Aldosterone and mineralocorticoid receptors: Orphan questions

Classically, mineralocorticoid receptors (MR) are activated by aldosterone to promote unidirectional transepithelial sodium transport. Activation of M R in nonepithelial tissues has been shown to elevate blood pressure (centra l nervous system, CNS) and to cause hypertrophy and fibrosis (heart). For b oth epithelial and nonepithelial tissues, there remain a variety of questio ns regarding MR which are not only unanswered but also essentially not addr essed. Seven such questions include: (1) how the physiologic glucocorticoid s (cortisol and corticosterone) can mimic aldosterone action in epithelial MR. but act as antagonists in the heart and AV3V region, (2) how salt facil itates the nonepithelial. pathophysiologic effects of aldosterone: (3) how aldosterone activates unprotected AV3V MR in the face of orders of magnitud e higher circulating glucocorticoid concentrations: (4) how unprotected non epithelial MR act as "always occupied" receptors in guinea pigs and other s pecies; (5) how, when 11 beta hydroxysteroid dehydrogenase type 2 is active , epithelial MR occupied by physiologic glucocorticoids appear transcriptio nally inactive: (6) how aldosterone activates epithelial MR in the Pace of approximately 10(3)-fold higher glucocorticoid levels, plasma binding and 1 1 beta hydroxysteroid dehydrogenase type 2 activity notwithstanding; and (7 ) how aldosterone produces changes in urinary [K+] before [Na+].