Glucuronidated quercetin lowers blood pressure in spontaneously hypertensive rats via deconjugation

Abstract

Background: Chronic oral quercetin reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (aglycone) is usually not present in plasma, because it is rapidly metabolized into conjugated, mostly inactive, metabolites. The aim of the study is to analyze whether deconjugation of these metabolites is involved in the blood pressure lowering effect of quercetin.

Methodology/principal findings: We have analyzed the effects on blood pressure and vascular function in vitro of the conjugated metabolites of quercetin (quercetin-3-glucuronide, Q3GA; isorhamnetin-3-glucuronide, I3GA; and quercetin-3'-sulfate, Q3'S) in spontaneously hypertensive rats (SHR). Q3GA and I3GA (1 mg/kg i.v.), but not Q3'S, progressively reduced mean blood pressure (MBP), measured in conscious SHR. The hypotensive effect of Q3GA was abolished in SHR treated with the specific inhibitor of β-glucuronidase, saccharic acid 1,4-lactone (SAL, 10 mg/ml). In mesenteric arteries, unlike quercetin, Q3GA had no inhibitory effect in the contractile response to phenylephrine after 30 min of incubation. However, after 1 hour of incubation Q3GA strongly reduced this contractile response and this effect was prevented by SAL. Oral administration of quercetin (10 mg/Kg) induced a progressive decrease in MBP, which was also suppressed by SAL.

Conclusions: Conjugated metabolites are involved in the in vivo antihypertensive effect of quercetin, acting as molecules for the plasmatic transport of quercetin to the target tissues. Quercetin released from its glucuronidated metabolites could be responsible for its vasorelaxant and hypotensive effect.

Figure 1. Structure of quercetin and its metabolites isorhamnetin, quercetin 3-glucuronide (Q3GA), isorhamnetin 3-glucuronide (I3GA) and quercetin 3′-sulfate (Q3'S).

Figure 2. Effects of intravenous Q3GA, Q3'S, and I3GA (1 mg/kg) and Q3GA (0.02, 0.2 mg/kg) on mean arterial blood pressure (A, C) and heart rate (B, D) measured by direct carotid artery recording in a conscious rat.

Results are means ± SEM of 4–6 experiments. * P<0.05 vs. saline.

Figure 3. Concentrations of quercetin, I3GA, and Q3GA measured in plasma from SHR treated with 1 mg/kg Q3GA.

(A) HPLC chromatograms recorded at 370 nm of plasma samples taken at 1 min. (B) Time-concentration relationship. Results are means ± SEM of 4 experiments.

Figure 4. Effects of (A) quercetin and (B) isorhamnetin (10 or 25 µM, incubated for 30 min) on the contractile responses to phenylephrine in mesenteric resistance arteries.

Control is treated with vehicle (DMSO). Results are means ± SEM of 4–8 experiments. * P<0.05 and **P<0.01 vs. control.

Figure 5. Effects of Q3GA (10 or 25 µM) on the contractile responses to phenylephrine in mesenteric resistance arteries, after 30 (A), 60 (B) or 120 (C) min of incubation.

Results are means ± SEM of 4–8 experiments. * P<0.05 and **P<0.01 vs. control.

Figure 6. Effects of Q3GA in arterial blood pressure (A) and heart rate (B) in SHR treated with SAL (10 mg/rat/day for 3 days) or vehicle (means ± SEM of 4 experiments).

Panel (C) shows the bands of β-glucuronidase expression by Western blot and the β-glucuronidase activity and its inhibition by SAL (1 mM) in vascular bed homogenates (means ± SEM of 8 experiments). (D) Effects of Q3GA (25 µM) on the contractile responses to phenylephrine in mesenteric arteries after 120 min in the presence of SAL (1 mM) (means ± SEM of 5 experiments). (E) Effects of quercetin (25 µM) on the contractile responses to phenylephrine in mesenteric arteries after 30 min in the presence of SAL (1 mM) (means ± SEM of 5 experiments). * P<0.05 and **P<0.01 vs. control.

Figure 7. Effects of oral quercetin (10 mg/kg) on arterial blood pressure (A, C) and heart rate (B, D) in SHR treated with SAL (10 mg/rat/day for 3 days) or vehicle (1 ml isotonic solution).

Results are means ± SEM of 4 experiments. *P<0.05 and **P<0.01 vs. quercetin vehicle (1 ml of 1% methylcellulose).