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Robert W. Schrier - One of the best experts on this subject based on the ideXlab platform.

  • aquaretic effect of lixivaptan an oral non peptide selective v2 receptor vasopressin antagonist in new york heart association functional class ii and iii chronic heart failure patients
    Journal of the American College of Cardiology, 2006
    Co-Authors: William T Abraham, Alireza A Shamshirsaz, Kim Mcfann, Ron M Oren, Robert W. Schrier
    Abstract:

    Objectives The purpose of this study was to examine the renal effects of a V2 receptor arginine vasopressin (AVP) antagonist in heart failure. Background Arginine vasopressin has been implicated in the renal water retention and dilutional hyponatremia associated with chronic heart failure. Methods We examined the effects of the oral, non-peptide, selective V2 receptor antagonist lixivaptan in 42 diuretic-requiring patients with mild-to-moderate heart failure in a randomized, double-blind, placebo-controlled, ascending single-dose study. After overnight fluid deprivation, patients received single-blind placebo on day −1 (baseline) and double-blind study medication (placebo [n = 12] or lixivaptan 10, 30, 75, 150, 250, or 400 mg [n = 5 per dose group]) on day 1, followed by 4 h of continued fluid restriction and additional 20 h with ad libitum fluid intake. Results At all but the 10-mg dose, lixivaptan produced a significant and dose-related increase in urine volume over 4 h, compared with placebo. During 24 h, increases in urine volume ranged from 1.8 l with placebo to 3.9 l after the 400-mg lixivaptan dose (p Conclusions These observations confirm a role for AVP in the renal water retention associated with heart failure and suggest that the V2 receptor antagonist lixivaptan may be a promising therapeutic agent for the treatment of heart failure.

  • hyponatremia in cirrhosis from pathogenesis to treatment
    Hepatology, 1998
    Co-Authors: M Pere D Gines, Daniel G. Bichet, Wladimiro Jiménez, Tomas Berl, M Bernardi, Guilles Hamon, Jeanfrancois Liard, Pierreyves Martin, Robert W. Schrier
    Abstract:

    A disturbance in body water homeostasis is a common feature of advanced cirrhosis.1-4 This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. This leads to water retention with subsequent increase in total body water and development of dilutional hyponatremia. The prevalence of hyponatremia (serum sodium ,130 mEq/L) in patients with cirrhosis and ascites is approximately 30%.5 Besides the clinical manifestations associated with low serum sodium concentration, hyponatremia has a negative impact on the quality of life of cirrhotic patients, because they should be subjected to fluid restriction to avoid further reduction in serum sodium concentration. In recent years, great advances have been made in the knowledge of mechanisms regulating water excretion, especially on the role of vasopressin (VP). These advances include a better understanding of the regulation of VP synthesis and secretion, identification and cloning of VP receptors, characterization of VP signaling in the collecting duct cells, identification and cloning of water channels responsible for water reabsorption, and development of drugs capable of selectively increasing water excretion either by inhibiting VP release or antagonizing the effects of VP in the renal tubules. These advances may prove to be very useful in the management of conditions, such as cirrhosis, associated with water retention and hyponatremia. The current article summarizes the contributions to a symposium on pathophysiology and treatment of water retention in cirrhosis organized by the International Ascites Club and held at the Palexpo Center in Geneva, Switzerland, on August 25, 1996. The symposium was chaired by Mauro Bernardi and was divided into two parts. In the first part, Tomas Berl, Daniel G. Bichet, and Robert W. Schrier discussed the renal regulation of water excretion, the synthesis and biological effects of VP, and the pathogenesis of water retention in cirrhosis, respectively. In the second part, Guilles Hamon, Jean Francois Liard, and Wladimiro Jimenez discussed the recently developed drugs that selectively increase water excretion, known as Aquaretics, and their effects in experimental cirrhosis.

Wladimiro Jiménez - One of the best experts on this subject based on the ideXlab platform.

