Correspondence
Mechanisms of Hypertension
N Engl J Med 2007; 357:827-829August 23, 2007
- Article
To the Editor:
In their review of the roles of sodium and potassium in the pathogenesis of hypertension, Adrogué and Madias (May 10 issue)1 appropriately emphasize the central roles of an excess of sodium, the expansion of extracellular fluid volume, the release of digitalis-like factor, a potassium deficit, and Na+/K+–ATPase inhibition. Digitalis-like factor is found mainly in the low-renin, volume-expanded types of hypertension. Recent studies suggest that ouabain is not the only Na+/K+–ATPase inhibitor in hypertension; marinobufagenin, a member of the bufadienolide family, is also often present and participates in the pathogenesis of sodium-induced hypertension.2
2 ReferencesFrancis J. Haddy, M.D., Ph.D.
Mayo Clinic College of Medicine, Rochester, MN 55901-2896
tbhaddy@aol.com 1
Adrogue HJ ,Madias NE . Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356:1966-1978
Full Text | Web of Science | Medline2
Bagrov AY ,Fedorova OV . Cardenolide and bufadienolide ligands of the sodium pump: how they work together in NaCl-sensitive hypertension. Front Biosci 2005;10:2250-2256
CrossRef | Web of Science | Medline
To the Editor:
Adrogué and Madias do not mention the potential contribution of chloride to the effect of sodium chloride on blood pressure. In experimental models of hypertension, dietary sodium with anions other than chloride does not cause hypertension.1 A few clinical observations suggest that, in contrast to the effect of sodium chloride, blood pressure is not increased when sodium is consumed in the absence of chloride.2,3 In stroke-prone, spontaneously hypertensive rats, the rate of increase of blood pressure over time is specifically related to the chloride content of the diet.4
It seems appropriate to acknowledge the potential importance of the chloride ion in the pathogenesis of sodium-sensitive hypertension. However, from a clinical perspective, since most dietary sodium is ingested in the form of sodium chloride, it may be more practical to relate dietary recommendations specifically to sodium.
4 ReferencesTheodore A. Kotchen, M.D.
Medical College of Wisconsin, Milwaukee, WI 53226
tkotchen@mcw.edu 1
Boegehold MA ,Kotchen TA . Importance of dietary chloride for salt sensitivity of blood pressure. Hypertension 1991;17:Suppl I:I-1582
Luft FC ,Zemel MB ,Sowers JA ,Fineberg NS ,Weinberger MH . Sodium bicarbonate and sodium chloride: effects on blood pressure and electrolyte homeostasis in normal and hypertensive man. J Hypertens 1990;8:663-670
CrossRef | Web of Science | Medline3
Schorr U ,Distler A ,Sharma AM . Effect of sodium chloride and sodium bicarbonate-rich mineral water on blood pressure and metabolic parameters in elderly normotensive individuals: a randomized double-blind crossover trial. J Hypertens 1996;14:131-135
Web of Science | Medline4
Schmidlin O ,Tanaka M ,Bollen AW ,Yi SL ,Morris RC . Chloride-dominant salt-sensitivity in the stroke-prone spontaneously hypertensive rat. Hypertension 2005;45:867-873
CrossRef | Web of Science | Medline
To the Editor:
Adrogué and Madias do not describe the role of nonosmotically active sodium in the context of sodium physiology. In one study, when large supplements of dietary sodium (550 mmol per day) were administered to healthy men, increases in total body water were not as large as increases in total body sodium.1 Titze and coworkers reported that the reduced capacity to store sodium nonosmotically can increase the sensitivity of inbred rats to sodium-induced hypertension.2 Hyponatremia after the ingestion of water by athletes can in part be attributed to the inability to mobilize osmotically inactive sodium.3 Schafflhuber and coworkers have shown that glycosaminoglycans in the skin of rats can accumulate sodium in the range of 400 to 500 mmol per liter, and the ability of glycosaminoglycans in the skin to store sodium declines as rats age.4 The role of this additional sodium-storage compartment should be considered in the pathogenesis of hereditary or age-induced hypertension in humans.
