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CJASN ePress. Published on January 24, 2007 as doi: 10.2215/CJN.04161206 Editorial

Vasopressin, Urine Concentration, and Hypertension: A New Perspective on an Old Story

Friedrich C. Luft Medical Faculty of the Charite´, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany Clin J Am Soc Nephrol ●●: ●●●-●●●, ●●●●. doi: 10.2215/CJN.04161206

ankir et al. (1) report that young, healthy black individ- every individual, allowing a more precise calculation of urine uals concentrate urine significantly more than matched solute and concentration. With this data set, a more B white individuals and excrete lower urine volumes. In precise analysis of any relationships among urine concentra- addition, they found that, among men, pulse pressure was tion, sodium concentration, urine volume, and BP could be significantly higher in normotensive black individuals than in performed. Gender differences and ethnic comparisons also white individuals, although there was no significant difference could be examined if only the INTERSALT investigators would in systolic and diastolic BP. These findings refocus attention on accept external analyses of their data set. as a hypertensive hormone, however with a new Support for the authors’ idea is provided by another recent mechanistic twist and a novel interpretation of an ethnic dif- study by Bankir et al. (4) that reported that V2 receptor stimulation ference. Bankir et al. also report a direct association between reduces sodium excretion in normal humans. In that study, infu- urine concentration and pulse pressure in men but not in sion of a V2 receptor agonist, dDAVP, reduced sodium excretion women. Again, the correlation coefficient was stronger in black concomitant with an increase in and a decrease in men than in white men. This early difference may be important urine volume. The inclusion of patients with central because elevated pulse pressure is associated with an increased insipidus, V2 receptor mutations, or aquaporin-2 mutations pro- risk for cardiovascular events. The authors suggest that vaso- vided an elegant control. The authors raised the notion that vaso- pressin could contribute to hypertension via its antidiuretic pressin might reduce sodium excretion by increasing epithelial effects and that vasopressin V2 receptor antagonists might sodium channel expression and activity as demonstrated in rats lower BP. Possibly, vasopressin plays a greater role in individ- (4) and proposed that this effect might represent an adaptation to uals with blunted -angiotensin system, as is the case in improved conservation (1). black individuals. Acutely, this notion has experimental sup- Nonetheless, the vasopressin-to-hypertension hypothesis has port (2). had tough sledding, even though dDAVP administration to In their analysis, Bankir et al. (1) relied on a data set that was rats over weeks increases BP by 10 mmHg and can make generated at Indiana University Medical Center 35 yr ago. desoxycorticosterone-salt hypertension worse (5). The litera- Neither urine osmolarity nor vasopressin was measured in the ture is extensive and cannot be reviewed in detail here. Renal Indiana University protocol. Nevertheless, the studies were medullary flow has an important impact on BP regula- performed meticulously on a metabolic ward. The patients tion (6). Vasopressin may influence renal medullary blood flow were in similar states of electrolyte intake, and the BP measure- via V1a receptors. Cowley et al. (6) investigated the effects of ments were controlled carefully. Such broad-based metabolic vasopressin infusion into the chronically. Unine- studies can never be performed again, so data dredging (now phrectomized Sprague-Dawley rats were prepared with im- termed “data mining”) for the purpose of hypothesis genera- planted renal cortical and medullary optical fibers for daily tion is a legitimate enterprise. In this case, the data that were measurements of cortical and medullary blood flow using la- collected allowed the a posteriori calculation of a urine concen- ser-Doppler flowmetry techniques. Vasopressin produced only tration index. Another data set that would be amenable for an initial, nonsignificant reduction of medullary blood flow and examination of this hypothesis further could be provided by failed to raise arterial pressure significantly (7). It is interesting the International Study of Sodium, , and Blood Pres- that the same group showed that a selective V1 agonist sure (INTERSALT) study (3). In INTERSALT, more than 10,000 ([Phe2,Ile3,Orn8]vasopressin) can chronically increase BP in the people were studied worldwide with meticulous 24-h urine rat (8). However, vasopressin also stimulates release of nitric collections and random-zero BP measurements. Urine volume, oxide probably via extrarenal stimulation of V2 receptors and electrolyte, , and excretion were measured in subsequent nitric oxide synthase activation. These effects likely buffer against the hypertensive actions of vasopressin. Acute

Published online ahead of print. Publication date available at www.cjasn.org. infusion of vasopressin is known to increase BP transiently, but acute infusion of the selective V2 agonist dDAVP lowers it (4). Address correspondence to: Dr. Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. Phone: ϩ49-30-9417-2202; Fax: ϩ49-30-9417- Therefore, an imbalance between the intensity of vasoconstric- 2206; E-mail: [email protected] tive V1a and nitric oxide–generating V2 effects could be ex-

