Vasopressin receptor heart failure

Several nonpeptidic, orally active vasopressin receptor antagonists have been developed. The dual V1A/V2R antagonist conivaptan is used in the treatment of hyponatraemia and could also become useful for diseases such as congestive heart failure, in which increased peripheral resistance and dilutional hyponatremia both are present [4]. Side effects of conivaptan include headache, injection site reactions, vomiting, diarrhoea, constipation and thirst. 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

The most important stimulus to the release of ANP from the heart is atrial stretch via mechanosensitive ion channels. ANP release is also increased by volume expansion, changing from the standing to the supine position, and exercise. ANP release can also be increased by sympathetic stimulation via aiA-adrenoceptors, endothelins via the -receptor subtype (see below), glucocorticoids, and vasopressin. Plasma ANP concentration increases in various pathologic states, including heart failure, primary aldosteronism, chronic renal failure, and inappropriate ADH secretion syndrome. 

Conivaptan Antagonist of vasopressin (and V2) receptors Vasodilation Potential use in hypertension and heart failure hyponatremia... 

When oxytocin is used judiciously, serious toxicity is rare. The toxicity that does occur is due either to excessive stimulation of uterine contractions or to inadvertent activation of vasopressin receptors. Excessive stimulation of uterine contractions before delivery can cause fetal distress, placental abruption, or uterine rupture. These complications can be detected early by means of standard fetal monitoring equipment. High concentrations of oxytocin with activation of vasopressin receptors can cause excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death. Bolus injections of oxytocin can cause hypotension. To avoid hypotension, oxytocin is administered intravenously as dilute solutions at a controlled rate. 

A group of nonpeptide antagonists of vasopressin receptors is being investigated for use in patients with hyponatremia or acute heart failure, which is often associated with elevated concentrations of vasopressin. Conivaptan has high affinity for both Vla and V2 receptors. Tolvaptan has a 30-fold higher affinity for V2 than for Vi receptors. In several clinical trials,... 

Udelson JE, Smith WB, Hendrix GH, Painchaud CA, Ghazzi M, Thomas I, Ghah JK, Selaru P, Chanoine F, Pressler ML, Konstam MA. Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001 104(20) 2417-23. 

Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J, Zampino M, Orlandi C Tolvaptan Investigators. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure results from a double-blind, randomized trial. Circulation 2003 107(21) 2690-6. 

Russell SD, DeWald T. Vasopressin receptor antagonists. Therapeutic potential in the management of acute and chronic heart failure. Am J Cardiovasc Drugs. 2003 3 13-20. 

Due to the dual renal and vascular action of AVP, scientists at Yamanouchi Pharmaceuticals became interested in the identification of dual Vla/V2 vasopressin receptor antagonists, particularly because such agents were anticipated to be of unique utility in the treatment of congestive heart failure (CHF), where aberrant AVP secretion appeared responsible for both the onset of hypervolemic hyponatremia and deleterious increases in vascular resistance.14 The resulting drug discovery program ultimately lead to the identification of conivaptan HCl (1). 

OTHER WATER-RETAINING STATES In patients with congestive heart failure, cirrhosis, or nephrotic syndrome, ejfective blood volume often is reduced, and hypovolemia frequently is exacerbated by the liberal use of diuretics. Since hypovolemia stimulates vasopressin release, patients may become hyponatremic owing to vasopressin-mediated retention of water. The development of potent orally active receptor antagonists and specific inhibitors of water chaimels in the collecting duct would provide an effective therapeutic strategy not only in patients with SIADH but also in the much more common setting of hyponatremia in patients with heart faftme, cirrhosis, or nephrotic syndrome. 

The major receptor-mediated adverse effect is water intoxication, which can occur with desmopressin or vasopressin. Many drugs, including carbamazepine, chlorpropamide, morphine, tricyclic antidepressants and NSAIDs, can potentiate the antidiuretic effects of these peptides, while lithium, demeclocycline and ethanol can attenuate the antidiuretic response to desmopressin. Desmopressin and vasopressin should be used cautiously when a rapid increase in extracellular water may impose risks (e.g., in angina, hypertension, and heart failure) and should not be used in patients with acute renal failure. Patients receiving desmopressin to maintain hemostasis should be... 

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