The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

Abstract

The renin-angiotensin-aldosterone (RAAS) and renal dopaminergic systems interact to maintain sodium balance. High NaCl intake increases renal synthesis of dopamine and dopaminergic receptor activity, decreasing epithelial sodium transport, whereas sodium deficit activates the RAAS, increasing epithelial sodium transport. We tested the hypothesis that attenuation of the natriuretic effect of dopamine D1-like receptors during salt restriction results in part from increased RAAS activity in seven salt-resistant normotensive adults using a double-blind placebo-controlled balanced crossover design. All subjects attained sodium balance on low (50 mmol Na(+)/day) and high (300 mmol Na(+)/day) NaCl diets, administered 4 weeks apart. Sodium, potassium, lithium, para-aminohippurate, and creatinine clearances were measured before, during, and after a 3-hour infusion of fenoldopam, a D1-like receptor agonist, with and without pretreatment with enalapril, an angiotensin converting enzyme inhibitor. On the high NaCl diet, fenoldopam-induced natriuresis was associated with the inhibition of renal proximal and distal tubule sodium transport. On the low NaCl diet, fenoldopam decreased renal distal tubule sodium transport but did not cause natriuresis. The addition of enalapril to fenoldopam restored the natriuretic effect of fenoldopam and its inhibitory effect on proximal tubule sodium transport. Thus, on a high NaCl diet fenoldopam causes natriuresis by inhibiting renal proximal and distal tubule transport, but on a low NaCl diet the increased RAAS activity prevents the D1-like receptor from inhibiting renal proximal tubule sodium transport, neutralizing the natriuretic effect of fenoldopam. These results demonstrate an interaction between the renin-angiotensin and renal dopaminergic systems in humans and highlight the influence of dietary NaCl on these interactions.

Keywords: dopamine; enalapril; hypertension; natriuresis; salt.

Figure 1.

Cohort recruitment and retention for study. Of the 93 responders to public advertisements, 45 subjects underwent physical examination; 17 subjects went on trial. Eight subjects completed both HS and LS diet phases 4 weeks apart. One salt-sensitive subject was excluded from the final evaluation of the data. *Obesity: BMI>30 (males), BMI>28.6 (females). ^♣Prehypertension: BP 120–139/80–89 JNC VII (2003). BMI, body mass index.

Figure 2.

(A) High salt (HS), relative to low salt (LS) diet, increases urinary dopamine. (B) Example of timed measurement of U_NaV showing that fenoldopam (Fen) increases sodium excretion (U_NaV) after 30 minutes in salt-resistant subjects on LS diet who were pretreated with enalapril (Enal). Data are shown as mean±SEM (n=7/group). (A) Urinary dopamine was higher on Day 5 of HS relative to LS. (B) Timed graph of U_NaV (mEq/min) measured at half-hourly intervals before (control), during (fenoldopam), and after discontinuing (postcontrol) fenoldopam infusion. Salt-resistant subjects given enalapril (2.5 mg×2 doses) represent the Control.

Figure 3.

Fenoldopam (Fen) alone increases renal sodium excretion and lithium clearance only on HS. Data are shown as mean±SEM or median (range), with *P<0.05 versus control (C) and postcontrol (not shown), RM ANOVA or Mann–Whitney/paired t test (LS versus HS), respectively. (A) Left to right, U_NaV (mEq/min) with control and Fen on LS and HS diets. Effect of Fen (Δ Fen-C) on LS versus HS and percentage effect of Fen (% Δ Fen-C) on LS and HS. (B) Left to right, fractional excretion of sodium, FE_Na, % with Fen and control on LS and HS diets. Effect of Fen (Δ Fen-C) on LS versus HS and percentage effect (% Δ Fen-C) of Fen on LS and HS. (C) Left to right, lithium clearance (ml/min per 1.73 m²) with Fen and control on LS and HS diets. Effect of Fen (Δ Fen-C) on LS versus HS and percentage effect of Fen (% Δ Fen-C) on lithium clearance on LS and HS.

Figure 4.

