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Medical Faculty of the Charité, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany
Address correspondence to: Dr. Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. Phone: +49-30-9417-2202; Fax: +49-30-9417-2206; E-mail: luft{at}fvk-berlin.de
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Introduction |
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In their analysis, Bankir et al. (1) relied on a data set that was generated at Indiana University Medical Center 35 yr ago. Neither urine osmolarity nor vasopressin was measured in the Indiana University protocol. Nevertheless, the studies were performed meticulously on a metabolic ward. The patients were in similar states of electrolyte intake, and the BP measurements were controlled carefully. Such broad-based metabolic studies can never be performed again, so data dredging (now termed "data mining") for the purpose of hypothesis generation is a legitimate enterprise. In this case, the data that were collected allowed the a posteriori calculation of a urine concentration index. Another data set that would be amenable for examination of this hypothesis further could be provided by the International Study of Sodium, Potassium, and Blood Pressure (INTERSALT) study (3). In INTERSALT, more than 10,000 people were studied worldwide with meticulous 24-h urine collections and random-zero BP measurements. Urine volume, electrolyte, creatinine, and urea excretion were measured in every individual, allowing a more precise calculation of urine solute excretion and concentration. With this data set, a more precise analysis of any relationships among urine concentration, sodium concentration, urine volume, and BP could be performed. Gender differences and ethnic comparisons also could be examined if only the INTERSALT investigators would accept external analyses of their data set.
Support for the authors’ idea is provided by another recent study by Bankir et al. (4) that reported that V2 receptor stimulation reduces sodium excretion in normal humans. In that study, infusion of a V2 receptor agonist, dDAVP, reduced sodium excretion concomitant with an increase in urine osmolality and a decrease in urine volume. The inclusion of patients with central diabetes insipidus, V2 receptor mutations, or aquaporin-2 mutations provided an elegant control. The authors raised the notion that vasopressin might reduce sodium excretion by increasing epithelial sodium channel expression and activity as demonstrated in rats (4) and proposed that this effect might represent an adaptation to improved water conservation (1).
Nonetheless, the vasopressin-to-hypertension hypothesis has had tough sledding, even though dDAVP administration to rats over weeks increases BP by 10 mmHg and can make desoxycorticosterone-salt hypertension worse (5). The literature is extensive and cannot be reviewed in detail here. Renal medullary blood flow has an important impact on BP regulation (6). Vasopressin may influence renal medullary blood flow via V1a receptors. Cowley et al. (6) investigated the effects of vasopressin infusion into the renal medulla chronically. Uninephrectomized Sprague-Dawley rats were prepared with implanted renal cortical and medullary optical fibers for daily measurements of cortical and medullary blood flow using laser-Doppler flowmetry techniques. Vasopressin produced only an initial, nonsignificant reduction of medullary blood flow and failed to raise arterial pressure significantly (7). It is interesting that the same group showed that a selective V1 agonist ([Phe2,Ile3,Orn8]vasopressin) can chronically increase BP in the rat (8). However, vasopressin also stimulates release of nitric oxide probably via extrarenal stimulation of V2 receptors and subsequent nitric oxide synthase activation. These effects likely buffer against the hypertensive actions of vasopressin. Acute infusion of vasopressin is known to increase BP transiently, but acute infusion of the selective V2 agonist dDAVP lowers it (4). Therefore, an imbalance between the intensity of vasoconstrictive V1a and nitric oxide–generating V2 effects could be expected to alter BP regulation. Ganten et al. (9) developed a strain of spontaneously hypertensive rats that also are homozygous for central diabetes insipidus (Brattleboro strain). The rats developed hypertension nonetheless, even though their vasopressin concentrations are zero, thereby showing that vasopressin actions are not a prerequisite in all forms of hypertension.
Could increased water intake counteract the effects of vasopressin? A well-accepted health homily is to "drink plenty of water and keep yourself on schedule." Acute water drinking (500 ml in 30 min) has independent cardiovascular and metabolic effects in patients with autonomic failure and normal older individuals but not in healthy individuals, except when exposed to phenylpropanolamine (10). This acute increase in BP does not necessarily contradict the hypothesis raised by Bankir et al. (1), which addresses long-term consequences of the vasopressin/thirst axis. The effects of chronic increased water intake on BP in normal or hypertensive individuals have not been studied but should be. In five-sixths nephrectomized rats, chronic increase in water intake reduced BP and urinary albumin excretion despite an increase in plasma renin activity (11).
What sort of prospective studies could Bankir et al. perform to test their hypothesis directly? Metabolic ward investigation of healthy black and white individual should be done but would be difficult. Careful balancing would be required. Solute (presumably salt and protein) intake would have to be studied at various intakes. Water intake would have to be manipulated independent of solute intake, at various water intakes. BP would have to be measured more precisely than generally is done, preferably continuously so as also to evaluate nocturnal BP dipping. The studies probably would require more than 1 mo, and the costs would be prohibitive. Also conceivable is a controlled trial of vasopressin V2 antagonist treatment in certain hypertensive individuals under stringent metabolic control conditions. The respective benefits of antagonizing either V1a or V2 receptors or both together need to be evaluated carefully (12).
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Footnotes |
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See the related article, "Ethnic Differences in Urine Concentration: Possible Relationship to Blood Pressure," on pages 304–312.
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Related Article
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  J. Perucca, D. G. Bichet, P. Bardoux, N. Bouby, and L. Bankir Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1721 - 1731. [Abstract] [Full Text] [PDF]
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