Abstract 1599: Beneficial Renal and Anti-Aldosterone Actions of Combined B-Type Natriuretic Peptide and Vasopressin-2 Receptor Antagonism with Tolvaptan in Experimental Congestive Heart Failure
Background: Hemodynamic and neurohumoral function can affect the efficacy of diuretic therapy in congestive heart failure (CHF). Arginine vasopressin increases water reabsorption via the V2 receptor in the collecting duct (CD), whereas B-type natriuretic peptide (B) decreases Na reabsorption also in the CD. We hypothesized that coadministration of the V2-receptor antagonist tolvaptan (T) and B would mediate a diuresis and natriuresis without adversely affecting renal hemodynamics in experimental CHF.
Methods: CHF was induced in dogs by tachypacing. Cardiorenal function was assessed in an acute experiment. After baseline measurements, one group received T alone (0.1 mg/kg IV bolus; n=6), one received infusion of B (50 ng/kg/min; n=6) and one received T+B (n=5). *p<0.05 between groups.
Results: Mean arterial pressure increased with T, decreased with B, and was unchanged with T+B (+5±1 vs −14±1 vs −1±1 mmHg*). Pulmonary capillary wedge pressure was unchanged with T and decreased with T+B, but more so with B alone (*B vs T, T+B). Renal blood flow and glomerular filtration rate were preserved in all groups. Urine flow increased most with T+B (T, B, and T+B: +0.4±0.1 vs +0.9±0.4 vs +2.4±0.5 mL/min, *T+B vs T, B), as did electrolyte-free water excretion. T was not natriuretic, whereas B and T+B were (+0±0 vs +76±40 vs +28±10 uEq/min,*T vs B, T+B). Distal fractional Na reabsorption increased with T, but not with B and T+B*, while proximal fractional Na reabsorption decreased with B* and T+B*. Aldosterone, which increased with T and B, was suppressed by T+B (*T vs T+B).
Conclusions: Coadministration of T and BNP enhanced urine flow and electrolyte-free water excretion greater than either agent alone suggesting a novel synergism possibly linked to a greater reduction in proximal tubular reabsorption of sodium and water with enhanced fluid delivery to the CD. Unlike T alone, co-administration with BNP also induced a natriuresis and reduced aldosterone. Whereas T increased and BNP decreased mean arterial and renal perfusion pressure, T+BNP had a neutral effect. In conclusion, tolvaptan and BNP coadministration may be a beneficial and novel physiologic strategy to counter sodium and water retention and aldosterone activation in CHF while preserving renal perfusion pressure.