Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension

Abstract

Objective: Peroxisome proliferator-activated receptor α agonists reduce blood pressure in rodents, but clinical trials provide conflicting data regarding their effects in humans. We tested the hypothesis that the effect of fenofibrate on blood pressure depends on salt sensitivity.

Methods: Thirty-one hypertensive volunteers (17 salt-resistant, 14 salt-sensitive) completed a randomized, crossover, double-blind protocol with three dietary phases: low salt diet (10 mmol/day) followed by two consecutive high salt diets (200 mmol/day), each for 6 days. During high salt, volunteers were randomized to fenofibrate 160 mg/day or placebo. Hemodynamic and metabolic parameters were measured on the last morning of each treatment arm.

Results: Fenofibrate reduced triglycerides similarly in salt-sensitive and salt-resistant volunteers. Fenofibrate did not affect blood pressure in salt-resistant volunteers. In salt-sensitive volunteers, fenofibrate significantly decreased diastolic (P = 0.02 versus placebo) and mean arterial (P = 0.04 versus placebo) blood pressure during high salt. In all volunteers, the decrease in systolic pressure during fenofibrate correlated inversely with the salt sensitivity of mean arterial pressure as a continuous variable. Fenofibrate significantly decreased heart rate, plasma renin activity, and renal vascular resistance during high salt in salt-sensitive volunteers, but not salt-resistant volunteers. Fenofibrate did not affect sodium excretion or weight gain during high salt. The effect of salt intake and fenofibrate on plasma and urine epoxyeicosatrienoic acid concentrations differed in salt-resistant and salt-sensitive volunteers.

Conclusion: Fenofibrate reduces blood pressure, heart rate and renal vasoconstriction in salt-sensitive volunteers, but not in salt-resistant volunteers. These findings have implications for the treatment of hyperlipidemia in hypertensive individuals.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1

Study protocol. All antihypertensive medications were washed out at least 3 weeks prior to the first study day. Volunteers underwent a washout period of at least 1 week between study arms.

FIGURE 2

Effect of salt intake and fenofibrate on mean arterial pressure (MAP), SBP and DBP. Changes from low salt to high salt intake and placebo (ΔPla-Low), from low salt to high salt intake and fenofibrate (ΔFeno-Low), and during high salt and fenofibrate compared with high salt intake and placebo (ΔFeno-Pla) are indicated. Volunteers were classified as salt-sensitive if their MAP was at least 5 mmHg higher during high salt and placebo compared with during low salt intake. Panel (d) shows the effect of fenofibrate treatment on SBP during high salt intake (Δ SBPFeno-Pla) as a function of salt sensitivity of blood pressure defined as the difference in MAP between low salt and high salt intake during placebo (Δ MAPPla-Low). Grey filled circles indicate those volunteers defined as salt-sensitive.

FIGURE 3

Effect of salt intake and fenofibrate on plasma epoxyeicosatrienoic acid concentrations. Changes in epoxyeicosatrienoic acid (EET) concentrations from low salt to high salt intake and placebo (Δ Pla-Low), from low salt to high salt intake and fenofibrate (Δ Feno-Low), and during high salt and fenofibrate compared with high salt intake and placebo (Δ Feno-Pla) are also shown. *P <0.05 versus low salt intake.

FIGURE 4

Effect of salt intake and fenofibrate on urine epoxyeicosatrienoic acid (EET) concentrations and soluble epoxide hydrolase (sEH) activity. Changes in EET concentrations from low salt to high salt intake and placebo (Δ Pla-Low), from low salt to high salt intake and fenofibrate (Δ Feno-Low), and during high salt and fenofibrate compared with high salt intake and placebo (Δ Feno-Pla) are also shown. *P <0.05 versus low salt intake, †P = 0.07 versus low salt intake.