Chronic vasodilation increases collecting duct (CD) PDE5A and αENaC through independent renin‐angiotensin‐aldosterone system (RAAS) pathways

Abstract

We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats (V) by chronic systemic vasodilation (VD). Fourteen‐day VD with NaNO2 or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution and increased renal medullary PDE5A protein. The present study examined the role of the RAAS in this mechanism. V were treated for 14 days with NIF; 10 mg/kg/day via diet, NIF with spironolactone (SPR; mineralocorticoid receptor (MR) blocker, 200–300 mg/kg/day via diet), enalapril (ENAL; ACE inhibitor, 62.5 mg/L via water), or vehicle (CON). Mean arterial pressure (MAP) was reduced 7.4±0.5% with NIF, 6.33±0.5% with NIF+SPR, and 12.0±0.4% with ENAL vs. baseline MAP. Compared to CON (3.6±0.3%) PV/BW was increased by NIF (5.2±0.4%) treatment but not by NIF+SPR (4.3±0.2%) or ENAL (4.0±0.3%). NIF increased PDE5A protein abundance only in the renal inner medulla (IM) and SPR did not prevent this increase (188±16% and 204±22% of CON respectively). NIF increased ∝ENaC protein in renal outer medulla (365±44%) and IM (526±83%) and SPR prevented these changes. With ENAL‐induced VD there was no change in either PDE5A or ∝ENaC abundance vs. CON. These data indicate that the PVE and CD adaptations in response to VD result from RAAS activation, with PDE5A being mediated through AII signaling and ∝ENaC through the MR. Funding: R01HD041571 and R01DK56843.