Pathophysiology of renal fluid retention
1998; Elsevier BV; Volume: 54; Linguagem: Inglês
10.1046/j.1523-1755.1998.06724.x
ISSN1523-1755
AutoresRobert W. Schrier, Robert G. Fassett, Mamiko Ohara, Pierre‐Yves Martin,
Tópico(s)Renal function and acid-base balance
ResumoPathophysiology of renal fluid retention. Central to a unifying hypothesis of body fluid regulation is maintenance of arterial circulatory integrity. This may be disturbed by arterial underfilling, either from reduction in cardiac output or by peripheral arterial vasodilation. In cardiac failure (CF), cardiac output falls and the nonosmotic release of arginine vasopressin (AVP) and expression of AVP mRNA in the hypothalamus are stimulated. V2 AVP receptor antagonists correct the impaired water excretion in rats with low-output CF, increase solute free water clearance, correct the hyponatremia in congestive CF patients, and normalize urinary concentrations of the aquaporin-2 (AQP-2) water channels. In conditions associated with peripheral vasodilation, such as cirrhosis, nonosmotic release of AVP also occurs, and AQP-2 gene expression in the rat kidney is up-regulated. In cirrhosis, nitric oxide-mediated vasodilation occurs early prior to water retention. V2 antagonists reverse the latter. In normal pregnancy, plasma AVP is relatively high for the degree of hypoosmolality. Pregnant rats up-regulate AQP-2 in the renal papilla, an effect reversed by V2 receptor antagonists. This supports the hypothesis that AVP is an important mediator of renal water retention in pregnancy. In summary, AVP-mediated water retention through collecting duct AQP-2 water channels is important in both low-output CF and high-output states such as cirrhosis and pregnancy. V2 receptor antagonists reverse the water retention and down-regulate AQP-2 water channels. Pathophysiology of renal fluid retention. Central to a unifying hypothesis of body fluid regulation is maintenance of arterial circulatory integrity. This may be disturbed by arterial underfilling, either from reduction in cardiac output or by peripheral arterial vasodilation. In cardiac failure (CF), cardiac output falls and the nonosmotic release of arginine vasopressin (AVP) and expression of AVP mRNA in the hypothalamus are stimulated. V2 AVP receptor antagonists correct the impaired water excretion in rats with low-output CF, increase solute free water clearance, correct the hyponatremia in congestive CF patients, and normalize urinary concentrations of the aquaporin-2 (AQP-2) water channels. In conditions associated with peripheral vasodilation, such as cirrhosis, nonosmotic release of AVP also occurs, and AQP-2 gene expression in the rat kidney is up-regulated. In cirrhosis, nitric oxide-mediated vasodilation occurs early prior to water retention. V2 antagonists reverse the latter. In normal pregnancy, plasma AVP is relatively high for the degree of hypoosmolality. Pregnant rats up-regulate AQP-2 in the renal papilla, an effect reversed by V2 receptor antagonists. This supports the hypothesis that AVP is an important mediator of renal water retention in pregnancy. In summary, AVP-mediated water retention through collecting duct AQP-2 water channels is important in both low-output CF and high-output states such as cirrhosis and pregnancy. V2 receptor antagonists reverse the water retention and down-regulate AQP-2 water channels. angiotensin II aquaporin-2 arginine vasopressin collecting duct cardiac failure endothelial NOS nitric oxide synthase neuronal NOS prostaglandin E prostacyclin total body water Body fluid volume regulation is a complex process requiring interaction of a variety of afferent (sensory) and neurohumoral efferent (effector) mechanisms. Central to a unifying hypothesis of body fluid regulation is the maintenance of arterial circulatory integrity1.Schrier R.W. A unifying