Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complex neurohormonal interactions dictate the body's volume status in different disease states. Besides the known pathologic activation of the renin-angiotensin-aldosterone axis and the effect of the adrenergic system, arginine vasopressin (AVP) represents a key element that is responsible for volume homeostasis. Serum AVP levels have been shown to be chronically elevated in different pathologic conditions that exhibit an imbalance in volume status, particularly in congestive heart failure. Evidently, elevated levels of AVP play an important role in the pathogenesis and progression of these diseases. AVP has many other receptor-mediated deleterious effects on vascular smooth muscles and cardiomyocytes. These effects are an integral part of the neurohormonal milieu in patients with heart failure. This assumption has propelled agents that antagonize the effects of vasopressin receptors to the forefront of clinical research, especially in heart failure management. This paper reviews current knowledge on conivaptan, a novel dual V1a/V2 vasopressin receptor antagonist.
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PMID:Conivaptan: a selective vasopressin antagonist. 1684 41

The inability to effectively regulate volume status is a major consequence of acute heart failure syndromes (AHFS). A variety of pathophysiologic processes contribute to this impairment, most notably neurohormonal activation of the renin-angiotensin-aldosterone system, arginine vasopressin, and the sympathetic nervous system. As a result, addressing volume overload is one of the most challenging aspects of AHFS management. Neurohormonal activation leads to substantial changes in hemodynamics and myocardial remodeling, which further contribute to the severity of heart failure (HF) disease and thereby cyclically increase the risk of further neurohormonal activation. Pulmonary capillary wedge pressure is a dependable reflection of volume status and has been used as a surrogate marker in recent studies to assess disease progression in response to innovative HF treatment strategies. Future approaches to HF treatment should focus on the more accurate assessment and management of volume status in an effort to improve patient care.
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PMID:Pathophysiology of volume overload in acute heart failure syndromes. 1711 94

Chronic vagal stimulation (VS) markedly improved long-term survival in the heart failure rats. We examined the effects of VS on arginine vasopressin (AVP) secretion and salt ingestion in heart failure rats after myocardial infarction (MI). Surviving rats after MI were randomly assigned to two groups. One group was treated with sham stimulation (SS), and the other group was treated with VS. All rats could access water and 1.8% NaCl solution ad libitum. Treatment started at 2 weeks after MI, and continued for 6 weeks. We monitored drinking behavior during treatment. At the end of treatment, we measured hemodynamics and plasma levels of AVP and brain natriuretic peptide (BNP). The plasma AVP and BNP levels were significantly lower in the VS group than the SS group. VS significantly inhibited the ingestion of 1.8% NaCl solution. The normalized biventricular weight of the VS group was significantly lower than that of the SS group. The VS group had significantly lower left ventricular end-diastolic pressure, and higher cardiac index than the SS group. In conclusion, these results suggest that chronic VS regulates the water balance by suppression of plasma AVP level and salt ingestion in the heart failure rats after MI.
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PMID:Chronic vagal stimulation decreased vasopressin secretion and sodium ingestion in heart failure rats after myocardial infarction. 1728 Oct 99

Tolvaptan is an orally effective nonpeptide arginine vasopressin (AVP) V(2)-receptor antagonist synthesized by Otsuka Pharmaceutical Co., Ltd. In in vitro receptor-binding studies, tolvaptan blocked the binding of [(3)H]AVP to human V(2) receptors with 29-fold greater selectivity than that for V(1a) receptors, and showed no inhibition of V(1b) receptors. Tolvaptan inhibited not only the binding of [(3)H]AVP but also the AVP-induced production of cyclic AMP in human V(2)-receptor-expressing HeLa cells. In addition, tolvaptan has no intrinsic V(2) receptor agonistic effect. In in vivo studies, tolvaptan showed marked aquaresis in healthy and diseased animals. In rat models with acute and chronic hyponatremia, tolvaptan improved hyponatremia, resulting in the prevention of death, and improved organ water retention. Tolvaptan reduced cardiac preload without unfavorable effects on renal functions, systemic hemodynamics, or circulating neurohormones in dogs with heart failure (HF). Furthermore, in animal models of human polycystic kidney disease (PKD), tolvaptan showed a decrease in kidney weight as well as in cyst and fibrosis volume. In clinical trials including the "ACTIV in CHF" study, tolvaptan in addition to standard therapy increased fluid loss resulting in decreased body weight, and improved edema and serum sodium without affecting blood pressure, heart rate, or renal functions in patients with HF. In patients with hyponatremia, treatment with tolvaptan without fluid restriction appeared to be more effective than fluid restriction alone at correcting hyponatremia without an increase in adverse events. A phase III trial EVEREST is currently being conducted to evaluate the long-term efficacy and safety of tolvaptan in hospitalized patients with severe HF. In conclusion, tolvaptan offers the possibility of a useful therapy in hyponatremia, congestive heart failure, and various other diseases that are associated with volume overload. Furthermore, tolvaptan is also expected to be effective in the treatment of PKD.
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PMID:Tolvaptan, an orally active vasopressin V(2)-receptor antagonist - pharmacology and clinical trials. 1744 84

