Signaling mechanisms that link salt retention to hypertension: endogenous ouabain, the Na(+) pump, the Na(+)/Ca(2+) exchanger and TRPC proteins.
Salt retention as a result of chronic, excessive dietary salt intake, is widely accepted as one of the most common causes of hypertension. In a small minority of cases, enhanced Na(+) reabsorption by the kidney can be traced to specific genetic defects of salt transport, or pathological conditions of the kidney, adrenal cortex, or pituitary. Far more frequently, however, salt retention may be the result of minor renal injury or small genetic variation in renal salt transport mechanisms. How salt retention actually leads to the increase in peripheral vascular resistance (the hallmark of hypertension) and the elevation of blood pressure remains an enigma. Here we review the evidence that endogenous ouabain (an adrenocortical hormone), arterial smooth muscle α2 Na(+) pumps, type-1 Na/Ca exchangers, and receptor- and store-operated Ca(2+) channels play key roles in the pathway that links salt to hypertension. We discuss cardenolide structure-function relationships in an effort to understand why prolonged administration of ouabain, but not digoxin, induces hypertension, and why digoxin is actually anti-hypertensive. Finally, we summarize recent observations which indicate that ouabain upregulates arterial myocyte Ca(2+) signaling mechanisms that promote vasoconstriction, while simultaneously downregulating endothelial vasodilator mechanisms. In sum, the reports reviewed here provide novel insight into the molecular mechanisms by which salt retention leads to hypertension.
Blaustein
Mordecai P
MP
Department of Physiology, University of Maryland School of Medicine, USA. mblaustein@som.umaryland.edu
Hamlyn
John M
JM
D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology; D004077:Digoxin / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010042:Ouabain / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*
D002316:Cardiotonic Agents; D019831:Sodium-Calcium Exchanger; D050052:TRPC Cation Channels; D010042:Ouabain; D004077:Digoxin; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase