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AJH 1991;4:615S-616S Salt Sensitivity as a Predictor of Hypertension Myron H. Weinberger Salt sensitivity of blood pressure can be identified in half of the hypertensive population and one- fourth of normotensive subjects. Salt sensitivity of blood pressure is especially frequent in normoten- sives from subpopulations known to have a higher frequency of hypertension, such as blacks, older subjects, and first-degree relatives of hypertensives, suggesting a link between salt and the subsequent A bundant experimental and clinical data pro- vide convincing and unequivocal evidence of the heterogeneity of blood pressure response to alterations in sodium balance. 1 In experi- mental animals, careful breeding studies have permitted identification of strains of animals that have a rise in blood pressure when dietary sodium intake is increased, and strains in whom resistance to this effect of sodium excess can be shown. 2 The specific factor or factors re- sponsible for sensitivity or resistance to salt have not been precisely identified. However elegant cross-trans- plantation experiments have demonstrated that the kid- ney is the organ responsible for determining sodium responsivity in these separate genetic strains. 2 Trans- planting the kidney from a "salt-sensitive" animal into a salt-resistant rat was associated with a rise in blood pressure when the rat was given a high salt diet; the reverse was also true. 2 In humans, data regarding the relationship between salt intake and blood pressure has focused primarily on epidemiological evidence. Re- cently interventional studies indicate that heterogeneity in blood pressure responsiveness to manipulations of sodium and extracellular fluid volume can be demon- strated in both hypertensive and normotensive humans. 3,4 While sodium sensitivity of blood pressure is From the Indiana University School of Medicine, Indianapolis. Address correspondence and reprint requests to Myron H. Wein- berger, MD, Director, Hypertension Research Center, Indiana Univer- sity School of Medicine, Indianapolis, IN 46202-5111. development of hypertension. A variety of asso- ciated markers of salt sensitivity has been de- scribed. Recent studies also link calcium and salt sensitivity of blood pressure. Am J Hypertens 1991;4:615S-616S KEY WORDS: Salt sensitivity, blood pressure, calcium. more commonly observed in hypertensive subjects, in whom at least 50% can be shown to have a rise in blood pressure with sodium excess, it is also present in a sub- stantial proportion (25%) of the normotensive popula- tion. 3 A potential link between sodium responsivity of blood pressure and the subsequent development of high blood pressure is suggested by the increased frequency of sodium sensitivity and impaired renal sodium excre- tion observed in normotensive individuals in subgroups of the population known to be at increased risk for the development of subsequent hypertension, ie, black indi- viduals, individuals over the age of 40, and those with first-degree relatives with known hypertension. In ad- dition, recent observations have suggested that sodium responsivity of blood pressure may be genetically deter- mined because of observations of differential haptoglo- bin phenotype frequencies among the different blood pressure response groups. 5 Among normotensive and hypertensive adults undergoing the saline infusion- volume expansion and low salt diet plus furosemide maneuver which we have used to define salt sensitivity and resistance, individuals with the haptoglobin 1-1 phenotype were significantly (P < .05) more salt-sensi- tive than those with the 2-2 phenotype. The heterozy- gotic phenotype (2-1,1-2) was intermediate in salt re- sponsivity. 5 These observations were extended in a different population of young adults and their children participating in a study of dietary salt restriction, in whom baseline blood pressure before dietary interven- © 1991 by the American Journal of Hypertension, Inc. 0895-7061/91/$3.50 at Florida Atlantic University on October 9, 2015 http://ajh.oxfordjournals.org/ Downloaded from
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AJH 1991;4:615S-616S
Salt Sensitivity as a Predictor of Hypertension Myron H. Weinberger
Salt sensitivity of blood pressure can be identified in half of the hypertensive population and one-fourth of normotensive subjects. Salt sensitivity of blood pressure is especially frequent in normotensives from subpopulations known to have a higher frequency of hypertension, such as blacks, older subjects, and first-degree relatives of hypertensives, suggesting a link between salt and the subsequent
Abundant experimental and clinical data provide convincing and unequivocal evidence of the heterogeneity of blood pressure response to alterations in sodium balance.1 In experi
mental animals, careful breeding studies have permitted identification of strains of animals that have a rise in blood pressure when dietary sodium intake is increased, and strains in whom resistance to this effect of sodium excess can be shown.2 The specific factor or factors responsible for sensitivity or resistance to salt have not been precisely identified. However elegant cross-transplantation experiments have demonstrated that the kidney is the organ responsible for determining sodium responsivity in these separate genetic strains.2 Transplanting the kidney from a "salt-sensitive" animal into a salt-resistant rat was associated with a rise in blood pressure when the rat was given a high salt diet; the reverse was also true. 2 In humans, data regarding the relationship between salt intake and blood pressure has focused primarily on epidemiological evidence. Recently interventional studies indicate that heterogeneity in blood pressure responsiveness to manipulations of sodium and extracellular fluid volume can be demonstrated in both hypertensive and normotensive humans. 3 , 4 While sodium sensitivity of blood pressure is
From the Indiana University School of Medicine, Indianapolis. Address correspondence and reprint requests to Myron H. Wein
berger, MD, Director, Hypertension Research Center, Indiana University School of Medicine, Indianapolis, IN 46202-5111.
development of hypertension. A variety of associated markers of salt sensitivity has been described. Recent studies also link calcium and salt sensitivity of blood pressure. Am J Hypertens 1991;4:615S-616S
K E Y W O R D S : Salt sensitivity, blood pressure, calcium.
