Contributions of sodium and chloride to NaCl-induced hypertension.

The recommendation to avoid high dietary “salt” intake for the prevention and treatment of hypertension is often expressed in terms of dietary sodium. However, a consistent body of evidence suggests that the chloride component of salt is an important contributor to NaClinduced elevations of blood pressure.1 In several rat models of salt-sensitive hypertension (Dahl salt-sensitive [S] rat, DOCA-salt hypertension, stroke-prone SHR [SHRSP], angiotensin II-induced salt-sensitive hypertension), selective dietary sodium loading, in the absence of chloride, fails to produce hypertension. In various feeding protocols, anions provided with sodium included various combinations of bicarbonate, phosphate, aspartate, glutamate, and glycinate. Overall, the failure of selective dietary sodium loading to produce hypertension in these studies was not related to group differences of body weight, net sodium balance, blood pH, or serum concentrations of sodium, potassium, or chloride. Similarly, a limited number of clinical observations also indicate that blood pressure is not increased in humans by high dietary sodium intakes in the absence of chloride. In 1929, Berghoff et al reported that blood pressure increased in 7 hypertensive individuals on a high NaCl intake, but not on a high sodium bicarbonate intake.2 This observation was subsequently confirmed.3 Similarly, other investigators have also observed that in contrast to the increase of blood pressure induced by a high NaCl intake in hypertensive patients, blood pressure is not increased by a high sodium intake provided as sodium phosphate or sodium citrate.1 Further suggesting a modulating effect of dietary chloride on blood pressure, in hypertensive and normotensive subjects, substitution of dietary NaCl with equimolar sodium bicarbonate leads to a reduction of blood pressure.4,5 Additionally, in hypertensive humans, the reduction of blood pressure by dietary potassium is attenuated by potassium chloride compared with that of potassium citrate.6 Because the blood pressure increment in response to dietary sodium is dependent on the provision of sodium as its chloride salt, several studies have evaluated the hypothesis that blood pressure is increased by a high dietary intake of chloride, provided without sodium. Tanaka et al have previously reported that in the SHRSP, arterial pressure and incidence of stroke are increased by supplementing a normal NaCl diet with KCl but not with KHCO3. Blood pressure was measured in chronically instrumented animals with an intraperitoneal radiotelemetric device. Group differences of blood pressure were first discerned after 4 weeks on the diets. There were no group differences in urine protein excretion, and plasma renin activity (PRA) was higher in KCl-fed than in KHC03-fed rats. In this issue of Hypertension, this same group of investigators confirm their earlier observation that in the SHRSP, the rate of increase of blood pressure over time is specifically related to the chloride content of the diet, provided as various combinations of NaCl, KCl, and KHC03. An augmented rate of increase of blood pressure in rats fed NaCl plus KCl was observed within the first 12-hour dark cycle after initiating the diet. High dietary chloride intakes were associated with a reduction of urinary creatinine excretion, an increase of protein excretion, and histological evidence of renal microangiopathy. PRA did not differ among the various dietary groups. The strength of these 2 studies is related to the repeated blood pressure measurements by telemetry in chronically instrumented animals. The results convincingly demonstrate an association between dietary chloride intake with the rate of increase of blood pressure and stroke incidence in the SHRSP. However, these observations also raise a number of questions. It is unclear if the chloride-related blood pressure increase occurs within 1 day or only after several weeks on the various diets. In addition, these results are at variance with several earlier observations that selective dietary chloride loading fails to produce hypertension. In the Dahl-S rat and the DOCA-salt hypertensive rat, selective dietary chloride loading, in the absence of sodium loading, fails to produce hypertension.1 In the SHRSP, Wyss et al reported that compared with NaCl-fed rats, the increase of blood pressure over a several-week period was delayed by selective chloride loading provided in the diet as glycine chloride and choline chloride in place of NaCl.9 In SHRSP and Dahl-S, Tobian et al reported that addition of potassium (1.36% potassium) in the form of either KCl or potassium citrate to the diet reduced blood pressure and stroke rate.10 The apparent discrepancy of the observations of Schmidlin et al with these earlier reports may be related to different experimental protocols, different rat models, and, as the authors suggest, to “genetic drift” of the SHRSP. Several potential mechanisms may account for the contribution of chloride to salt sensitivity of blood pressure.1 In Dahl-S rats, DOCA-salt rats, and in humans, plasma volume is higher on a high NaCl intake than when sodium is provided with anions other than chloride, although net sodium balances do not differ. This suggests that the anion ingested with sodium affects the distribution of sodium between the intracellular and extracellular The opinions expressed in this editorial commentary are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Medical College of Wisconsin, Milwaukee, Wis. Correspondence to Theodore A. Kotchen, MD, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail [email protected] (Hypertension. 2005;45:849-850.) © 2005 American Heart Association, Inc.