Tetrahydrobiopterin ameliorates the exaggerated exercise pressor response in patients with chronic kidney disease: a randomized controlled trial

Abstract

Chronic kidney disease (CKD) patients have an exaggerated increase in blood pressure (BP) during rhythmic handgrip exercise (RHG 20%) and static handgrip exercise (SHG 30%). Nitric oxide levels increase during exercise and help prevent excessive hypertension by both increasing vasodilation and reducing sympathetic nerve activity (SNA). Therefore, we hypothesized that tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, would ameliorate the exaggerated exercise pressor response in CKD patients. In a randomized, double-blinded, placebo-controlled trial, we tested the effects of 12 wk of sapropterin dihydrochloride (6R-BH4; n = 18) versus placebo (n = 14) treatement on BP and muscle SNA (MSNA) responses during RHG 20% and SHG 30% in CKD patients. The 6R-BH4-treated group had a significantly lower systolic BP (+6 ± 1 vs. +13 ± 2 mmHg, P = 0.002) and mean arterial pressure response (+5 ± 1 vs. +10 ± 2 mmHg, P = 0.020) during RHG 20% and a significantly lower systolic BP response (+19 ± 3 vs. +28 ± 3 mmHg, P = 0.043) during SHG 30%. Under baseline conditions, there was no significant difference in MSNA responses between the groups; however, when the BP response during exercise was equalized between the groups using nitroprusside, the 6R-BH4-treated group had a significantly lower MSNA response during RHG 20% (6R-BH4 vs. placebo, +12 ± 1 vs. +21 ± 2 bursts/min, P = 0.004) but not during SHG 30%. These findings suggest that 6R-BH4 ameliorates the augmented BP response during RHG 20% and SHG 30% in CKD patients. A reduction in reflex activation of SNA may contribute to the decreased exercise pressor response during RHG 20% but not during SHG 30% in CKD patients.

Trial registration: ClinicalTrials.gov NCT01356966.

Keywords: exercise pressor reflex; handgrip exercise; sympathetic nerve activity.

Figures

Fig. 1.

Mean change in systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) during 3 min of low-level rhythmic handgrip exercise (RHG 20%) at 20% maximum voluntary contraction (MVC) in the sapropterin dihydrochloride (6R-BH4)-treated group (n = 14) before treatment and after 12 wk of treatment and the placebo group (n = 11) before treatment and after 12 wk of treatment. **P < 0.05 indicates that the overall ANOVA F-test was significant for a difference between the 6R-BH4- and placebo-treated groups after treatment. *P < 0.05 indicates a significant difference between the groups posttreatment at that time point.

Fig. 2.

Mean change in SBP, MAP, HR, and MSNA during 3 min of moderate SHG (SHG 30%) at 30% MVC in the 6R-BH4-treated group (n = 14) before treatment and after 12 wk of treatment and the placebo group (n = 11) before treatment and after 12 wk of treatment. **P < 0.05 indicates that the overall ANOVA F-test was significant for a difference between the 6R-BH4- and placebo-treated groups after treatment. *P < 0.05 indicates a significant difference between the groups posttreatment at that time point.

Fig. 3.

Mean change in SBP during the third minute of RHG 20% at 20% MVC (A) and SHG 30% at 30% MVC (B) before and after 12 wk of treatment with placebo (n = 11) or 6R-BH4 (n = 14). **P < 0.05 indicates a significant difference between the 6R-BH4- and placebo-treated groups. *P < 0.05 indicates a significant difference within groups.

Fig. 4.

Mean change in MAP and MSNA after treatment in the 6R-BH4-treated group (n = 9) and placebo-treated group (n = 4) during concomitant intravenous nitroprusside (NTP) infusion during low-level RHG (RHG 20%) at 20% MVC and moderate SHG (SHG 30%) at 30% MVC.