Arginine vasopressin as a target in the treatment of acute heart failure

Table 1 Location and effect of vasopressin receptors[13,17,21,23-25]

Receptor subtype	Location	Action	Cardiovascular end effects
V1A	Liver, vascular smooth muscle, platelets, adrenal cortex, kidney, spleen, adipocytes, reproductive organs, brain, lung	Vasoconstriction	Left ventricular hypertrophy and remodeling, increase in afterload, myocyte hypertrophy
V1B	Corticotroph cells, pancreas, adrenal medulla, possibly kidney	Release of adrenocorticotropic hormone	May mediate release of aldosterone
V2	Renal collecting ducts	Antidiuresis via increased water permeability	Hyponatremia, edema, increase in preload, pulmonary vascular congestion and left sided filling pressures

Table 2 Summary of key studies of vasopressin antagonists

Vasopressin antagonist	Study	Design	Endpoint	Results
Lixivaptan (VPA985)	Martin et al[30], 1999	21 NYHA II and III patients randomized to placebo vs one of four doses (30, 75, 150, 250 mg)	Urinary AQP-2 excretion	Decrease in urinary AQP-2 excretion, increased solute-free water clearance and urine output, decreased urinary osmolality
	Wong et al[32], 2003	44 hyponatremic patients randomized to placebo vs one of three doses (25, 125, or 250 mg bid) over a 7-d inpatient stay	Correction of hyponatremia	Increased free water clearance and serum sodium
	Abraham et al[31], 2006	42 patients with mild to moderate CHF randomized to placebo vs ascending single-dose drug (10-400 mg)	24 h urine volume and serum sodium	Increased urine volume at 4 h and 24 h, increased serum sodium at higher doses
	BALANCE[35]	650 CHF patients randomized to placebo vs lixivaptan	Correction of hyponatremia	Increased serum sodium levels
Conivaptan	Udelson et al[41], 2001	142 NYHA III and IV patients randomized to placebo vs single IV-dose (10, 20, 40 mg)	Effect on hemodynamic parameters	Reduced PCWP, RAP Increased urine output
	Goldsmith et al[42], 2008	Dose-ranging pilot study of IV conivaptan in 170 randomized patients with worsening CHF	Assessment of global and respiratory status Effect on urine output	No change in status Increased urine output
	Russell et al[43], 2003	143 patients randomized to placebo vs one of three po doses	Change in time to reach 70% of peak O2 consumption	No change in exercise endpoint
	Zeltser et al[45], 2007	84 euvolemic or hypervolemic hyponatremic patients randomized to placebo vs IV conivaptan for 4 d (40 or 80 mg/d)	Change in serum sodium, measured by area under the sodium-time curve	Increased serum sodium
	Annane et al[46], 2009 (The Conivaptan Study Group)	83 euvolemic or hypervolemic hyponatremic patients randomized to placebo vs po conivaptan for 5 d (40 or 80 mg/d)	Change in serum sodium, measured by area under the sodium-time curve	Increased serum sodium
Tolvaptan (OPC-41061)	Gheorghiade et al[47], 2003	254 patients randomized to placebo vs 30, 45 or 60 mg/d for 25 d	Change in body weight	Decreased body weight, increased urine output, increased serum sodium, decreased edema
	Gheorghiade et al[48], 2004 (ACTIV CHF)	Phase II study in 319 patients randomized to placebo vs 30, 60, or 90 mg/d for 60 d	Change in body weight at 24 h Heart failure outcomes	Significant decrease in body weight No change in worsening heart failure at 60 d
	Gheorghiade et al[42,50], 2007 (EVEREST)	Large 4133 patient multi-center randomized study of short and long term effects of tolvaptan in ADHF	CHF symptoms Mortality and heart failure related morbidity	Improvement in some CHF symptoms No difference in long-term mortality or morbidity
	Udelson et al[54], 2007 (METEOR)	240 patients, NYHA II or III, randomized to placebo vs tolvaptan	LVEDV	No change in LVEDV at one year
	Udelson et al[55], 2008	181 patients, NYHA III and IV, randomized	Hemodynamic effects	Decreased PCWP, RAP, PAP

IV: Intravenous; PO: Oral; PCWP: Pulmonary capillary wedge pressure; RAP: Right atrial pressure; O2: Oxygen; CHF: Congestive heart failure; ADHF: Acute decompensated heart failure; LVEDV: Left ventricular end diastolic volume; PAP: Pulmonary artery pressure.