Similar to other neurohormones that are activated in chronic heart failure (CHF), circulating arginine vasopressin (AVP) is elevated in patients with CHF. The precise role of AVP in the pathophysiology of cardiovascular disease is controversial. AVP is a peptide hormone that contributes to water retention and vasoconstriction in CHF through effects on V(2) and V(1a) receptors, respectively. In the present study, the effect of V(2) receptor (V(2)R) blockade using tolvaptan was assessed in a rat model of myosin-induced experimental autoimmune myocarditis. CHF was elicited in Lewis rats by immunization with porcine cardiac myosin, and 28 days after immunization rats were treated for 28 days with oral tolvaptan (3 or 10mg/(kg day)) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic and diastolic function. Chronic V(2)R blockade increased urine volume and urinary AVP excretion and decreased urine osmolality but had no natriuretic effect, and as a result caused increases in plasma osmolality and sodium. High doses of tolvaptan markedly elevated electrolyte-free water clearance. V(2)R blockade did not activate the renin-angiotensin system, not influence cardiac remodeling, cardiac function, or survival. The upregulation of aquaporin 2 protein in the kidney of CHF rats was inhibited by the administration of V(2)R antagonist. These results suggest that in a rat model of CHF, AVP plays a major role in water retention through the renal V(2)R.
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PMID:Effects of nonpeptide vasopressin V2 antagonist tolvaptan in rats with heart failure. 1772 Jan 44

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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PMID:Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. 1791 59

Hyponatremia is the most common electrolyte abnormality in hospitalized patients and is associated with increased mortality, morbidity, and longer hospital stays. Because patients with this disorder are often asymptomatic, hyponatremia is frequently undiagnosed and untreated. Serious neurologic complications may ensue when hyponatremia develops too rapidly or the serum sodium concentration ([Na(+)]) falls below 120 mEq/l. Hypotonic dilutional hyponatremia is the most common form of this disorder, which may present as euvolemic [e.g., due to failure to suppress secretion of arginine vasopressin (AVP)] or hypervolemic (due to edema-forming conditions such as heart failure). Hypovolemic hyponatremia is due to conditions promoting renal or extrarenal sodium loss. Because AVP, which is intimately involved in regulating osmolar homeostasis, is often elevated in patients with hypervolemic and euvolemic hyponatremia, treatments that directly target the effects of this hormone may provide a more predictable correction of serum [Na(+)] than those traditionally used. The AVP receptor antagonists (conivaptan, tolvaptan, lixivaptan, and satavaptan) are a new class of agents that have been shown to normalize serum [Na(+)] by promoting aquaresis - the electrolyte-sparing excretion of free water.
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PMID:Mechanisms, risks, and new treatment options for hyponatremia. 1843 17

Acute decompensated heart failure accounts for more than 1 million hospitalizations in the USA every year. Currently, the most common treatment for symptom relief is the use of loop diuretics, despite recent concerns for potential adverse effects. With the growing understanding of the role of neurohormonal dysregulation in the pathophysiology of heart failure, there has been increasing interest in novel pharmacologic therapies targeting specific neurohormonal axes. Serum arginine vasopressin is a potent vasoconstrictor, as well as an antidiuretic, and serum concentrations are upregulated in heart failure. Tolvaptan, a vasopressin receptor antagonist, has been shown to improve diuresis and symptom relief without adversely affecting renal function, and may be a promising novel therapeutic agent in the growing population of patients with heart failure.
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PMID:Role of tolvaptan in acute decompensated heart failure. 1851 Apr 77

Endothelin 1 (ET-1) is increased in heart failure, both in plasma and within the central nervous system. Centrally, ET-1 induces sympathetic hyperactivity and arginine vasopressin (AVP) secretion. Both sympathetic activity and AVP secretion are regulated by the arterial baroreflex, which is typically impaired in heart failure. We hypothesized that central blockade of ETA receptors (ETAR) alters the baroreflex response of heart rate, renal sympathetic nerve activity (RSNA), and plasma AVP levels in a cardiomyopathic model of heart failure. Female Sprague-Dawley rats received weekly intraperitoneal injections of doxorubicin 2.5 mg x kg(-1) (doxorubicin heart failure, doxo-HF) or saline vehicle (control). After 8 weeks, they were instrumented, conditioned to the study environment, and then studied in the awake, non-restrained state. Baseline mean arterial pressure (MAP), RSNA, and plasma osmolality were similar in both groups, but heart rate (p<0.02), left ventricular pressure (p<0.001), and plasma AVP (p<0.01) were higher in the doxo-HF group. ET-1 dose dependently increased MAP, but the rise was significantly attenuated in doxo-HF rats at all doses. Baseline baroreflex control of heart rate and RSNA was similar in both groups. ETAR blockade with 4 nmol BQ123 i.c.v. significantly decreased both the upper plateau (p<0.05) and the range (p<0.05) of the baroreflex response of both heart rate and RSNA in doxo-HF but not in control rats. Despite higher basal plasma levels of AVP, ET-1 evoked a rise in plasma AVP of 13.6+/-3.2 pg x mL(-1) in doxo-HF compared with 0.4+/-0.4 pg x mL(-1) in control rats (p<0.001). To account for the blunted pressor response to ET-1 in the doxo-HF rats, gain of AVP release was calculated as DeltaAVP/DeltaMAP and was also found to be significantly greater in the doxo-HF rats (p<0.001). BQ123 prevented the rise in AVP and restored the gain in doxo-HF rats to that seen in controls. Thus, central ETAR contribute to the sympathoexcitation and AVP responses observed in heart failure due to doxorubicin cardiomyopathy.
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PMID:Central endothelin: effects on vasopressin and the arterial baroreflex in doxorubicin heart failure rats. 1851 97

Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, oxytocin administration, hypothyroidism, glucocorticoid, and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the nonosmotic stimulation of arginine vasopressin release with up-regulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin resistant. They may involve several factors, such as impaired countercurrent concentration secondary to down-regulation of Na-K-2Cl cotransporter. Vasopressin-resistant down-regulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.
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PMID:Vasopressin and aquaporin 2 in clinical disorders of water homeostasis. 1851 89


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