A hallmark of Congestive heart failure (CHF) is avid sodium and water retention by the kidney in response to decreases in cardiac output and arterial pressure and activation of sodium-and water-retaining hormones. Because fluid retention further increases the load on an already failing heart, congestive symptoms such as dyspnea and peripheral edema consequently develop. Indeed, the major reason for hospitalization for acute decompensated heart failure is congestive symptoms; thus therapies to reduce this complication of heart failure are of high priority.
Loop diuretics have for decades been a mainstay to treat congestion by inhibiting sodium reabsorption in the loop of Henle with the secondary action of passively increasing the excretion of water. As saluretics, loop diuretics may become less efficient in the setting of hyponatremia and may worsen hyponatremia. Furthermore, despite the widespread and long history of use of diuretics in CHF, some detrimental actions of diuretics continue to emerge. Importantly, by increasing distal tubular delivery of sodium, loop diuretics activate the tubuloglomerular feedback mechanism, which causes vasoconstriction of the afferent arteriole and a reduction in renal blood flow (RBF) (3
). Thus loop diuretics may compromise renal function, which has been identified in retrospective analyses as a powerful predictive factor for CHF mortality (6
). Potassium-wasting diuretics, which have been associated with increased mortality, can also lead to serum potassium depletion, which, in turn, can promote arrhythmias (4
). This has prompted efforts to develop more physiological strategies to treat volume overload.
Similar to other neurohormones that are activated in CHF, circulating arginine vasopressin (AVP) is elevated in patients with CHF (12
). AVP, a nonapeptide, is secreted by the posterior pituitary gland in response to reduced cardiopulmonary blood volume, reduced systolic blood pressure, or increased plasma osmolality. AVP acts via three receptor types: V1A
), and V2
receptors are located in vascular smooth muscle cells, where they mediate vasoconstriction, and in the myocardium, where they may affect hypertrophy (24
receptors are located in the anterior pituitary and mediate adrenocorticotropin release. V2
receptors are located in the renal collecting duct, where AVP binding to the V2
receptor leads to a rise in intracellular cAMP. This promotes renal water reabsorption via translocation of intracellular vesicles containing the water channel aquaporin-2 into the apical plasma membrane and increased transcription of aquaporin-2 (19
). Taken together, it would appear as though blocking the renal effects of AVP with a selective V2
-receptor antagonist would produce a diuresis and maintain renal function by antagonizing elevated endogenous AVP levels rather than unphysiologically blocking sodium reabsorption.
Tolvaptan, which is named OPC-41061 in earlier literature, is a modified benzazepine derivative that acts as a selective V2
-receptor antagonist (). Its synthesis has been described in detail by Kondo et al. (14
). The potent aquaretic properties of this V2
antagonist in rats and its pharmacological profile were reported by Yamamura et al. (27
). Its oral availability now permits studies in humans that address the physiological significance of the V2
receptor in human CHF and also the development of a V2
antagonist as therapeutic agents.
Fig. 1 Chemical structure of tolvaptan. The chloride on the 7 position of the benzazepine and the methyl group on the 2 position of the aminobenzoyl moiety give tolvaptan good oral availability (14).
Gheorghiade and colleagues (9
) performed the first human studies using this V2
antagonist in patients with CHF. In a double-blind, placebo-controlled study, these investigators examined the effects of V2
antagonism in humans with CHF. They found that, on the first day, V2
-blocked patients had an increase in urine volume, and this was accompanied by a decrease in weight that was maintained throughout the study. In a subsequent study, Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV), these investigators also again found that V2
-receptor antagonism improved congestion with a decrease in body weight without causing electrolyte abnormalities or worsening renal function (8
To date, the role of V2 receptors in the regulation of renal function in human CHF remains poorly defined. Therefore, the objective of the present study was to define the role of V2 receptors in renal hemodynamics as well as in the control of regulation of water and sodium excretion. We also compared the renal response of V2-receptor antagonism with the response to acute furosemide. We hypothesized that V2-receptor antagonism would have a diuretic effect comparable to furosemide but would not impair renal hemodynamics or induce plasma electrolyte abnormalities in humans with stable CHF.