renal disease. It is concluded that the endogenous ADM system located in the ZG is upregulated in immature rats, and plays an important autocrine-paracrine role in the maintenance of the elevated growth rate during adrenal maturation.Aldosterone, which plays a central role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal gland. L1-R expression was enhanced in immature rat ZG, while CRLR and RAMP2,3 expression did not display significant differences. ADM acts via two subtypes of ADM22-52-sensitive receptors: the L1 receptor (L1-R) and the calcitonin-receptor-like-receptor (CRLR), the latter behaves as selective ADM receptor only in the presence of the receptor-activity-modifying proteins (RAMPs)2 and 3. Plasma ADM concentration did not show significant age-related differences. ProADM mRNA and ADM-immunoreactivity were both more elevated in immature- than adult-rat ZG. Hence, we investigated by semiquantitative reverse transcription-polymerase chain reaction and radioimmune assay the expression of ADM system in adult and immature rat ZG. In contrast, in the companion paper, we showed that ADM22-52 depresses the proliferation rate of ZG in 20-day-old rats, suggesting the involvement of endogenous ADM system in adrenal maturation. However, the selective ADM receptor antagonist ADM22-52, although being able to block ADM effect, was per se ineffective. Evidence has been provided that adrenomedullin (ADM) stimulates the proliferative activity of adult rat adrenal zona glomerulosa (ZG).

Zona glomerulosa