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Abstract: TH-PO508

Level of ENaC Activity Drives Hypertension from Chronic Activation of Vasopressin V2 Receptors

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Pao, Alan C., Stanford University , Palo Alto, California, United States
  • Xiang, Hong, Stanford University , Palo Alto, California, United States
  • Mironova, Elena V., University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Gurley, Susan B., Oregon Health & Science University, Portland, Oregon, United States
  • Ferdaus, Mohammed Zubaerul, Oregon Health & Science University, Portland, Oregon, United States
  • McCormick, James A., Oregon Health & Science University, Portland, Oregon, United States
  • Stockand, James D., University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Background

Vasopressin can contribute to sodium homeostasis and blood pressure regulation by stimulating the epithelial sodium channel (ENaC) through activation of vasopressin V2 receptors (V2R) in principal cells of the distal nephron. However, a direct link between chronic activation of V2R, high ENaC activity, and high blood pressure remains to be established in vivo.

Methods

We asked whether an isolated increase in V2R-mediated ENaC activity can lead to high blood pressure. We tested the blood pressure effects of chronic activation of V2R in mice with varying levels of ENaC activity. We infused dDAVP (100 ng/hr), a specific V2R agonist, for two weeks into Liddle (beta-ENaC-R566X), Pseudohypoaldosteronism Type 1 (PHA) mice, or wild type (WT) littermates and used radiotelemetry to compare blood pressure responses. We fed all mice normal sodium chow because they have similar blood pressures at this level of dietary sodium.

Results

We found that infusion of dDAVP into WT mice increased baseline blood pressure (systolic (SBP) by 4.3±0.47 mmHg and mean arterial pressure (MAP) by 3.7±0.45 mmHg, P<0.05); infusion of dDAVP into Liddle mice increased baseline blood pressure to a greater extent (SBP increase by 7.3±1.16 mmHg and MAP increase by 7.0 mmHg±1.57, P<0.05). Infusion of dDAVP into PHA1 mice induced no rise in baseline blood pressure. Blood pressure was highest in dDAVP-infused Liddle mice compared to dDAVP-infused WT or PHA mice (SBP 146±5.75 mmHg (Liddle) vs 135 or 137 mmHg; MAP 127±4.16 mmHg (Liddle) vs 119 or 120 mmHg). We also found that administration of benzamil, a specific ENaC inhibitor, only restored blood pressures of dDAVP-infused Liddle mice (SBP decrease by 4.86±1.31 mmHg and MAP decrease by 4.9±1.21 mmHg, P<0.05).

Conclusion

Our findings demonstrate that a specific increase in V2R-mediated ENaC activity in Liddle mice is sufficient to raise blood pressure. Since infusion of dDAVP can raise blood pressure in Liddle mice, our findings also suggest that the Liddle (beta-ENaC-R566X) mutation and V2R can stimulate ENaC through distinct pathways. Finally, since V2R-mediated increase in blood pressure in WT mice is not sensitive to benzamil inhibition, chronic activation of V2R is also sufficient to raise blood pressure through ENaC-independent pathways.

Funding

  • NIDDK Support