Vasopressin and vasopressin antagonists in heart failure and hyponatremia

Abstract

Increased synthesis of arginine vasopressin (AVP) plays a critical role in fluid retention and hyponatremia in patients with heart failure. The AVP receptor antagonists constitute a new class of agents that are promising in the management of hyponatremia and congestion. Three of these agents--conivaptan, tolvaptan, and lixivaptan--have been studied in clinical settings. All are effective in inducing aquaresis (ie, electrolyte-free water excretion) and normalizing serum sodium concentration. They are well tolerated without causing electrolyte disorders, hypotension, or renal impairment. Conivaptan has been approved by the US Food and Drug Administration for short-term intravenous treatment of euvolemic hyponatremia of variable etiology but has not been adequately studied in heart failure. The addition of tolvaptan to standard therapy in hospitalized patients with heart failure has led to symptomatic improvement and decreased body weight, but there is no long-term clinical benefit. Early data on lixivaptan in heart failure suggest a dose-dependent aquaresis effect, and larger studies are under way.

Neurohormonal activation in canine degenerative mitral valve disease: implications on pathophysiology and treatment

“…In human beings, the role of AVP antagonism in long‐term management of heart failure is questionable. V 2 or combined V 1a and V 2 receptor antagonists increase free water excretion and increase serum sodium concentrations, but do not delay the progression of heart failure or reduce mortality (Farmakis and others 2008, Schweiger and Zdanowicz 2008).…”

Heart Failure and Chronic Kidney Disease in Type 2 Diabetes

“…11 Angiotensin II and aldosterone stimulate the release of natriuretic peptides (atrial natriuretic peptide and B-type natriuretic peptide, also released in response to other neurohormonal and mechanical stimuli, such as increased cardiac wall stress, which reduces peripheral vascular resistance, myocardial fibrosis and hypertrophy and reduces aldosterone secretion), arginine vasopressin (causing vasoconstriction, fluid retention and hyponatremia), pro-inflammatory cytokines, macrophage-derived galectin-3 (causing cardiac and renal fibrosis and remodeling, inflammation and oxidative stress). 11,16,17 In HF, the natriuretic peptide system is not able to counterbalance the RAAS and sodium-retention it induces, therefore there is a fluid overload, increased venous return and cardiac congestion. 11,18 This creates and accentuates a vicious cycle that aggravates the progression of the disease (Figure 1).…”

Potential of Nonpeptide (Ant)agonists to Rescue Vasopressin V2 Receptor Mutants for the Treatment of X‐linked Nephrogenic Diabetes Insipidus

“…Because of potential interference with the cytochrome P450 metabolic pathway, however, the trial with SR49059 had to be discontinued. Recently, the cell‐permeable antagonist OPC41061 (Tolvaptan) has been approved in the USA and Europe for the treatment of hyponatraemia in the syndrome of inappropriate antidiuretic hormone secretion and congestive heart failure (26, 27). This positive safety assessment, together with OPC41061 being an efficient pharmacological chaperone at clinically feasible concentrations, paves the road for clinical trials to test the potential of Tolvaptan for treating NDI in the future.…”