title: 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.
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Research Service Line, Department of Veterans Affairs Medical Center, Decatur, Georgia;
authors.forename: Ann M
authors.initials: AM
authors.lastname: Lin
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia;
authors.forename: Peizhou
authors.initials: P
authors.lastname: Liao
authors.affiliation: Clinical Research Network, Atlanta Clinical and Translational Science Institute, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Erin C
authors.initials: EC
authors.lastname: Millson
authors.affiliation: Cardiology Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Research Service Line, Department of Veterans Affairs Medical Center, Decatur, Georgia; jeanie.park@emory.edu.
authors.forename: Jeanie
authors.initials: J
authors.lastname: Park
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D004311:Double-Blind Method; D015444:Exercise / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000187:drug effects
chemical_list: D001708:Biopterins; C003402:sapropterin
keywords: exercise pressor reflex; handgrip exercise; sympathetic nerve activity