Copyright © ●●●● by the American Society of Nephrology ISSN: 1555-9041/●●●●–0001 2 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol ●●: ●●●-●●●, ●●●● pected to alter BP regulation. Ganten et al. (9) developed a References strain of spontaneously hypertensive rats that also are homozy- 1. Bankir L, Perucca J, Weinberger MH: Ethnic differences in gous for central diabetes insipidus (Brattleboro strain). The rats urine concentration: Possible relationship to blood pres- developed hypertension nonetheless, even though their vaso- sure. Clin J Am Soc Nephrol 2: ●●●–●●●, 2007 pressin concentrations are zero, thereby showing that vasopres- 2. Bakris G, Bursztyn M, Gavras I, Bresnahan M, Gavras H: sin actions are not a prerequisite in all forms of hypertension. Role of vasopressin in : Racial dif- Could increased water intake counteract the effects of vaso- ferences. J Hypertens 15: 545–550, 1997 3. Intersalt Cooperative Research Group: Intersalt: An inter- pressin? A well-accepted health homily is to “drink plenty of national study of electrolyte excretion and blood pressure. water and keep yourself on schedule.” Acute water drinking Results for 24-hour urinary sodium and potassium excre- (500 ml in 30 min) has independent cardiovascular and meta- tion. BMJ 297: 319–328, 1988 bolic effects in patients with autonomic failure and normal 4. Bankir L, Fernandes S, Bardoux P, Bouby N, Bichet DG: older individuals but not in healthy individuals, except when Vasopressin-V2 receptor stimulation reduces sodium ex- exposed to phenylpropanolamine (10). This acute increase in cretion in healthy humans. J Am Soc Nephrol 16: 1920–1928, BP does not necessarily contradict the hypothesis raised by 2005 Bankir et al. (1), which addresses long-term consequences of the 5. Fernandes S, Bruneval P, Hagege A, Heudes D, Ghostine S, vasopressin/ axis. The effects of chronic increased water Bouby N: Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycor- intake on BP in normal or hypertensive individuals have not ticosterone acetate-salt hypertension. 143: been studied but should be. In five-sixths nephrectomized rats, 2759–2766, 2002 chronic increase in water intake reduced BP and urinary albu- 6. Cowley AW Jr, Mattson DL, Lu S, Roman RJ: The renal min excretion despite an increase in (11). medulla and hypertension. Hypertension 25: 663–673, 1995 What sort of prospective studies could Bankir et al. per- 7. Cowley AW Jr, Szczepanska-Sadowska E, Stepniakowski form to test their hypothesis directly? Metabolic ward inves- K, Mattson D: Chronic intravenous administration of V1 tigation of healthy black and white individual should be arginine vasopressin agonist results in sustained hyperten- done but would be difficult. Careful balancing would be sion. Am J Physiol 267: H751–H756, 1994 required. Solute (presumably salt and ) intake would 8. Cowley AW Jr, Szczepanska-Sadowska E, Stepniakowski K, Mattson D: Chronic intravenous administration of V1 have to be studied at various intakes. Water intake would arginine vasopressin agonist results in sustained hyperten- have to be manipulated independent of solute intake, at sion. Am J Physiol 267: H751–H756, 1994 various water intakes. BP would have to be measured more 9. Ganten U, Rascher W, Lang RE, Dietz R, Rettig R, Unger T, precisely than generally is done, preferably continuously so Taugner R, Ganten D: Development of a new strain of as also to evaluate nocturnal BP dipping. The studies prob- spontaneously hypertensive rats homozygous for hypotha- ably would require more than 1 mo, and the costs would be lamic diabetes insipidus. Hypertension 5: I119–I128, 1983 prohibitive. Also conceivable is a controlled trial of vaso- 10. Jordan J: Effect of water drinking on sympathetic nervous pressin V2 antagonist treatment in certain hypertensive in- activity and blood pressure. Curr Hypertens Rep 7: 17–20, dividuals under stringent metabolic control conditions. The 2005 11. Bouby N, Bachmann S, Bichet D, Bankir L: Effect of water respective benefits of antagonizing either V1a or V2 recep- intake on the progression of chronic renal failure in the 5/6 tors or both together need to be evaluated carefully (12). nephrectomized rat. Am J Physiol Renal Physiol 258: F973– F979, 1990 12. Goldsmith SR: Is there a cardiovascular rationale for the Disclosures use of combined vasopressin V1a/V2 receptor antago- None. nists? Am J Med 119[Suppl 1]: S93–S96, 2006

See the related article, “Ethnic Differences in Urine Concentration: Possible Relationship to Blood Pressure,” on pages ●●●–●●●.