4 ReferencesGarry Handelman, Ph.D.
University of Massachusetts Lowell, Lowell, MA 01854
garry_handelman@uml.edu Peter Kotanko, M.D.
Krankenhaus der Barmherzigen Brüder, 8020 Graz, AustriaNahan W. Levin, M.D.
Renal Research Institute, New York, NY 101281
Heer M ,Baisch F ,Kropp J ,Gerzer R ,Drummer C . High dietary sodium chloride consumption may not induce body fluid retention in humans. Am J Physiol Renal Physiol 2000;278:F585-F595
Web of Science | Medline2
Titze J ,Krause H ,Hecht H , et al. Reduced osmotically inactive Na storage capacity and hypertension in the Dahl model. Am J Physiol Renal Physiol 2002;283:F134-F141
Web of Science | Medline3
Noakes TD ,Sharwood K ,Speedy D , et al. Three independent biological mechanisms cause exercise-associated hyponatremia: evidence from 2,135 weighed competitive athletic performances. Proc Natl Acad Sci U S A 2005;102:18550-18555
CrossRef | Web of Science | Medline4
Schafflhuber M ,Volpi N ,Dahlmann A , et al. Mobilization of osmotically inactive Na+ by growth and by dietary salt restriction in rats. Am J Physiol Renal Physiol 2007;292:F1490-F1500
CrossRef | Web of Science | Medline
To the Editor:
Adrogué and Madias state, “Digitalis-like factor mediates sodium retention by increasing the activity and expression of the renal sodium pump.” However, most studies have shown that ouabain and other digitalis-like steroids specifically inhibit the activity of the Na+/K+–ATPase sodium pump in all cells tested.1
1 ReferencesFranklin H. Epstein, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
fepstein@bidmc.harvard. edu Author/Editor Response
We agree with Haddy that the pathogenic importance of digitalis-like factor is most evident in low-renin, volume-expanded forms of experimental and human hypertension. Our article noted that there are elevated levels of digitalis-like factor in the plasma in approximately 40% of untreated patients with primary hypertension. We recognize that additional inhibitors of the vascular Na+/K+–ATPase (e.g., marinobufagenin, proscillaridin A, and bufalin) have been implicated in the pathogenesis of hypertension. However, we chose to limit our remarks to endogenous digitalis-like factor, a substance identical to ouabain or a stereoisomer of ouabain, because its role in hypertension is better documented.
Most dietary sodium is in the form of sodium chloride. In discussing the role of sodium in the pathogenesis of hypertension, our article refers often to sodium chloride. We agree with Kotchen that considerable evidence implicates the chloride anion in the pressor effect of sodium chloride. In an analogous fashion, as we mention in our review, nonchloride forms of potassium, such as those found naturally in fruits and vegetables, offer larger cellular entry in exchange for sodium and greater antihypertensive effects.
Handelman et al. raise the interesting possibility that a reduced capacity to store osmotically inactive sodium might be involved in the pathogenesis of hypertension. Space constraints and relatively limited information on this topic led us to omit this possibility and several other potential mechanisms from our review.
Regarding Epstein's comment that the immediate and short-term effect of ouabain and related compounds is inhibition of the sodium pump, we indicated that in vitro and in vivo studies showed that in the long term, digitalis-like factor increases the activity and expression of the sodium pump in renal tubular cells, thereby mediating sodium retention. This long-term effect on the renal sodium pump contrasts with the persistently inhibitory effect of digitalis-like factor on the vascular sodium pump, and the two effects collaborate in the generation of hypertension.
Horacio J. Adrogué, M.D.
Baylor College of Medicine, Houston, TX 77030Nicolaos E. Madias, M.D.
Caritas St. Elizabeth's Medical Center, Boston, MA 02135
nicolaos.madias@caritaschristi. org - Citing Articles (1)
Citing Articles
1
Jie Qiu, Hai-Qing Gao, Bao-Ying Li, Lin Shen. (2008) Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. Journal of Cellular Biochemistry 104:3, 1054-1064
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