Tetrahydrobiopterin: a novel antihypertensive therapy
Tetrahydrobiopterin: a novel antihypertensive therapy
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DOI：
10.1038/sj.jhh.1002329
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发表时间：
2008-06-01
影响因子：
2.7
通讯作者：
Quyyumi, A. A.
中科院分区：
文献类型：
--
作者：
Porkert, M.;Sher, S.;Quyyumi, A. A.
四氢生物蝶呤 (BH(4)) 是一氧化氮 (NO) 合酶的辅助因子，其不足会导致酶解偶联，导致在疾病状态（包括高血压）中释放超氧化物而不是 NO。我们假设口服 BH(4) 将降低高血压受试者的动脉血压 (BP) 并改善内皮功能。高血压控制不佳（血压 > 135/85 mm Hg）的受试者口服 BH(4)，并每周测量血压和内皮功能。在研究1中，口服给予5或10 mg kg(-1) day(-1) BH(4) (n= 8)，持续8周；在研究2中，分剂量给予200和400 mg BH(4) (n = 16)，持续4周。研究 1：两种剂量的 BH(4) 均观察到收缩压 (P=0.005) 和平均血压 (P=0.01) 显着降低。 5 周后收缩压降低了 15 +/- 15 mm Hg (P=0.04)，并且在为期 8 周的研究期间持续存在。研究2：给予400 mg BH(4)的受试者收缩压(P=0.03)和平均血压(P=0.04)下降，3周时峰值下降16 +/- 19 mm Hg (P=0.04)。停药后 4 周血压恢复至基线。在研究 1 受试者和接受 400 mg BH(4) 治疗的受试者中观察到内皮功能显着改善。给予 200 毫克剂量的受试者没有显着变化。这项初步研究表明，每日剂量为 400 mg 或更高的口服 BH(4) 对于高血压控制不佳的受试者具有显着且持续的抗高血压作用，这种作用与改善内皮 NO 生物利用度相关。
Tetrahydrobiopterin (BH(4)) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH(4) will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH(4) was given to subjects with poorly controlled hypertension (BP > 135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg(-1) day(-1) of BH(4) (n= 8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH(4) (n = 16) was given in divided doses for 4 weeks. Study 1: significant reductions in systolic (P=0.005) and mean BP (P=0.01) were observed with both doses of BH(4). Systolic BP was 15 +/- 15 mm Hg (P=0.04) lower after 5 weeks and persisted for the 8-week study period. Study 2: subjects given 400 mg BH(4) had decreased systolic (P=0.03) and mean BP (P=0.04), with a peak decline of 16 +/- 19 mm Hg (P=0.04) at 3 weeks. BP returned to baseline 4 weeks after discontinuation. Significant improvement in endothelial function was observed in Study 1 subjects and those receiving 400 mg BH(4). There was no significant change in subjects given the 200 mg dose. This pilot investigation indicates that oral BH(4) at a daily dose of 400 mg or higher has a significant and sustained antihypertensive effect in subjects with poorly controlled hypertension, an effect that is associated with improved endothelial NO bioavailability.