Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system 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 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 renin-angiotensin-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 α-subunit of the epithelial sodium channel (α-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 α-ENaC 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 α-ENaC through the MR.

Keywords: arterial underfilling; phosphodiesterase 5A; α-subunit of the epithelial sodium channel.

Fig. 1.

Percent change in mean arterial pressure (MAP) as measured by telemetry in control (CON)-, nifedipine (NIF)-, nifedipine in combination with spironolactone (NIF + SPR)-, nifedipine in combination with losartan (NIF + LOS)-, and enalapril (ENAL)-treated virgin female rats. A one-way repeated-measures ANOVA was performed. Values are presented as means ± SE. P < 0.05 vs. CON (*), NIF (§), NIF + SPR (†), NIF + LOS (£), and ENAL (‡).

Fig. 2.

Phosphodiesterase 5A (PDE5A) protein abundance in kidney cortex (CTX) and outer (OM) and inner (IM) medulla of CON, NIF-, and NIF + SPR-treated (A), CON and NIF + LOS-treated (B), and CON and ENAL-treated (C) virgin female rats after 14-day treatment. Densitometry was normalized to virgin controls with controls set at 100% and summarized as bar graphs. A one-way ANOVA with Tukey's post hoc was run in A, and an unpaired t-test was performed in B and C. Data are presented as means ± SE. *P < 0.05 vs. CON.

Fig. 3.

Protein abundance of the thiazide-sensitive cotransporter [sodium-chloride cotransporter (NCC)] and the three subunits of ENaC (α, β, and γ) in CTX (A), OM (B), and IM (C) in CON, NIF-, and NIF + SPR-treated virgin female rats. Band densities were normalized to virgin controls with virgins set at 100% and summarized as bar graphs. A one-way ANOVA with Tukey's post hoc was performed. Data are presented as means ± SE. P < 0.05 vs. CON (*), and NIF + SPR (†).

Fig. 4.

Protein abundance of the thiazide-sensitive cotransporter (NCC) and the three subunits of ENaC (α, β, and γ) in CTX (A), OM (B), and IM (C) in CON and NIF + LOS-treated virgin female rats. Band densities were normalized to virgin controls with virgins set at 100% and summarized as bar graphs. An unpaired t-test was performed. Data are presented as means ± SE.

Fig. 5.

Protein abundance of the thiazide-sensitive cotransporter (NCC) and the three subunits of ENaC (α, β, and γ) in CTX (A), OM (B), and IM (C) in CON and ENAL-treated virgin female rats. Band densities were normalized to virgin controls with virgins set at 100% and summarized as bar graphs. An unpaired t-test was performed. Data are presented as means ± SE.