Abstract 584: Simultaneous Antagonism of the V2 Receptor with Tolvaptan and Activation of the Natriuretic Peptide A-Receptor with B-Type Natriuretic Peptide: A Novel Strategy to Physiologically Enhance Water and Sodium Excretion Without Adversely Affecting Renal Function in a Canine Model of Congestive Heart Failure
Background: Water and sodium (Na) retention are hallmarks of congestive heart failure (CHF). While widely employed, conventional diuretics may adversely affect renal function. Therefore, physiological strategies that enhance water and Na excretion while maintaining renal function are a high priority. Arginine vasopressin (AVP) increases water reabsorption after binding to the V2 receptor in the collecting duct (CD). In contrast, B-type natriuretic peptide (BNP) decreases Na reabsorption via activation of the NPR-A receptor also in the CD and at higher doses also in the proximal tubule. We hypothesized that coadministration of the V2-receptor antagonist tolvaptan (TLV) and BNP would mediate a potent diuresis and natriuresis without adversely affecting renal hemodynamics in experimental CHF. We also assessed plasma and urinary excretion of AVP.
Methods: Severe CHF was induced in 2 groups of dogs by tachypacing. On day 11 cardiorenal function was assessed. One group received TLV alone (0.1 mg/kg IV bolus; n=6), whereas the other group received infusion of BNP (50 ng/kg/min) in addition to TLV (n=5).
Results: Renal hemodynamics were preserved in both groups. TLV alone increased urine flow from 0.07±0.01 to 0.48±0.09 mL/min, while urinary Na excretion (UNaV) remained unchanged. TLV+BNP-50 increased urine flow from 0.17±0.07 to 2.58±0.47 mL/min and UNaV from 1±1 to 77±23 uEq/min while decreasing proximal fractional Na reabsorption (all p<0.05 vs. TLV alone). TLV alone increased plasma aldosterone and distal fractional Na reabsorption, both of which were prevented with BNP-50. In addition, while plasma AVP did not change with TLV or TLV+BNP, urinary AVP excretion markedly increased with TLV+BNP (from 16±5 to 694±196 pg/min) as compared to TLV alone (from 1±1 to 69±23 pg/min).
Conclusions: TLV and BNP coadministration enhances aquaresis and natriuresis through proximal and distal tubular actions without changing renal hemodynamics. Further, TLV with BNP uniquely enhances urinary elimination of AVP warranting further study. We conclude from these findings in experimental CHF that simultaneously antagonizing the V2 receptor by TLV and activating the NPR-A receptor with BNP may be a novel and physiologic diuretic and natriuretic strategy in overt CHF.