hypothesis of body fluid volume regulation (The Lilly Lecture 1992).J R Coll Physicians Lond. 1992; 26: 295-306PubMed Google Scholar. Arterial circulatory integrity can be disturbed by either a reduction of cardiac output, as in congestive cardiac failure (CF), or peripheral vasodilation, as in high-output states such as high-output CF, cirrhosis, and normal pregnancy. This review concentrates on water retention in these conditions including evidence for nonosmotic arginine vasopressin (AVP) release, excessive AVP synthesis, and changes in aquaporin-2 (AQP-2) water channels in the apical membrane of the collecting duct (CD). The use of AVP V2 receptor antagonists in animals and humans is reviewed in the context of these water-retaining conditions. Changes in the integrity of the arterial circulation are sensed by receptors in the left ventricle, carotid artery, aortic arch, and afferent arterioles of the kidney. Impulses from these receptors are conducted via the autonomic nervous system along glossopharyngeal and vagal pathways to the nucleus of the tractus solitarus then to the supraoptic and paraventricular nuclei of the hypothalamus. It is this reflex that senses arterial underfilling and results in nonosmotic AVP release from the posterior pituitary. The AVP gene in the hypothalamus has been cloned2.Richter D. Schmale H. Molecular aspects of the expression of the AVP gene,.in: Czernichow P. Robinson A.G. Diabetes Insipidus in Man (Frontiers of Hormone Research Series. 13. Karger, Basel1985: 37-41Google Scholar and has three exons that encode for a signal peptide, AVP, a neurophysin-binding protein, and a glycopeptide. Cleavage of the signal peptide leaves a prohormone that is packaged in neurovesicles, undergoes proteolytic cleavage, and is transported down neural axons to the posterior pituitary, where AVP, neurophysin, and the glycopeptide are released in response to either osmotic or nonosmotic stimuli. The actions of AVP are mediated through AVP receptors. There are at least three distinct types–V1a, V1b, and V2–that have been cloned and sequenced3.Morel A. O'Carroll A.-M. Brownstein M.J. Lolait S.J. Molecular cloning and expression of a rat V1a arginine AVP receptor.Nature. 1992; 356: 523-526Crossref PubMed Scopus (441) Google Scholar,5.Sugimoto T. Saito M. Mochizuki S. Watanabe Y. Hashimoto S. Kawashima H. Molecular cloning and functional expression of a cDNA encoding the human V1b AVP receptor.J Biol Chem. 1994; 269: 27088-27092Abstract Full Text PDF PubMed Google Scholar. 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Long term regulation of four renal aquaporins in rat.Am J Physiol. 1996; 271: F414-F422PubMed Google Scholar. Early animal studies, prior to the availability of a sensitive AVP radioimmunoassay, indirectly implicated AVP in the mechanism of water retention in CF. In a dog experiment with CF induced by thoracic vena caval constriction, surgical hypophysectomy, and hence AVP deficiency, virtually abolished the defect in water retention12.Anderson R.J. Cadnapaphornchai P. Harbottle J.A. Mc Donald K.M. Schrier R.W. Mechanism of effect of thoracic inferior vena caval constriction renal water excretion.J Clin Invest. 1974; 54: 1473-1479Crossref PubMed Scopus (57) Google Scholar. Similarly, the impaired water excretion in rats with high-output CF cannot be reproduced in animals with central diabetes insipidus13.Handelman W. Lum G. Schrier R.W. Impaired water excretion in high-output heart failure in the rat.Clin Res. 1979; 27 (abstract): 173AGoogle Scholar. Radioimmunoassay demonstrated elevated plasma AVP in congestive CF14.Szatalowicz V.L. Arnold P.A. Chaimovitz C. Bichet D. Berl T. Schrier R.W. Radioimmunoassay of plasma arginine AVP in hyponatremic patients with congestive cardiac failure.N Engl J Med. 1981; 305: 263-266Crossref PubMed Scopus (294) Google Scholar,18.Goldsmith S.R. Francis G.S. Cowley A.W. Arginine AVP and the renal response to water loading in congestive cardiac failure.Am J Cardiol. 