  • sustained aquaretic effect of the v2 avp receptor antagonist rwj 351647 in cirrhotic rats with ascites and water retention
    British Journal of Pharmacology, 2005
    Co-Authors: Josefa Ros, Vicente Arroyo, Juan Rodés, Guillermo Fernandezvaro, Joseph W. Gunnet, Keith T. Demarest, Javier Munozluque, Wladimiro Jiménez
    Abstract:

    1 A disturbance in body water homeostasis is a common feature in advanced cirrhosis. This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. Vasopressin (AVP) is of major importance in the pathogenesis of water retention and hyponatremia in cirrhosis. 2 The current study assessed the renal, hormonal and hemodynamic effects induced by 10-day chronic oral administration of RWJ-351647 (0.5 mg kg(-1) daily), a new nonpeptide V(2)-AVP antagonist, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention. Urine volume (UV), urine osmolality and sodium and potassium excretion were measured daily. At the end of the study, systemic hemodynamic parameters were also assessed. 3 Long-term administration of RWJ-351647 has an aquaretic effect in rats with cirrhosis, ascites, water retention and hypo-osmolality. It increases UV (ANOVA: F=7.32, P<0.0001) and reduces urine osmolality (ANOVA: F=12.69, P<0.0001) throughout the entire period of treatment, thereby leading to a greater renal ability to excrete a water load at the end of the 10-day treatment period (the percentage of water load excreted improved from 30+/-8 to 92+/-21%, P<0.025). 4 The nonpeptide AVP V(2)-receptor antagonist RWJ-351647 also increased sodium excretion without affecting creatinine clearance and blood pressure. 5 These data suggest that RWJ-351647 could be therapeutically useful in the treatment of water retention in human cirrhosis.

  • effect of the v1a v2 avp receptor antagonist conivaptan on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites
    Journal of Hepatology, 2003
    Co-Authors: Guillermo Fernandezvaro, Josefa Ros, Carmen Cano, Vicente Arroyo, Francisca Rivera, Juan Rodés, Pilar Cejudomartin, Wladimiro Jiménez
    Abstract:

    Abstract Background : Selective V 2 -AVP receptor antagonists are effective in inducing aquaresis in humans and rats with cirrhosis, hyponatremia and water retention. However, it is unknown whether dual V 1a /V 2 -AVP antagonists are also efficacious as aquaretic agents under these conditions. This is important, particularly considering that blockade of V 1a -AVP receptors could aggravate cardiocirculatory function in decompensated cirrhosis. Aims : To evaluate the renal, hormonal and hemodynamic effects induced by the chronic oral administration of the V 1a /V 2 -AVP antagonist, Conivaptan, in rats with CCl 4 -induced cirrhosis, ascites and severe water retention. Methods : We assessed the aquaretic efficacy of 10-day chronic oral administration of Conivaptan (0.5mg/kg body weight (bw)) in cirrhotic rats with hyponatremia and water retention. Urine volume (UV), osmolality (UOsm), and sodium excretion (U Na V) were measured daily. At the end of the study arterial pressure was also measured. Results : Conivaptan produced an acute increase in UV, a reduction in UOsm and, at the end of the investigation, cirrhotic rats receiving the V 1a /V 2 -AVP receptor antagonist did not show hyponatremia or hypoosmolality. Conivaptan also normalized U Na V without affecting creatinine clearance and arterial pressure. Conclusions : Dual V 1a /V 2 -receptor antagonists may be therapeutically useful for the treatment of water retention and dilutional hyponatremia in human cirrhosis.

  • long term aquaretic efficacy of a selective nonpeptide v2 vasopressin receptor antagonist sr121463 in cirrhotic rats
    Journal of Pharmacology and Experimental Therapeutics, 2000
    Co-Authors: Wladimiro Jiménez, Josefa Ros, Carmen Cano, Vicente Arroyo, Francisca Rivera, Claudine Serradeil-le Gal, Pilar Cejudo, Marc Pascal, Manuel Moralesruiz, Jean-pierre Maffrand
    Abstract:

    Water retention in experimental cirrhosis can be reversed by blocking V2-vasopressin (AVP) receptors with the nonpeptide antagonist OPC-31260 or by using the κ-opioid receptor agonist niravoline, a compound inhibiting central AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 days of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective nonpeptide V2-AVP receptor antagonist, SR121463, has been developed that could be useful for the treatment of dilutional hyponatremia in human cirrhosis. The current study assessed the aquaretic efficacy of 10-day chronic oral administration of SR121463 (0.5 mg/kg/day) in cirrhotic rats with ascites and impaired water excretion after a water load (minimum urinary osmolality >160 mOsm/kg and percentage of water load excreted <60%). Urine volume (UV), osmolality (UOsmV), and sodium excretion (UNaV) were measured daily. At the end of the 10-day treatment, mean arterial pressure also was measured. In basal conditions cirrhotic rats showed ascites, sodium retention, and impaired water excretion. UV, UOsmV, and UNaV did not change throughout the study in cirrhotic rats receiving the vehicle. In contrast, SR121463 increased UV and reduced UOsmV during the 10-day treatment. This resulted in a greater renal ability to excrete a water load and normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased UNaV without affecting mean arterial pressure. These data suggest that SR121463 could be of therapeutical value for chronic management of human cirrhosis.

  • hyponatremia in cirrhosis from pathogenesis to treatment
    Hepatology, 1998
    Co-Authors: M Pere D Gines, Daniel G. Bichet, Wladimiro Jiménez, Tomas Berl, M Bernardi, Guilles Hamon, Jeanfrancois Liard, Pierreyves Martin, Robert W. Schrier
    Abstract:

    A disturbance in body water homeostasis is a common feature of advanced cirrhosis.1-4 This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. This leads to water retention with subsequent increase in total body water and development of dilutional hyponatremia. The prevalence of hyponatremia (serum sodium ,130 mEq/L) in patients with cirrhosis and ascites is approximately 30%.5 Besides the clinical manifestations associated with low serum sodium concentration, hyponatremia has a negative impact on the quality of life of cirrhotic patients, because they should be subjected to fluid restriction to avoid further reduction in serum sodium concentration. In recent years, great advances have been made in the knowledge of mechanisms regulating water excretion, especially on the role of vasopressin (VP). These advances include a better understanding of the regulation of VP synthesis and secretion, identification and cloning of VP receptors, characterization of VP signaling in the collecting duct cells, identification and cloning of water channels responsible for water reabsorption, and development of drugs capable of selectively increasing water excretion either by inhibiting VP release or antagonizing the effects of VP in the renal tubules. These advances may prove to be very useful in the management of conditions, such as cirrhosis, associated with water retention and hyponatremia. The current article summarizes the contributions to a symposium on pathophysiology and treatment of water retention in cirrhosis organized by the International Ascites Club and held at the Palexpo Center in Geneva, Switzerland, on August 25, 1996. The symposium was chaired by Mauro Bernardi and was divided into two parts. In the first part, Tomas Berl, Daniel G. Bichet, and Robert W. Schrier discussed the renal regulation of water excretion, the synthesis and biological effects of VP, and the pathogenesis of water retention in cirrhosis, respectively. In the second part, Guilles Hamon, Jean Francois Liard, and Wladimiro Jimenez discussed the recently developed drugs that selectively increase water excretion, known as Aquaretics, and their effects in experimental cirrhosis.

Bertram Pitt - One of the best experts on this subject based on the ideXlab platform.

  • pathophysiology of diuretic resistance and its implications for the management of chronic heart failure
    Hypertension, 2020
    Co-Authors: Christopher S Wilcox, Jeffrey M Testani, Bertram Pitt
    Abstract:

    Diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na+ losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na+ reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and Aquaretics combined in severely diuretic-resistant patients with heart failure.

  • vasopressin v1 receptor mediated aldosterone production as a result of selective v2 receptor antagonism a potential explanation for the failure of tolvaptan to reduce cardiovascular outcomes in the everest trial
    European Journal of Heart Failure, 2011
    Co-Authors: Bertram Pitt, Mihai Gheorghiade
    Abstract:

    Plasma volume expansion in patients with heart failure (HF) is associated with neurohumeral activation; symptom and signs of pulmonary congestion and peripheral oedema; an increase in hospitalizations for HF; and cardiovascular mortality. A reduction in plasma volume, as evidenced by haemoconcentration, has recently been suggested to be associated with an improvement in cardiovascular mortality. However, while loop diuretics reduce plasma volume and relieve the symptoms and signs of pulmonary congestion, they activate the renin–angiotensin–aldosterone system (RAAS) and, in experimental studies and some, although not all, retrospective clinical studies have been associated with an increase in cardiovascular mortality. Due to the controversy associated with the use of high-dose loop diuretics and their effect on cardiovascular mortality in patients with HF and a reduced left ventricular ejection fraction (REF) there has been increasing interest in alternative and or supplemental diuretic strategies to reduce plasma volume and to improve cardiovascular outcomes in patients with HFREF. Tolvaptan, a selective V2 vasopressin antagonist, has been shown in pre-clinical and short-term studies in patients with HF to be a potent aquaretic with a resultant increase in urine output; a decrease in body weight; a decrease in pulmonary capillary wedge pressure; an increase in serum sodium concentration; without activation of the RAAS. However when studied over the longer term in patients with HFREF, it has not been shown to reduce natriuretic peptide levels or left ventricular remodelling, and did not improve cardiovascular outcomes despite an early improvement in symptoms of dyspnoea, a prolonged reduction in body weight, and normalization of serum sodium in hyponatraemic patients. The finding that tolvaptan failed to reduce natriuretic peptide levels and cardiovascular outcomes despite a reduction in body weight is especially notable since an increase in body weight post-discharge is the single most important predictor for readmission in patients with heart failure and a major predictor of mortality. The explanation for the failure of tolvaptan to improve ventricular remodelling, natriuretic peptide levels, and cardiovascular outcomes despite a reduction in body weight remains uncertain. Several explanations have, however, been proposed, including the suggestion that the dose of tolvaptan (30 mg/day) may have been inadequate; that patients selected for study did not have hyponatraemia; and the possibility that a reactive increase in vasopressin levels might over the long term stimulate the V1a receptor with a resultant increase in vasoconstriction, which might negate the beneficial effects associated with aquareses. Without further prospective mechanistic studies it is difficult to confirm or refute these explanations. Recently, however, it has been shown that a deficiency of the V1a receptor causes hyporeninaemic hypoaldsteronism, and stimulation of the V1a receptor causes the adrenal production of aldosterone. The V1a receptor also affects the renal tubular effects of aldosterone. We postulate that these findings may explain the paradox of a persistent reduction in body weight despite the lack of an improvement in natriuretic peptide levels and cardiovascular outcomes associated with the use of tolvaptan in EVEREST. This hypotheses and its implications for the therapy of patients with HF will be briefly discussed below. As noted above, V2 receptor antagonism results in a sustained reduction in body weight along with an early transient decrease in pulmonary capillary wedge pressure without activation of the RAAS. However, over the long term there is a reactive increase in vasopressin levels, with a resultant increased activation of the unprotected V1a receptor in the myocardium and vascular wall. This increase in vasopressin levels in patients receiving tolvaptan has recently been associated with an increase in aldosterone levels.

Paul J Thuluvath - One of the best experts on this subject based on the ideXlab platform.

  • a vasopressin receptor antagonist vpa 985 improves serum sodium concentration in patients with hyponatremia a multicenter randomized placebo controlled trial
    Hepatology, 2003
    Co-Authors: M Florence D Wong, Andres T Blei, Laurence M Blendis, Paul J Thuluvath
    Abstract:

    Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V2 receptors in the distal renal nephron to increase water reabsorption. This study investigates the efficacy and safety of 3 different doses of the V2 receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P < .05) and serum sodium (P < .05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions. End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use. (HEPATOLOGY 2003;37:182-191.)

  • a vasopressin receptor antagonist vpa 985 improves serum sodium concentration in patients with hyponatremia a multicenter randomized placebo controlled trial
    Hepatology, 2003
    Co-Authors: M Florence D Wong, Andres T Blei, Laurence M Blendis, Paul J Thuluvath
    Abstract:

    Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V2 receptors in the distal renal nephron to increase water reabsorption. This study investigates the efficacy and safety of 3 different doses of the V2 receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P < .05) and serum sodium (P < .05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions. End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use.

Josefa Ros - One of the best experts on this subject based on the ideXlab platform.

  • sustained aquaretic effect of the v2 avp receptor antagonist rwj 351647 in cirrhotic rats with ascites and water retention
    British Journal of Pharmacology, 2005
    Co-Authors: Josefa Ros, Vicente Arroyo, Juan Rodés, Guillermo Fernandezvaro, Joseph W. Gunnet, Keith T. Demarest, Javier Munozluque, Wladimiro Jiménez
    Abstract:

    1 A disturbance in body water homeostasis is a common feature in advanced cirrhosis. This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. Vasopressin (AVP) is of major importance in the pathogenesis of water retention and hyponatremia in cirrhosis. 2 The current study assessed the renal, hormonal and hemodynamic effects induced by 10-day chronic oral administration of RWJ-351647 (0.5 mg kg(-1) daily), a new nonpeptide V(2)-AVP antagonist, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention. Urine volume (UV), urine osmolality and sodium and potassium excretion were measured daily. At the end of the study, systemic hemodynamic parameters were also assessed. 3 Long-term administration of RWJ-351647 has an aquaretic effect in rats with cirrhosis, ascites, water retention and hypo-osmolality. It increases UV (ANOVA: F=7.32, P<0.0001) and reduces urine osmolality (ANOVA: F=12.69, P<0.0001) throughout the entire period of treatment, thereby leading to a greater renal ability to excrete a water load at the end of the 10-day treatment period (the percentage of water load excreted improved from 30+/-8 to 92+/-21%, P<0.025). 4 The nonpeptide AVP V(2)-receptor antagonist RWJ-351647 also increased sodium excretion without affecting creatinine clearance and blood pressure. 5 These data suggest that RWJ-351647 could be therapeutically useful in the treatment of water retention in human cirrhosis.

  • effect of the v1a v2 avp receptor antagonist conivaptan on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites
    Journal of Hepatology, 2003
    Co-Authors: Guillermo Fernandezvaro, Josefa Ros, Carmen Cano, Vicente Arroyo, Francisca Rivera, Juan Rodés, Pilar Cejudomartin, Wladimiro Jiménez
    Abstract:

    Abstract Background : Selective V 2 -AVP receptor antagonists are effective in inducing aquaresis in humans and rats with cirrhosis, hyponatremia and water retention. However, it is unknown whether dual V 1a /V 2 -AVP antagonists are also efficacious as aquaretic agents under these conditions. This is important, particularly considering that blockade of V 1a -AVP receptors could aggravate cardiocirculatory function in decompensated cirrhosis. Aims : To evaluate the renal, hormonal and hemodynamic effects induced by the chronic oral administration of the V 1a /V 2 -AVP antagonist, Conivaptan, in rats with CCl 4 -induced cirrhosis, ascites and severe water retention. Methods : We assessed the aquaretic efficacy of 10-day chronic oral administration of Conivaptan (0.5mg/kg body weight (bw)) in cirrhotic rats with hyponatremia and water retention. Urine volume (UV), osmolality (UOsm), and sodium excretion (U Na V) were measured daily. At the end of the study arterial pressure was also measured. Results : Conivaptan produced an acute increase in UV, a reduction in UOsm and, at the end of the investigation, cirrhotic rats receiving the V 1a /V 2 -AVP receptor antagonist did not show hyponatremia or hypoosmolality. Conivaptan also normalized U Na V without affecting creatinine clearance and arterial pressure. Conclusions : Dual V 1a /V 2 -receptor antagonists may be therapeutically useful for the treatment of water retention and dilutional hyponatremia in human cirrhosis.

  • long term aquaretic efficacy of a selective nonpeptide v2 vasopressin receptor antagonist sr121463 in cirrhotic rats
    Journal of Pharmacology and Experimental Therapeutics, 2000
    Co-Authors: Wladimiro Jiménez, Josefa Ros, Carmen Cano, Vicente Arroyo, Francisca Rivera, Claudine Serradeil-le Gal, Pilar Cejudo, Marc Pascal, Manuel Moralesruiz, Jean-pierre Maffrand
    Abstract:

    Water retention in experimental cirrhosis can be reversed by blocking V2-vasopressin (AVP) receptors with the nonpeptide antagonist OPC-31260 or by using the κ-opioid receptor agonist niravoline, a compound inhibiting central AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 days of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective nonpeptide V2-AVP receptor antagonist, SR121463, has been developed that could be useful for the treatment of dilutional hyponatremia in human cirrhosis. The current study assessed the aquaretic efficacy of 10-day chronic oral administration of SR121463 (0.5 mg/kg/day) in cirrhotic rats with ascites and impaired water excretion after a water load (minimum urinary osmolality >160 mOsm/kg and percentage of water load excreted <60%). Urine volume (UV), osmolality (UOsmV), and sodium excretion (UNaV) were measured daily. At the end of the 10-day treatment, mean arterial pressure also was measured. In basal conditions cirrhotic rats showed ascites, sodium retention, and impaired water excretion. UV, UOsmV, and UNaV did not change throughout the study in cirrhotic rats receiving the vehicle. In contrast, SR121463 increased UV and reduced UOsmV during the 10-day treatment. This resulted in a greater renal ability to excrete a water load and normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased UNaV without affecting mean arterial pressure. These data suggest that SR121463 could be of therapeutical value for chronic management of human cirrhosis.