Volume 7 Supplement 1
Coadministration of B-type natriuretic peptide and the vasopressin-2 receptor antagonist tolvaptan: a novel physiologic strategy to enhance water and sodium excretion without adversely affecting renal or neurohumoral function in experimental congestive heart failure
© Costello-Boerrigter et al; licensee BioMed Central Ltd. 2007
Published: 25 July 2007
Efficacy of diuretic therapy in congestive heart failure (CHF) can be affected by renal hemodynamics, neurohumoral activation, and diuretic-induced changes in renal function. Physiological strategies that enhance water and sodium (Na) excretion while maintaining renal function are a high priority. Arginine vasopressin increases water reabsorption after binding to the V2 receptor in the collecting duct (CD). In contrast, B-type natriuretic peptide (B) decreases Na reabsorption via the particulate guanylyl cyclase linked natriuretic peptide A receptor (NPR-A) 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 and results
Severe CHF was induced in 3 groups of dogs by tachypacing. On day 11 cardiorenal function was assessed. 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 both drugs (n = 5). Changes from baseline were compared with 1-ANOVA. *p < 0.05. Mean arterial pressure increased with T, decreased with B, and was unchanged with T+B (+5 ± 1 vs -14 ± 1 vs -1 ± 1 mmHg, *between groups) with renal perfusion pressure paralleling changes in mean arterial pressure. 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 (GFR) were preserved in all groups. Increase in urine flow was greatest with combined V2 antagonism with T and NPR A activation with 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). Electrolyte-free water excretion was higher with T+B compared to T and B*. T was not natriuretic, whereas B and T+B were (+0 ± 0 vs +76 ± 40 vs +28 ± 10 Eq/min,*T vs B, T+B). Distal fractional Na reabsorption increased with T, but not with B and T+B*. Decreases in proximal fractional Na reabsorption occurred only with B* and T+B*. Plasma renin activity was unchanged with T, but suppressed with B and T+B (*T vs B) while aldosterone which was increased with T and B, was suppressed by T+B (*T vs T+B).
Coadministration of tolvaptan and BNP enhanced urine flow and electrolyte-free water excretion greater than either alone demonstrating a novel mechanism for aquaresis in CHF by co-targeting of the V2 and NPR-A receptor in the CD and linked in part to inhibition of proximal tubular sodium and water reabsorption during co-administration. Unlike tolvaptan alone, co-administration with BNP also induced a natriuresis. Whereas tolvaptan increased and BNP decreased mean arterial and renal perfusion pressure, tolvaptan and BNP coadministration had a neutral effect. Thus, tolvaptan and BNP coadministration may be an important and novel physiologic strategy to counter sodium and water retention in CHF.
This article is published under license to BioMed Central Ltd.