more commonly observed in hypertensive subjects, in whom at least 50% can be shown to have a rise in blood pressure with sodium excess, it is also present in a substantial proportion (25%) of the normotensive population.3
A potential link between sodium responsivity of blood pressure and the subsequent development of high blood pressure is suggested by the increased frequency of sodium sensitivity and impaired renal sodium excretion observed in normotensive individuals in subgroups of the population known to be at increased risk for the development of subsequent hypertension, ie, black individuals, individuals over the age of 40, and those with first-degree relatives with known hypertension. In addition, recent observations have suggested that sodium responsivity of blood pressure may be genetically determined because of observations of differential haptoglobin phenotype frequencies among the different blood pressure response groups.5 Among normotensive and hypertensive adults undergoing the saline infusion-volume expansion and low salt diet plus furosemide maneuver which we have used to define salt sensitivity and resistance, individuals with the haptoglobin 1-1 phenotype were significantly (P < .05) more salt-sensitive than those with the 2-2 phenotype. The heterozy-gotic phenotype (2-1,1-2) was intermediate in salt responsivity.5 These observations were extended in a different population of young adults and their children participating in a study of dietary salt restriction, in whom baseline blood pressure before dietary interven-
© 1991 by the American Journal of Hypertension, Inc. 0895-7061/91/$3.50
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616S WEINBERGER AJH-NOVEMBER 1991-VOL 4, NO. 11 (SUPPLEMENT)
tion was found to differ on the basis of haptoglobin type. Both parents and children with the 1-1 phenotype had significantly (P < .05) higher blood pressures than those with the 2-2 phenotype, despite the fact that the population was young and normotensive.5 Recent observations have suggested that an anomalous response of the renal vasculature and/or the adrenal cortex to angiotensin II may be related in some way to sodium responsivity of blood pressure,6 although precise details regarding the relationships of "non-modulation" and blood pressure are not yet clear. Other investigators have suggested links between insulin secretion and/or sensitivity, sympathetic nervous system activity, and the renal excretion of sodium and water, which may be interrelated and may contribute to the development of salt sensitive hypertension. While intriguing, these observations and hypotheses are not yet clearly confirmed.
Recent studies have suggested that the anionic form of sodium may be the determinant of blood pressure responsivity, with rises in blood pressure seen in sodium sensitive individuals given sodium chloride, but not when equimolar amounts of sodium are administered in the form of other anions.7 We have recently studied 10 normotensive and 10 hypertensive subjects given the same amount of sodium, but in the forms of chloride or bicarbonate in a random, crossover design.8 In this study, sodium bicarbonate reduced blood pressure, while sodium chloride did not. 8 Other investigators have reported similar differential effects of sodium on blood pressure in hypertensives given as two different salts.9 In addition, sodium chloride administration was associated with a significant (P < .05) increase in urinary calcium excretion which was not seen with sodium bicarbonate.8 These observations are similar to those of Kurtz et al. 7 Exploration of the interactions between calcium, sodium salts and sodium responsivity of blood pressure is clearly needed.
The benefit of intervention in dietary sodium intake has been most clearly evident in salt sensitive hypertensive individuals, and no direct evidence of an adverse effect of modest dietary sodium reduction can be ob
served in salt resistant individuals.1 Nonetheless, it would be useful to be able to identify individuals who are likely to benefit from dietary sodium restriction or other similar modifications to target interventional activities more precisely. Clarification of the mechanisms, mediators, and modulators of sodium responsivity are obvious requisites for the development of effective interventional maneuvers. Finally, the potential benefit of primary prevention in high risk individuals is a most attractive, but still remote concept awaiting future knowledge.
REFERENCES
1. MacGregor G A: Sodium is more important than calcium inessential hypertension. Hypertension 1985;7:628-637.
2. Dahl LK, Heine M, Thompson K: Genetic influence of the kidneys on blood pressure: evidence from chronic renal homografts in rats with opposite predisposition to hypertension. Circulation Res 1974;34:94-101.
3. Weinberger MH, Miller JZ, Luft FC, et al: Definitions and characteristics of sodium sensitivity and resistance of blood pressure. Hypertension 1986;8:11127-11134.
4. Sullivan JM, Prewitt RL, Ratts TE, et al: Hemodynamic characteristics of sodium-sensitive human subjects. Hypertension 1987;9:398-406.
5. Weinberger MH, Miller JZ, Fineberg NS, et al: Association of haptoglobin with sodium sensitivity and resistance of blood pressure. Hypertension 1987;10:443-446.
6. Hollenberg NK, Chenitz WR, Adams DF, Williams GH: Reciprocal influence of salt intake on adrenal glomerulosa and renal vascular responses to angiotensin II in normal man. J Clin Invest 1974;54:34-42.
7. Kurtz TW, Al-Bander HA, Morris RC Jr: "Salt-sensitive" essential hypertension in man: is the sodium ion alone important? Ν Engl J Med 1987;317:1043-1048.
8. Luft FC, Zemel MB, Sowers JA, et al: Sodium bicarbonate and sodium chloride: effects on blood pressure and electrolyte homeostasis in normal and hypertensive man. J Hypertens 1990:8:633-670.
9. Shore AC, Markandu ND, MacGregor G A: A randomized crossover study to compare the blood pressure response to sodium loading with and without chloride in patients with essential hypertension. J Hypertens 1988;6:613-617.
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