Sodium transport and hypertension. Where are we going?

T HE idea that high salt intake plays a key role in the development of "essential'' (or "primary") hypertension was first suggested 80 years ago. Since then, numerous epidemiological and experimental 4 observations and therapeutic maneuvers (i.e., low sodium diets and treatment with natriuretic agents) have provided ample support for the view that Na plays a role in the etiology of hypertension. Indeed, while the data in any one of these areas may not be conclusive, taken together, these three more-or-less independent approaches seem to provide compelling evidence that dietary Na is an important factor in the etiology of essential hypertension. The mechanism by which Na actually leads to the elevation of blood pressure is currently under intensive investigation. Genetic factors also contribute critically to the development of hypertension both in animal models and in humans. Renal transplant studies in several rat models"" demonstrate that the genetic defects are expressed as defects in renal function and that the hypertension "goes with the kidneys." Recent observations in humans raise the possibility that the genetic defect in human essential hypertension may also be expressed as a malfunction of the kidneys:""" the blood pressure may rise (producing a pressure natriuresis) when the kidneys are otherwise unable to excrete the Na load with which they are presented. Thus, not surprisingly, the pathophysiology of hypertension focuses on the interrelationship between the kidneys and the cardiovascular system, and on fluid and electrolyte metabolism. The kidneys are the end-organs that normally control Na and water balance and thereby influence the hemodynamic status of the body. In recent years a major effort has been made to identify possible genetic markers, such as defects in Na transport, that might be useful for 1) identifying salt-sensitive individuals or those predisposed to the development of essential hypertension, and 2) elucidating the underlying pathophysiological basis of the disease. This approach was fueled by the initial observations that red blood cell (RBC) and white blood cell (WBC) Na content was increased in many individuals with essential hypertension."These cells are conveniently studied, and intracellular electrolyte composition can be readily and reliably measured without contamination by extracellular electrolytes. Since many of the Na transport mechanisms that are present in kidney cell membranes (such as Na + K cotransport and Na pumps) are also present in RBC and WBC membranes, much attention has recently been devoted to the study of Na transport in RBCs and WBCs. Moreover, it seems reasonable to expect that genetic defects in electrolyte transport might be present in many tissues.