The central role of the brain aldosterone-"ouabain" pathway in salt-sensitive hypertension.
Na(+)-transport regulating mechanisms classically considered to reflect renal control of sodium homeostasis and BP, i.e. aldosterone-mineralocorticoid receptors (MR)-epithelial sodium channels (ENaC)-Na(+)/K(+)-ATPase have now been demonstrated to also be present in the central nervous system. This pathway is being regulated independently of the peripheral/renal pathway and contributes to regulation of cerebrospinal fluid [Na(+)] by the choroid plexus, of brain tissue [Na(+)] by the ependyma and to neuronal responses to e.g. Na(+) or angiotensin II. Increases in CSF [Na(+)] by central infusion of Na(+)-rich aCSF or by high salt intake in Dahl S or SHR cause sympatho-excitation and hypertension. These responses appear to depend on activation of a CNS cascade starting with aldosterone-MR-ENaC-"ouabain," the latter lowering neuronal membrane potential leading to enhanced angiotensin II release in e.g. the PVN. Specific CNS blockade of any of the steps in this cascade from aldosterone synthase blockade to AT(1)-receptor blockade prevents the sympathetic hyperactivity and hypertension on high salt intake, irrespective of the presence of a "salt-sensitive kidney." We propose that in salt-sensitive hypertension an increase in CSF [Na(+)] causes a local increase in aldosterone biosynthesis which activates an aldosterone dependent neuromodulatory pathway which enhances activity of angiotensinergic sympatho-excitatory pathways leading to hypertension.
University of Ottawa Heart Institute, Ottawa, Ontario, Canada. fleenen@ottawaheart.ca
Frans H H
FH
Leenen
D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002831:Choroid Plexus / Q000378:metabolism / Q000503:physiopathology; D004805:Ependyma / Q000378:metabolism / Q000503:physiopathology; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D008564:Membrane Potentials; D009474:Neurons / Q000378:metabolism; D010042:Ouabain; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D014882:Water-Electrolyte Balance
D053503:Epithelial Sodium Channels; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D000450:Aldosterone; D010042:Ouabain; D012964:Sodium