1986; 58: 295-299Abstract Full Text PDF PubMed Scopus (91) Google Scholar. In an early such study, 30 out of 37 hyponatremic patients with CF had detectable plasma AVP concentrations14.Szatalowicz V.L. Arnold P.A. Chaimovitz C. Bichet D. Berl T. Schrier R.W. Radioimmunoassay of plasma arginine AVP in hyponatremic patients with congestive cardiac failure.N Engl J Med. 1981; 305: 263-266Crossref PubMed Scopus (294) Google Scholar. 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In a rat model of low-output CF from left coronary artery ligation, administration of the V2 receptor antagonist OPC-31260 induced significant diuresis, decreased urinary osmolality, and raised plasma osmolality26.Xu D.-L. Martin P.-Y. Ohara M. St John J. Pattison T. Meng X. Morris K. Kim J.K. Schrier R.W. Upregulation of Aquaporin-2 water channel expression in chronic heart failure rat.J Clin Invest. 1997; 99: 1500-1505Crossref PubMed Scopus (257) Google Scholar. CD AQP-2 mRNA and protein are elevated in these CF rats and are reduced significantly when these rats are treated with OPC-31260. These studies therefore confirm the efficacy of V2 antagonists in reversing the water retention in low-output CF and support the hypothesis that AVP-mediated water retention is a major factor in CF. The latter study, demonstrating up-regulation of AQP-2 mRNA and protein in rats with CF and its reversal by a V2 receptor antagonist, indicates a major role for AVP-regulated water channels in experimental CF26.Xu D.-L. Martin P.-Y. Ohara M. St John J. Pattison T. Meng X. Morris K. Kim J.K. Schrier R.W. Upregulation of Aquaporin-2 water channel expression in chronic heart failure rat.J Clin Invest. 1997; 99: 1500-1505Crossref PubMed Scopus (257) Google Scholar. The orally active, nonpeptide, selective V2 receptor antagonist WAY-VPA-985 has been used in humans with congestive CF in a randomized, double-blind, placebo-controlled ascending single-dose study27.Abraham W.T. Oren R.M. Robertson A.D. Schrier R.W. Effects of an oral, nonpeptide, selective V2 receptor AVP antagonist in human heart failure.Nephrology. 1997; 3 (abstract): S15Google Scholar. At all doses, WAY-VPA-985 increased urine flow and serum [Na] and elicited significant dose-related reductions in urinary osmolality, thus indicating an increase in solute-free water clearance. This finding supports a major role of plasma AVP in the impaired water excretion in humans with CF. Moreover, it indicates that these aquaretic agents may have a major clinical role in the treatment of water retention in CF. Severe liver disease with cirrhosis and ascites is associated with water retention, an increase in total body water, and dilutional hyponatremia28.Abraham W.T. Schrier R.W. Cardiac failure, liver disease and nephrotic syndrome,.in: Schrier R.W. Gottschalk C.W. Diseases of the Kidney. Little Brown & Co, Boston1996Google Scholar. Of patients with cirrhosis and ascites, 30% will have hyponatremia29.Arroyo V. Rodes J. Gutierrez Lizarraga M.A. Revert L. 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The release of a circulating vasodilator has been suggested to initiate the fall in systemic vascular resistance, and hence arterial underfilling stimulates the nonosmotic release of AVP with the concomitant occurrence of hypoosmolality55.Schrier R.W. Briner V.A. Peripheral arterial vasodilation hypothesis of sodium and water retention in pregnancy: Implications for pathogenesis of preeclampsia-eclampsia.Obstet Gynecol. 1991; 77: 632-639PubMed Google Scholar. A variety of vasodilators have been proposed as potential mediators of the fall in systemic vascular resistance, such as vasodilatory prostaglandins including prostaglandin E (PGE)2 and prostacyclin (PGI2)56.Fitzgerald J.D. Mayo G. Catella et al.Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platelets.Am J Obstet Gynecol. 1987; 157: 325-330Abstract Full Text PDF PubMed Scopus (92) Google Scholar. NO is also released by the endothelium and has potent vasorelaxing effects. The calcium-dependent NOS in the endothelium is also stimulated by estrogen57.Weiner C.P. Lizasoain I. Baylis S.A. et al.Introduction of calcium-dependent nitric oxide synthetase by sex hormones.Proc Natl Acad Sci USA. 1994; 91: 5212-5216Crossref PubMed Scopus (1042) Google Scholar. NO production has been shown to be increased during pregnancy in rats58.Conrad K.P. Joffe G.M. Krusayna H. et al.Identification of increased nitric oxide biosynthesis during pregnancy in rats.FASEB J. 1993; 7: 566-571PubMed Google Scholar. A recent study in pregnant rats has also shown the up-regulation of the constitutive NOS isoforms endothelial NOS (eNOS) and neuronal NOS (nNOS). Specifically, eNOS was increased in the aorta and mesenteric artery of pregnant rats. Furthermore, nNOS was increased in the hypothalamus, in parallel with a rise in AVP mRNA in the pregnant rat59.Xu D.-L. Martin P.-Y. St John J. Tsai P. Summer S.N. Ohara M. Kim J.K. Schrier R.W. Upregulation of endothelial and neuronal constitutive nitric oxide synthetase in pregnant rats.Am J Physiol. 1996; 271: R1739-R1745PubMed Google Scholar. It is possible that the up-regulated eNOS and nNOS both could contribute to AVP release, eNOS secondarily by mediating the peripheral arterial vasodilation and subsequent nonosmotic AVP release and nNOS by a direct effect on the hypothalamus. Further support for the role of AVP in the water retention in pregnancy comes from a recent study in pregnant rats showing up-regulation of the CD water channel AQP-2 mRNA and protein60.Ohara M. Martin P.-Y. Xu D.-L. St John J. Schrier R.W. Increased aquaporin-2 gene expression in inner medulla of pregnant rats.J Clin Invest. 1998; 101: 1076-1083Crossref PubMed Scopus (96) Google Scholar. Administration of the V2 receptor antagonist OPC-31260 decreased expression of AQP-2 mRNA and protein to the same level seen in nonpregnant rats. Interestingly, plasma AVP was not different in pregnant rats compared with nonpregnant rats; however, the concentrations in the pregnant rats were relatively high for the degree of hypoosmolality. Nevertheless, although stimulation of V2 receptors by AVP is a likely explanation for AQP-2 up-regulation, other possibilities such as oxytocin61.Chou C.L. Digiovanni S.R. Mejia S. Neilsen S. Knepper M.A. Oxytocin as an antidiuretic hormone. I. Concentration dependence of action.Am J Physiol. 1995; 269: F70-F77PubMed Google Scholar,62.Chou C.L. Digiovanni S.R. Luther A. Lollait S.J. Knepper M.A. Oxytocin as an antidiuretic hormone. II. Role of V2 AVP receptor.Am J Physiol. 1995; 269: F78-F85PubMed Google Scholar need to be considered. Also of interest is the persistence of hypoosmolality in pregnant rats receiving a V2 receptor antagonist, indicating that factors other than AVP are involved. The increased thirst and water intake of pregnancy is one such potential factor. Nonosmotic stimulated, AVP-mediated water retention is a significant contributor to water retention in low cardiac output CF and high cardiac output states associated with peripheral vasodilation such as cirrhosis and pregnancy. Studies of the CD water channel AQP-2 have assisted in the understanding of water retention in these conditions, as has the development of AVP V2 receptor antagonists Figure 1. These drugs, now available in nonpeptide orally active form, have shown promising clinical results in hyponatremic patients with CF. A study using a V2 receptor antagonist in patients with liver disease and hyponatremia is currently in progress.
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