Enalapril (Enal) alone has no effect on renal sodium excretion and lithium clearance. Data are shown as mean±SEM or median (range), with *P<0.05 versus control (C) and postcontrol (not shown), RM ANOVA or Mann–Whitney/paired t test (LS versus HS), respectively, paired t test (LS-vs HS). (A) Left to right, U_NaV with control and Enal on LS and HS diets. Effect of Enal (Δ Enal-C) on LS versus HS and percentage effect (% Δ Enal-C) on U_NaV with Enal compared with C on LS and HS. (B) Left to right, fractional excretion of sodium, FE_Na, % with Enal and control on LS and HS diets. Effect of Enal (Δ Enal-C) on LS versus HS and percentage effect on FE_Na, % with Enal (% Δ Enal-C) compared with C on LS and HS. (C) Left to right, lithium clearance (ml/min per 1.73 m²) with Enal and controlon LS and HS diets, effect of Enal (Δ Enal-C) on LS versus HS and percentage effect on lithium clearance with Enal (% Δ Enal-C) compared with C on LS and HS.

Figure 5.

Fenoldopam (Fen) increases renal sodium excretion and lithium clearance on LS more than HS when pretreated with enalapril (Enal). Data are shown as mean±SEM with *P<0.05 versus control (C), RM ANOVA (Fen+Enal versus Enal alone and/or paired t test (LS versus HS)). (A) Left to right, U_NaV with Enal and Fen + Enal on LS and HS diets. Effect of Fen + Enal (Δ Fen+ Enal–Enal) on LS versus HS and percentage effect of Fen + Enal compared with Enal alone (% Δ Fen+Enal–Enal) on LS and HS. (B) Left to right, fractional excretion of sodium, FE_Na, % with Enal and Fen + Enal on LS and HS diets. Effect of Fen + Enal (ΔFen+Enal–Enal) on LS versus HS and percentage effect on FE_Na, % with Fen + Enal compared with Enal alone (% Δ Fen+Enal–Enal) on LS and HS. (C) Left to right, lithium clearance (ml/min per 1.73 m²) with Enal and Fen + Enal on LS and HS diets. Effect of Fen + Enal (Δ Fen+Enal–Enal) on LS versus HS and percentage effect of Fen + Enal compared with Enal alone (% Δ Fen+Enal–Enal) on LS and HS.

Figure 6.

The combination of fenoldopam + enalapril (Fen+Enal) has a greater effect in decreasing sodium transport in proximal nephron than fenoldopam (Fen) alone on low salt. (A) Fen + Enal causes a greater percentage increase in U_NaV, FE_Na, lithium clearance and distal sodium delivery than Fen alone on low salt. Percentage changes in U_NaV, FE_Na, lithium clearance and distal sodium delivery on LS and HS are shown,*P<0.05, one-way ANOVA, Bonferroni. Data are expressed as percentage effects compared with pre-infusion values, mean±SEM. (B) Timed graph showing that the increase in FE_Na is greater with Fen + Enal than Fen alone on low salt. Timed graph of the increase in the ratio of FE_Na before (control) and during fenoldopam infusion on LS with or without pretreatment with Enal. *P<0.05, versus control and LS Fen two-way ANOVA, Bonferroni post-hoc.

Figure 7.

Fenoldopam (Fen) alone increases distal sodium delivery only on HS and decreases distal sodium transport on both LS and HS. Data are shown as mean±SEM with *P<0.05 versus control (C), RM ANOVA (Fen + Enal versus Enal alone and/or paired t test (LS versus HS)). (A) Left to right, distal sodium delivery during control and Fen on LS and HS. Effect of Fen (Δ Fen-C) on LS versus HS and percentage effect of Fen (% Δ Fen-C) on LS and HS. (B) Left to right, absolute distal reabsorption of sodium, with Fen and control on LS and HS. Effect of Fen (Δ Fen-C) on LS versus HS and percentage effect of Fen (% Δ Fen-C) compared with control on LS and HS. (C) Left to right, fractional distal reabsorption (FrDR %) with Fen and control on LS and HS. Effect of Fen (Δ Fen-C) on LS versus HS and percentage effect of Fen (% Δ Fen-C) compared with control on LS and HS.

Figure 8.

Comparison of percentage effect of fenoldopam (Fen) alone versus fenoldopam + enalapril (Fen + Enal) on sodium transport in the distal nephron on LS and HS diet. Data are expressed as percentage effects compared with pre-infusion values, mean±SEM, *P<0.05, one-way ANOVA, Holm–Sidak. The percentage decrease in absolute distal reabsorption of sodium in response to fenoldopam (Fen) alone on LS and HS was different from the percentage change with the combination of Fen + Enal on LS.