Vasopressin Antagonism and Sodium Excretion

Presentation Number: SUN 534
Date of Presentation: April 2nd, 2017

Geraldine Skurnik*1, Ellen W. Seely2, Noha Ahmed1, Michelle Ngeouyang1 and Jonathan S Williams2
1Brigham and Women's Hospital, Boston, MA, 2Brigham & Women's Hospital, Harvard Medical School, Boston, MA

Abstract

Vasopressin is known for its primary role in water and osmosis regulation through its binding with V2 receptors (V2R). Recent reports suggest V2R may play a role in sodium (Na) reabsorption. Accordingly, we hypothesized that administration of the V2R antagonist tolvaptan would increase Na excretion in healthy subjects.

Methods: Healthy subjects were recruited to participate in a randomized, double blind, placebo-controlled, parallel arm, physiologic study at Brigham and Women’s Hospital (BWH; Boston, MA) to assess the effect of V2R antagonism on Na excretion. After a 1-week low dietary salt run-in period (10 mEqNa/day), subjects were admitted for 5 days to the BWH clinical research center and randomized to daily (7:00AM) oral administration of either placebo, 15mg or 30 mg tolvaptan. Subjects could drink water ad lib throughout the protocol. After overnight supine posture and study drug administration, they received 400cc IV saline (0.9% NaCl) infusion over one hour followed by hourly urine collections for 6hrs. Participants then received daily study drug and consumed a high salt diet (250mEq Na/day) for 4 days. Urine collections were obtained every 12 hrs (7:00AM-7:00PM and 7:00PM-7:00AM). Mean urine Na excretion during the saline infusion and the oral loading phase was compared by study drug using a mixed design ANOVA.

Results: 23 subjects (mean age 27±8 yrs, BMI 22.9±3.2 kg/m2, 60% female) completed the study. The 24h urine Na at the end of the low salt diet run-in period differed significantly between groups (placebo: 20.4±10.4 mmol, 15mg tolvaptan: 17.2±11.1 mmol, 30mg tolvaptan: 23.3±30.7 mmol; p=0.007). There were no other statistically significant differences between the 3 groups.

In response to saline infusion, cumulative 6hr urine output increased, for subjects receiving tolvaptan (placebo: 2291±702ml, 15mg tolvaptan: 3067±791ml, 30mg tolvaptan: 3633±996ml; p=0.02), based on its antagonistic ADH action. After adjusting for run-in urine Na excretion, randomization to tolvaptan (30mg) significantly altered hourly Na excretion compared to placebo, with lower excretion observed (p<0.01).

During oral salt loading, urinary Na excretion increased from baseline across the 4 days in all 3 groups. Tolvaptan significantly altered nighttime (7:00 PM-7:00 AM) Na excretion with less Na excretion observed relative to placebo (p< 0.001), but no consistent effect of tolvaptan on daytime (7:00 AM-7:00 PM) urine Na was observed. There was no change in LFT, serum sodium or glucose, blood pressure or heart rate.

Conclusion: Contrary to our hypothesis, V2R antagonism with tolvaptan appears to decrease Na excretion in response to intravenous and short-term oral salt loading in healthy subjects. Determination of renin-angiotensin-aldosterone system and/or natriuretic peptide system activity in response to V2R antagonism may provide important mechanistic insight for these findings.

 

Nothing to Disclose: GS, EWS, NA, MN, JSW