Molecular mechanisms linking sodium to hypertension: report of a symposium.
There is abundant clinical and epidemiologic data linking excess body sodium with hypertension. The mechanism(s) at the molecular level to explain this relationship are unknown. Recent studies by multiple investigators, have identified several ion transport mechanisms in the vascular wall that interact to control vascular tone and contractility. These new data include 1) biochemical, pharmacologic, and molecule structural studies, 2) experiments in transgenic and knockout mice, and 3) results in clinical hypertension. The overall results provide compelling evidence for the concept that salt-dependent hypertension involves the secretion of endogenous ouabain (EO), an adrenal steroid synthesized with the same initial steps as aldosterone and secreted by the zona glomerulosa. Circulating EO inhibits arterial smooth muscle Na+ pumps with alpha 2 subunits. These are functionally coupled to the type 1 Na/Ca exchanger (NCX1). Thus when a2 Na pumps are inhibited in arterial smooth muscle, the resulting subplasma membrane increase in Na+ concentration triggers, via NCX1 Ca2+ entry, a rise in cytosolic Ca2+ concentration and increased myogenic tone and contractility. The ultimate result is a rise in peripheral vascular resistance-the hemodynamic hallmark of hypertension. The elucidation of this pathway has facilitated the development of pharmacologic agents that have therapeutic potential for hypertension and other cardiovascular diseases. These include agents that compete with EO for binding to the Na+ pump and inhibitors of NCX1.
Department of Medicine, Baltimore VA Medical Center and University of Maryland School of Medicine, Baltimore, MD 21201, USA. bruce.hamilton@med/va.gov
Bruce P
BP
Hamilton
Mordecai P
MP
Blaustein
D000818:Animals; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology*; D010042:Ouabain / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D021122:Protein Subunits; D019831:Sodium-Calcium Exchanger / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology*; D014661:Vasoconstriction
D021122:Protein Subunits; D019831:Sodium-Calcium Exchanger; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase