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Jalal K Ghali - One of the best experts on this subject based on the ideXlab platform.
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Conivaptan and its role in the treatment of hyponatremia
Drug design development and therapy, 2009Co-Authors: Jalal K Ghali, Suleiman Daifallah, Jareer Farah, Hassan A Zabalawi, Hammam ZmilyAbstract:Hyponatremia is the most common electrolyte abnormality in hospitalized patients and is associated with increased morbidity and mortality. The recognition of the central role that arginin vasopressin plays in the pathogenesis of hyponatremia and the discovery that its actions are mediated by stimulation of V1A and V2 receptors have led to the development of a new class of drugs, the arginin vasopressin antagonists. Conivaptan is a nonselective V1A and V2 receptors antagonist that was the first of this class to be approved by the FDA for the management of euvolemic and hypervolemic hyponatremia. Its short-term safety and efficacy for the correction of hyponatremia have been established by multiple double-blind, randomized, controlled studies. Blocking the effects of arginin vasopressin on V2 receptors produces aquaresis – the electrolyte-sparing excretion of water – an ideal approach to correct hypervolemic hyponatremia. The nonselectivity of Conivaptan offers a theoretical advantage for its use in heart failure that may merit further exploration.
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Conivaptan and its role in the treatment of hyponatremia
Dove Medical Press, 2009Co-Authors: Jalal K Ghali, Jareer O Farah, Suleiman DaifallahAbstract:Jalal K Ghali,1 Jareer O Farah,2 Suleiman Daifallah,3 Hassan A Zabalawi,4 Hammam D Zmily51Detroit Medical Center, Detroit, MI, USA; 2Wayne State University/Detroit Medical Center, Detroit, MI, USA; 3John D Dingell VA Medical Center, Detroit, MI, USA; 4,5Wayne State University/Detroit Medical Center, Detroit, MI, USAAbstract: Hyponatremia is the most common electrolyte abnormality in hospitalized patients and is associated with increased morbidity and mortality. The recognition of the central role that arginin vasopressin plays in the pathogenesis of hyponatremia and the discovery that its actions are mediated by stimulation of V1A and V2 receptors have led to the development of a new class of drugs, the arginin vasopressin antagonists. Conivaptan is a nonselective V1A and V2 receptors antagonist that was the first of this class to be approved by the FDA for the management of euvolemic and hypervolemic hyponatremia. Its short-term safety and efficacy for the correction of hyponatremia have been established by multiple double-blind, randomized, controlled studies. Blocking the effects of arginin vasopressin on V2 receptors produces aquaresis – the electrolyte-sparing excretion of water – an ideal approach to correct hypervolemic hyponatremia. The nonselectivity of Conivaptan offers a theoretical advantage for its use in heart failure that may merit further exploration.Keywords: arginine vasopressin antagonist, Conivaptan, heart failure, hyponatremia 
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Conivaptan a dual receptor vasopressin v1a v2 antagonist
Cardiovascular Drug Reviews, 2007Co-Authors: Farhan Ali, Adnan M Raufi, Barbara Washington, Jalal K GhaliAbstract:Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis. The actions of AVP are mediated by three receptor subtypes V1a, V2, and V1b. The V1a receptor regulates vasodilation and cellular hypertrophy while the V2 receptor regulates free water excretion. The V1b receptor regulates adrenocorticotropin hormone release. Conivaptan is a nonpeptide dual V1a/V2 AVP receptor antagonist. It binds with high affinity, competitively, and reversibly to the V1a/V2 receptor subtypes; its antagonistic effect is concentration dependent. It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme. It is approved only for short-term intravenous use. Infusion site reaction is the most common reason for discontinuation of the drug. In animals Conivaptan increased urine volume and free water clearance. In heart failure models it improved hemodynamic parameters and free water excretion. Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients. Its efficacy and safety for short-term use have led to the Food and Drug Administration (FDA) approval of its intravenous form for the correction of hyponatremia in euvolemic and hypervolemic states. Despite its ability to block the action of AVP on V1a receptors, no demonstrable benefit from this action was noted in patients with chronic compensated heart failure and it is not approved for this indication. Consideration should be given to further evaluation of its potential benefits in patients with acute decompensated heart failure.
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Conivaptan: A Dual Receptor Vasopressin V1a/V2 Antagonist
Cardiovascular drug reviews, 2007Co-Authors: Farhan Ali, Barbara Washington, M. Adnan Raufi, Jalal K GhaliAbstract:Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis. The actions of AVP are mediated by three receptor subtypes V1a, V2, and V1b. The V1a receptor regulates vasodilation and cellular hypertrophy while the V2 receptor regulates free water excretion. The V1b receptor regulates adrenocorticotropin hormone release. Conivaptan is a nonpeptide dual V1a/V2 AVP receptor antagonist. It binds with high affinity, competitively, and reversibly to the V1a/V2 receptor subtypes; its antagonistic effect is concentration dependent. It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme. It is approved only for short-term intravenous use. Infusion site reaction is the most common reason for discontinuation of the drug. In animals Conivaptan increased urine volume and free water clearance. In heart failure models it improved hemodynamic parameters and free water excretion. Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients. Its efficacy and safety for short-term use have led to the Food and Drug Administration (FDA) approval of its intravenous form for the correction of hyponatremia in euvolemic and hypervolemic states. Despite its ability to block the action of AVP on V1a receptors, no demonstrable benefit from this action was noted in patients with chronic compensated heart failure and it is not approved for this indication. Consideration should be given to further evaluation of its potential benefits in patients with acute decompensated heart failure.
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efficacy and safety of oral Conivaptan a v1a v2 vasopressin receptor antagonist assessed in a randomized placebo controlled trial in patients with euvolemic or hypervolemic hyponatremia
The Journal of Clinical Endocrinology and Metabolism, 2006Co-Authors: Jalal K Ghali, Michael Koren, James R Taylor, Esther Brooksasplund, Walker Long, Neila SmithAbstract:Context: Hyponatremia [serum sodium concentration ([Na+]), <135 mEq/liter] is the most common fluid and electrolyte abnormality among hospitalized patients. It is frequently caused by the inappropriate release of arginine vasopressin. Objective: The objective of this study was to evaluate the efficacy and safety of oral Conivaptan, a vasopressin V1A/V2 receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia. Design: The study design was a 5-d placebo-controlled, randomized, double-blind study. Setting: The study was performed at a hospital. Intervention: Oral Conivaptan (40 or 80 mg/d) or placebo was given in two divided doses. Patients: Seventy-four patients (average baseline serum [Na+], 115 to <130 mEq/liter) were studied. Main Outcome Measure: The main outcome measure was the change from baseline in serum [Na+] area under the curve. Results: The least-squares mean change from baseline in the serum [Na+] area under the curve with Conivaptan (40 and 80 mg/d) was 2.0-fold (P = 0.03) ...
Steven R. Goldsmith - One of the best experts on this subject based on the ideXlab platform.
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hemodynamic effects of short term infusion of a vasopressin v1a v2 receptor antagonist Conivaptan in patients withchronic heart failure during submaximal exercise
American Heart Journal, 2018Co-Authors: Louise Balling, Steven R. Goldsmith, Jakob Hartvig Thomsen, Emil Wolsk, Christian Hassager, Soren Boesgaard, Finn GustafssonAbstract:Heart failure is associated with a reduced exercise capacity. Our aim was to investigate if infusion with a V1A/V2-receptor antagonist, Conivaptan, leads to an increase in cardiac output at a constant or reduced filling pressure (pulmonary capillary wedge pressure) during submaximal exercise.
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Hemodynamic effects of short-term infusion of a vasopressin V1A/V2 receptor antagonist Conivaptan in patients withchronic heart failure during submaximal exercise.
American heart journal, 2018Co-Authors: Louise Balling, Steven R. Goldsmith, Jakob Hartvig Thomsen, Emil Wolsk, Christian Hassager, Soren Boesgaard, Finn GustafssonAbstract:Heart failure is associated with a reduced exercise capacity. Our aim was to investigate if infusion with a V1A/V2-receptor antagonist, Conivaptan, leads to an increase in cardiac output at a constant or reduced filling pressure (pulmonary capillary wedge pressure) during submaximal exercise.
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Renal Effects of Conivaptan, Furosemide, and the Combination in Patients With Chronic Heart Failure
Journal of cardiac failure, 2011Co-Authors: Steven R. Goldsmith, David T. Gilbertson, Shari A. Mackedanz, Suzanne K. SwanAbstract:Abstract Background Loop diuretics, though often effective for treating congestion, have significant limitations. Discovering ways to limit exposure to loop diuretics while achieving effective decongestion is an important goal of current clinical research in heart failure (HF). Vasopressin antagonists are effective in removing large amounts of water, but not salt, in HF. Few data exist about the detailed renal and hormonal effects of these agents compared with or in combination with loop diuretics. This study investigated the renal and neurohormonal effects of loop diuretics, the mixed vasopressin antagonist Conivaptan, and the combination in patients with chronic stable HF. Methods and Results In 8 patients with chronic stable HF on standard medical treatment, heart rate, arterial pressure, systemic vascular resistance, and cardiac output (the latter 2 by using impedance cardiography), as well as glomerular filtration rate (iothalamate clearance), renal blood flow (para-aminohippurate clearance), urinary volumes and urinary sodium, plasma catecholamines, renin activity, arginine vasopressin, and B-type natriuretic peptide were assessed before and at hourly intervals for 4 hours after receiving furosemide, Conivaptan, or the combination on 3 different study days at a minimum of 1-week intervals. There were no significant effects of Conivaptan, furosemide, or the combination on any hemodynamic variable, neurohormonal level, renal blood flow, or glomerular filtration rate. Conivaptan and furosemide similarly increased urine volumes; the effect of the combination was significantly greater. Furosemide, but not Conivaptan, increased urinary sodium excretion, and the combination was significantly greater than after furosemide alone. Conclusions Without adversely affecting important hemodynamic variables, neurohormones, renal blood flow, or glomerular filtration rate, Conivaptan significantly augmented both the diuretic and the natriuretic response to furosemide in patients with chronic HF. These results may have implications for the design of furosemide-sparing regimens in the treatment of acute HF.
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efficacy and safety of the vasopressin v1a v2 receptor antagonist Conivaptan in acute decompensated heart failure a dose ranging pilot study
Journal of Cardiac Failure, 2008Co-Authors: Steven R. Goldsmith, Uri Elkayam, Herbert W Haught, Abhijit BarveAbstract:Abstract Background Hospitalization for acute decompensated heart failure (ADHF) involves substantial morbidity and mortality. Current management strategies have major limitations, and there has been little progress in the development of newer therapies. Arginine vasopressin–receptor antagonists may have promise in the treatment of ADHF in view of their ability to facilitate diuresis. This pilot study was designed to evaluate the efficacy and safety of intravenous Conivaptan, a dual arginine vasopressin V1A/V2-receptor antagonist, in treating ADHF. Methods and Results In a double-blind, multicenter trial, 170 patients hospitalized for worsening heart failure and given standard therapy were randomly assigned to treatment with Conivaptan (20-mg loading dose followed by 2 successive 24-hour continuous infusions of 40, 80, or 120 mg/d) or placebo. The Conivaptan and placebo groups did not differ significantly in patient or clinician assessments of global and respiratory status at 48 hours. There was no evidence of worsening heart failure in any group. Conivaptan at each dosage increased urine output significantly more than placebo at 24 hours (P ≤ .02), with the difference averaging 1.0 to 1.5 L. Decreases in mean body weight with Conivaptan 40 and 80 mg/d (∼ 1–2 kg) paralleled the increases in urine output but did not reach statistical significance. Conivaptan was well tolerated and not associated with clinically important changes in vital signs, electrolyte disturbances, or cardiac rhythm. The most common adverse events were infusion-site reactions. Conclusion When added to standard therapy for ADHF, Conivaptan safely improves urine output. Further study of this compound in ADHF may be warranted, especially in view of the limitations of current treatment for this syndrome.
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Efficacy and Safety of the Vasopressin V1A/V2-Receptor Antagonist Conivaptan in Acute Decompensated Heart Failure: A Dose-Ranging Pilot Study
Journal of cardiac failure, 2008Co-Authors: Steven R. Goldsmith, Uri Elkayam, W. Herbert Haught, Abhijit BarveAbstract:Abstract Background Hospitalization for acute decompensated heart failure (ADHF) involves substantial morbidity and mortality. Current management strategies have major limitations, and there has been little progress in the development of newer therapies. Arginine vasopressin–receptor antagonists may have promise in the treatment of ADHF in view of their ability to facilitate diuresis. This pilot study was designed to evaluate the efficacy and safety of intravenous Conivaptan, a dual arginine vasopressin V1A/V2-receptor antagonist, in treating ADHF. Methods and Results In a double-blind, multicenter trial, 170 patients hospitalized for worsening heart failure and given standard therapy were randomly assigned to treatment with Conivaptan (20-mg loading dose followed by 2 successive 24-hour continuous infusions of 40, 80, or 120 mg/d) or placebo. The Conivaptan and placebo groups did not differ significantly in patient or clinician assessments of global and respiratory status at 48 hours. There was no evidence of worsening heart failure in any group. Conivaptan at each dosage increased urine output significantly more than placebo at 24 hours (P ≤ .02), with the difference averaging 1.0 to 1.5 L. Decreases in mean body weight with Conivaptan 40 and 80 mg/d (∼ 1–2 kg) paralleled the increases in urine output but did not reach statistical significance. Conivaptan was well tolerated and not associated with clinically important changes in vital signs, electrolyte disturbances, or cardiac rhythm. The most common adverse events were infusion-site reactions. Conclusion When added to standard therapy for ADHF, Conivaptan safely improves urine output. Further study of this compound in ADHF may be warranted, especially in view of the limitations of current treatment for this syndrome.
Takeyuki Yatsu - One of the best experts on this subject based on the ideXlab platform.
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Intravenous administration of Conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure.
European journal of pharmacology, 2005Co-Authors: Kohichi Wada, Takeyuki Yatsu, Akira Fujimori, Yukinori Arai, Katsumi Sudoh, Masao Sasamata, Utane Matsukawa, Keiji MiyataAbstract:We investigated the effects of intravenously administered Conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on cardiac function in rats with congestive heart failure following myocardial infarction, and compared results with those for the selective vasopressin V2 receptor antagonist SR121463A. Rats were subjected to left coronary artery occlusion to induce myocardial infarction, which in turn led to congestive heart failure. At 4 weeks after coronary occlusion, Conivaptan (0.03, 0.1 and 0.3 mg/kg i.v.) dose-dependently increased urine volume and reduced urine osmolality in both myocardial infarction and sham-operated rats. SR121463A (0.3 mg/kg i.v.) also increased urine volume and decreased urine osmolality in myocardial infarction rats, to a degree comparable to that by Conivaptan (0.3 mg/kg i.v.). At 6 weeks after surgery, myocardial infarction rats showed increases in right ventricular systolic pressure, right atrial pressure, left ventricular end-diastolic pressure and relative weights of the heart and the lungs, and a decrease in first derivative of left ventricular pressure (dP/dt(max))/left ventricular pressure, showing that congestive heart failure was well established. Conivaptan (0.3 mg/kg i.v.) significantly reduced right ventricular systolic pressure, left ventricular end-diastolic pressure, lung/body weight and right atrial pressure in myocardial infarction rats. Moreover, Conivaptan (0.3 mg/kg i.v.) significantly increased dP/dt(max)/left ventricular pressure. SR121463A at a dose of 0.3 mg/kg i.v. significantly decreased left ventricular end-diastolic pressure and right atrial pressure, and tended to decrease right ventricular systolic pressure and relative lung weight in myocardial infarction rats. Although the aquaretic and preload-reducing effects of SR121463A were similar to those of Conivaptan, SR121463A failed to improve dP/dt(max)/left ventricular pressure. These results suggest that dual vasopressin V1A and V2 receptor antagonists provide greater benefit than selective vasopressin V2 receptor antagonists in the treatment of congestive heart failure.
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Effect of the vasopressin receptor antagonist Conivaptan in rats with heart failure following myocardial infarction.
European journal of pharmacology, 2002Co-Authors: Kohichi Wada, Yuichi Tomura, Atsuo Tahara, Junko Tsukada, Yukinori Arai, Motonori Aoki, Takeyuki YatsuAbstract:Abstract Myocardial infarction often induces congestive heart failure accompanied by a significant increase in plasma vasopressin concentration. To delineate the role of vasopressin in the pathogenesis of congestive heart failure, the acute hemodynamic and aquaretic effects of Conivaptan (YM087, 4′-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a combined vasopressin V1A and V2 receptor antagonist, were assessed in rats with heart failure induced by myocardial infarction. Left coronary artery ligation resulted in decreased left ventricular systolic pressure and first derivatives of left ventricular developed pressure, as well as increased left ventricular end-diastolic pressure, lung and right ventricular weight. Single oral administration of Conivaptan (0.3 to 3.0 mg/kg) dose-dependently increased urine volume and decreased urine osmolality in heart failure rats. Furthermore, Conivaptan (3.0 mg/kg) attenuated the changes in left ventricular end-diastolic pressure, lung and right ventricular weight induced by heart failure while reducing blood pressure. These results show that vasopressin plays a significant role in elevating vascular tone through vasopressin V1A receptors and plays a major role in retaining free water through vasopressin V2 receptors in this model of congestive heart failure. Additionally, Conivaptan, with its dual vasopressin V1A and V2 receptor-inhibiting properties, could exert a beneficial effect on cardiac function in the congestive heart failure rat model.
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EFFECT OF Conivaptan, A COMBINED VASOPRESSIN V1a AND V2 RECEPTOR ANTAGONIST, ON VASOPRESSIN-INDUCED CARDIAC AND HAEMODYNAMIC CHANGES IN ANAESTHETISED DOGS
Pharmacological research, 2002Co-Authors: Takeyuki Yatsu, Yuichi Tomura, Atsuo Tahara, Kohichi Wada, Toshiyuki Kusayama, Yukinori Arai, Motonori Aoki, Junko TsukadaAbstract:Abstract The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V 1a and V 2 receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) infusion of AVP on cardiovascular parameters and the effect of Conivaptan (YM087, 4′-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5- d ][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V 1a /V 2 receptor antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12–4 mU kg −1 min −1 ) dose-dependently produced decreases in the cardiac contractility indicator LV d P /d t max and cardiac output (CO) and increases in left ventricular end-diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes accurately mimic the cardiovascular symptoms of congestive heart failure. The i.v. bolus injection of Conivaptan (0.1 mg kg −1 ) rapidly attenuated the AVP (4 mU kg −1 min −1 )-induced decrease in CO and reversed the AVP-induced elevation in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan demonstrated the ability to dramatically improve the impaired cardiovascular parameters induced by AVP. The results suggest the potential usefulness of Conivaptan in treating congestive heart failure.
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cardiovascular and renal effects of Conivaptan hydrochloride ym087 a vasopressin v1a and v2 receptor antagonist in dogs with pacing induced congestive heart failure
European Journal of Pharmacology, 1999Co-Authors: Takeyuki Yatsu, Yuichi Tomura, Atsuo Tahara, Kohichi Wada, Toshiyuki Kusayama, Junko Tsukada, Tomoko Tokioka, Wataru Uchida, Osamu Inagaki, Yuichi IizumiAbstract:The systemic hemodynamic and renal responses to Conivaptan hydrochloride (YM087; 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine -6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V1A and V2 receptor antagonist, were determined in pentobarbital-anesthetized dogs after 2 to 3 weeks of rapid right ventricular pacing. Congestive heart failure, characterized by decreases in first derivative of left ventricular pressure (left ventricular d P/dt(max)) and cardiac output, and increases in left ventricular end-diastolic pressure and total peripheral vascular resistance, was induced by chronic rapid right ventricular pacing at 260-280 beats/min. Intravenous administration of Conivaptan (0.1 mg/kg) significantly increased left ventricular dP/dt(max) and cardiac output and significantly decreased left ventricular end-diastolic pressure and total peripheral vascular resistance. Conivaptan also increased urine flow and reduced urine osmolality by markedly increasing free water clearance. These results indicate that Conivaptan produced hemodynamic improvement and marked aquaresis in dogs with congestive heart failure. Therefore, Conivaptan may find clinical use in treating patients with congestive heart failure.
Kohichi Wada - One of the best experts on this subject based on the ideXlab platform.
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a novel vasopressin dual v1a v2 receptor antagonist Conivaptan hydrochloride improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone siadh
Biological & Pharmaceutical Bulletin, 2007Co-Authors: Kohichi Wada, Utane Yamanouchi Pharm Co Ltd Matsukawa, Akira Fujimori, Yukinori Arai, Katsumi Sudoh, Masao Sasamata, Keiji MiyataAbstract:We investigated the effects of intravenous administration of Conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on blood electrolytes and plasma osmolality in rats with an experimental syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The experimental SIADH rat model was developed by means of continuous administration of arginine vasopressin (AVP) via a subcutaneously implanted osmotic mini pump, and hyponatremia was induced by additional water loading. This model possesses similar characteristics to those observed in patients with SIADH, specifically decreases in blood sodium concentration and plasma osmolality. In this experimental model, intravenous administration of Conivaptan (0.1, 1 mg/kg) significantly increased blood sodium concentration and plasma osmolality. On the other hand, intravenous administration of furosemide (10 mg/kg) did not increase either blood sodium concentration or plasma osmolality in the SIADH rats. Moreover, furosemide significantly lowered blood potassium concentration. These results show that Conivaptan improves hyponatremia in rats with SIADH, supporting the therapeutic potential of Conivaptan in treatment of patients with hyponatremia associated with SIADH.
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A novel vasopressin dual V1A/V2 receptor antagonist, Conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Biological & pharmaceutical bulletin, 2007Co-Authors: Kohichi Wada, Utane Yamanouchi Pharm Co Ltd Matsukawa, Akira Fujimori, Yukinori Arai, Katsumi Sudoh, Masao Sasamata, Keiji MiyataAbstract:We investigated the effects of intravenous administration of Conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on blood electrolytes and plasma osmolality in rats with an experimental syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The experimental SIADH rat model was developed by means of continuous administration of arginine vasopressin (AVP) via a subcutaneously implanted osmotic mini pump, and hyponatremia was induced by additional water loading. This model possesses similar characteristics to those observed in patients with SIADH, specifically decreases in blood sodium concentration and plasma osmolality. In this experimental model, intravenous administration of Conivaptan (0.1, 1 mg/kg) significantly increased blood sodium concentration and plasma osmolality. On the other hand, intravenous administration of furosemide (10 mg/kg) did not increase either blood sodium concentration or plasma osmolality in the SIADH rats. Moreover, furosemide significantly lowered blood potassium concentration. These results show that Conivaptan improves hyponatremia in rats with SIADH, supporting the therapeutic potential of Conivaptan in treatment of patients with hyponatremia associated with SIADH.
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Intravenous administration of Conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure.
European journal of pharmacology, 2005Co-Authors: Kohichi Wada, Takeyuki Yatsu, Akira Fujimori, Yukinori Arai, Katsumi Sudoh, Masao Sasamata, Utane Matsukawa, Keiji MiyataAbstract:We investigated the effects of intravenously administered Conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on cardiac function in rats with congestive heart failure following myocardial infarction, and compared results with those for the selective vasopressin V2 receptor antagonist SR121463A. Rats were subjected to left coronary artery occlusion to induce myocardial infarction, which in turn led to congestive heart failure. At 4 weeks after coronary occlusion, Conivaptan (0.03, 0.1 and 0.3 mg/kg i.v.) dose-dependently increased urine volume and reduced urine osmolality in both myocardial infarction and sham-operated rats. SR121463A (0.3 mg/kg i.v.) also increased urine volume and decreased urine osmolality in myocardial infarction rats, to a degree comparable to that by Conivaptan (0.3 mg/kg i.v.). At 6 weeks after surgery, myocardial infarction rats showed increases in right ventricular systolic pressure, right atrial pressure, left ventricular end-diastolic pressure and relative weights of the heart and the lungs, and a decrease in first derivative of left ventricular pressure (dP/dt(max))/left ventricular pressure, showing that congestive heart failure was well established. Conivaptan (0.3 mg/kg i.v.) significantly reduced right ventricular systolic pressure, left ventricular end-diastolic pressure, lung/body weight and right atrial pressure in myocardial infarction rats. Moreover, Conivaptan (0.3 mg/kg i.v.) significantly increased dP/dt(max)/left ventricular pressure. SR121463A at a dose of 0.3 mg/kg i.v. significantly decreased left ventricular end-diastolic pressure and right atrial pressure, and tended to decrease right ventricular systolic pressure and relative lung weight in myocardial infarction rats. Although the aquaretic and preload-reducing effects of SR121463A were similar to those of Conivaptan, SR121463A failed to improve dP/dt(max)/left ventricular pressure. These results suggest that dual vasopressin V1A and V2 receptor antagonists provide greater benefit than selective vasopressin V2 receptor antagonists in the treatment of congestive heart failure.
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Effect of the vasopressin receptor antagonist Conivaptan in rats with heart failure following myocardial infarction.
European journal of pharmacology, 2002Co-Authors: Kohichi Wada, Yuichi Tomura, Atsuo Tahara, Junko Tsukada, Yukinori Arai, Motonori Aoki, Takeyuki YatsuAbstract:Abstract Myocardial infarction often induces congestive heart failure accompanied by a significant increase in plasma vasopressin concentration. To delineate the role of vasopressin in the pathogenesis of congestive heart failure, the acute hemodynamic and aquaretic effects of Conivaptan (YM087, 4′-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a combined vasopressin V1A and V2 receptor antagonist, were assessed in rats with heart failure induced by myocardial infarction. Left coronary artery ligation resulted in decreased left ventricular systolic pressure and first derivatives of left ventricular developed pressure, as well as increased left ventricular end-diastolic pressure, lung and right ventricular weight. Single oral administration of Conivaptan (0.3 to 3.0 mg/kg) dose-dependently increased urine volume and decreased urine osmolality in heart failure rats. Furthermore, Conivaptan (3.0 mg/kg) attenuated the changes in left ventricular end-diastolic pressure, lung and right ventricular weight induced by heart failure while reducing blood pressure. These results show that vasopressin plays a significant role in elevating vascular tone through vasopressin V1A receptors and plays a major role in retaining free water through vasopressin V2 receptors in this model of congestive heart failure. Additionally, Conivaptan, with its dual vasopressin V1A and V2 receptor-inhibiting properties, could exert a beneficial effect on cardiac function in the congestive heart failure rat model.
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EFFECT OF Conivaptan, A COMBINED VASOPRESSIN V1a AND V2 RECEPTOR ANTAGONIST, ON VASOPRESSIN-INDUCED CARDIAC AND HAEMODYNAMIC CHANGES IN ANAESTHETISED DOGS
Pharmacological research, 2002Co-Authors: Takeyuki Yatsu, Yuichi Tomura, Atsuo Tahara, Kohichi Wada, Toshiyuki Kusayama, Yukinori Arai, Motonori Aoki, Junko TsukadaAbstract:Abstract The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V 1a and V 2 receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) infusion of AVP on cardiovascular parameters and the effect of Conivaptan (YM087, 4′-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5- d ][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V 1a /V 2 receptor antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12–4 mU kg −1 min −1 ) dose-dependently produced decreases in the cardiac contractility indicator LV d P /d t max and cardiac output (CO) and increases in left ventricular end-diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes accurately mimic the cardiovascular symptoms of congestive heart failure. The i.v. bolus injection of Conivaptan (0.1 mg kg −1 ) rapidly attenuated the AVP (4 mU kg −1 min −1 )-induced decrease in CO and reversed the AVP-induced elevation in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan demonstrated the ability to dramatically improve the impaired cardiovascular parameters induced by AVP. The results suggest the potential usefulness of Conivaptan in treating congestive heart failure.
Wladimiro Jiménez - One of the best experts on this subject based on the ideXlab platform.
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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, 2003Co-Authors: Guillermo Fernandezvaro, Josefa Ros, Carmen Cano, Vicente Arroyo, Francisca Rivera, Juan Rodés, Pilar Cejudomartin, Wladimiro JiménezAbstract: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.
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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, 2003Co-Authors: Guillermo Fernández-varo, Josefa Ros, Pilar Cejudo-martı́n, Carmen Cano, Vicente Arroyo, Francisca Rivera, Juan Rodés, Wladimiro JiménezAbstract: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.