Pregnane X Receptor Activator Rifampin Increases Blood Pressure and Stimulates Plasma Renin Activity

Abstract

We conducted a clinical trial with 22 healthy volunteers to investigate the effects of pregnane X receptor (PXR) agonist rifampin on blood pressure (BP). The study was randomized, crossover, single‐blind, and placebo‐controlled. Rifampin 600 mg or placebo once daily was administered for a week and the 24‐hour ambulatory BP was monitored at the end of each arm on the eighth day. Rifampin elevated the mean systolic and diastolic 24‐hour BP (4.7 mmHg, P < 0.0001, and 3.0 mmHg, P < 0.001, respectively) as well as the mean heart rate (3.5 bpm, P = 0.038). The serum renin concentration and the plasma renin activity were increased. Although rifampin increased circulating 4β‐hydroxycholesterol (4βHC) as expected, the plasma 4βHC concentration strongly negatively correlated with 24‐hour BP, especially systolic, in both rifampin and placebo arms (rifampin systolic BP, r = −0.69, P < 0.001; placebo systolic BP, r = −0.70, P < 0.001). The 4βHC, an agonist for liver X receptor (LXR), induced renin expression modestly in LXR‐α expressing Calu‐6 cells but only at unphysiologically high 4βHC concentrations. In conclusion, rifampin stimulates renin activity and has a hypertensive effect. This finding should be considered when designing interaction studies involving rifampin or other PXR agonists. Furthermore, PXR may represent a putative therapeutic target for the treatment of hypertension.

PXR and 4β-Hydroxycholesterol Axis and the Components of Metabolic Syndrome

“…Both LXRα and LXRβ are activated by 4βHC [50]. We showed in our ambulatory BP study [14] that plasma 4βHC concentration strongly negatively correlated with 24-hour systolic BP. This negative correlation was present in both rifampicin and placebo arms (rifampicin, r = −0.69, p < 0.001; placebo, r = −0.70, p < 0.001), although rifampicin dosing elevated 4βHC concentration more than 3-fold, and 24 h BP was increased as detailed above.…”

“…It is also interesting that laminar shear stress, the atheroprotective blood flow, activates PXR in bovine aortic and human umbilical vein endothelial cells, whereas atherogenic oscillatory shear stress suppresses PXR [43]. It should also be noted that in our ambulatory BP study, the heart rate and renin activity were elevated in addition to systolic and diastolic BP [14]. All of these effects are also seen when the sympathetic nervous system is activated [46,47].…”

“…In addition to BP indices, the mean 24 h heart rate was increased by 3.5 bpm (p = 0.038). Thus, we have evidence from two trials on healthy volunteers that PXR activation elevates office and 24 h ambulatory systolic and diastolic BP and heart rate [14,22].…”

“…The office systolic blood pressure (BP) was elevated by 4.8 mmHg (p = 0.027), diastolic BP by 3.5 mmHg (p = 0.020), and heart rate by 5.0 bpm (p = 0.042) after 1 week of rifampicin dosing compared with the placebo arm. Therefore, in our recent study, we set out to test the hypothesis that PXR activation by rifampicin elevates 24-h BP [14]. In a randomized, single-blind, placebo-controlled, and crossover trial, 22 healthy volunteers were given rifampicin 600 mg vs. placebo daily for a week, and 24 h ambulatory BP was measured at the end of the study arms.…”

“…Several molecular mechanisms mediating the effects of EDCs on metabolism have been proposed, including estrogen and other sex hormone receptors, glucocorticoid receptor, peroxisome proliferator-activated receptors, and xenobiotic-sensing receptors such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR) [6,12]. In this review, we concentrate on the effects of PXR on MetS and discuss the possibility that, due to its roles as a xenosensor and a regulator of glucose and lipid metabolism as well as blood pressure [13,14], PXR activation could contribute to the development of MetS.…”