Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system pathways

We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats by chronic systemic vasodilation. Fourteen-day vasodilation with sodium nitrite or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution, and increased renal medullary phosphodiesterase 5A (PDE5A) protein. The present study examined the role of the reninangiotensin-aldosterone system (RAAS) in this mechanism. Virgin females were treated for 14 days with NIF (10 mg·kg ^-1·day ^-1 via diet), NIF with spironolactone SPR; mineralocorticoid receptor (MR) blocker, 200-300 mg·kg ¹·day ¹ via diet], NIF with losartan LOS; angiotensin type 1 (AT₁) receptor blocker, 20 mg·kg^-1·day ^-1 via diet], enalapril (ENAL; angiotensin-converting enzyme 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, 13.3±0.9% with NIF+LOS, and 12.0±0.4% with ENAL vs. baseline MAP. Compared with CON (3.6±0.3%), plasma volume factored for body weight was increased by NIF (5.2±0.4%) treatment but not by NIF+SPR (4.3±0.3%), NIF LOS (3.6±0.1%), or ENAL (4.0±0.3%). NIF increased PDE5A protein abundance in the renal inner medulla, and SPR did not prevent this increase (188±16 and 204±22% of CON, respectively). NIF increased the subunit of the epithelial sodium channel (ENaC) protein in renal outer (365±44%) and inner (526±83%) medulla, and SPR prevented these changes. There was no change in either PDE5A or αENaC abundance vs. CON in rats treated with NIF+LOS or ENAL. These data indicate that the PVE and renal medullary adaptations in response to chronic vasodilation result from RAAS signaling, with increases in PDE5A mediated through AT₁ receptor and αENaC through the MR.