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.

Two Pools of Epoxyeicosatrienoic Acids in Humans

“…Second, they may have defective renal expression of epoxygenases. This is supported by our results, those of a dietary experiment, in which SS had diminished urine EETs during the low-salt phase, 27 and by reduced renal expression of epoxygenases and urine excretion of EETs in Dahl-S rats. 5 Third, a defect may be downstream of the EETs, impairing signaling to renal sodium transporters.…”

“…However, despite this, we documented a different set of correlates for urine and plasma measurements, that is, the small n's did not preclude detection of significant relationships. (2) Inability to detect active EETs in urine samples, different from other studies, 1,27,28 was most likely produced by nonenzymatic conversion to DHETs during prolonged storage. The relative proportion of EETs and DHETs at collection must have been different in each patient, and this unknown variance should have weakened our statistical analyses.…”

“…In the dietary study mentioned above, SS also had lower plasma EET than SR albeit during the lowsalt period. 27 Rather than a flat pattern with changes in salt intake (as their UTP exhibited), SS had decreased plasma sEH and DHETs with salt loading and increased EETs and DHETs with salt depletion, again analogous to the dietary study. 27 These responses are not consistent with those of a natriuretic system.…”

“…27 Rather than a flat pattern with changes in salt intake (as their UTP exhibited), SS had decreased plasma sEH and DHETs with salt loading and increased EETs and DHETs with salt depletion, again analogous to the dietary study. 27 These responses are not consistent with those of a natriuretic system. Finally, equal to SR, no plasma epoxyeicosatrienoic acid fraction of SS correlated with natriuresis or inhibition of ENaC.…”

Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production

“…Such an idea is consistent with data in hereditary hypertriglyceridemic rats, in which both a statin and the mineralocorticoid antagonist spironolactone are able to inhibit elevated blood pressure values (Torok et al 2007). Fibrates reduce serum triglyceride levels as well; these agents also appear to decrease blood pressure (Jonkers et al 2001, Gilbert et al 2013. Thus, although the exact mechanism(s) by which the fibrates and statins improve hypertension is/are not yet known, clearly these agents appear to be beneficial, and further research is needed.…”