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Tetrahydrobiopterin: a Novel Antihypertensive Therapy

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Tetrahydrobiopterin: a Novel Antihypertensive Therapy Journal of Human Hypertension (2008) 22, 401–407 & 2008 Nature Publishing Group All rights reserved 0950-9240/08 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Tetrahydrobiopterin: a novel antihypertensive therapy M Porkert1, S Sher1, U Reddy1, F Cheema1, C Niessner1, P Kolm2, DP Jones3, C Hooper4, WR Taylor1, D Harrison1 and AA Quyyumi1 1Division of Cardiology, Emory University, Atlanta, GA, USA; 2Christiana Care Center for Outcomes Research, Newark, DE, USA; 3General Clinical Research Center, Emory University, Atlanta, GA, USA and 4Centers for Disease Control, Atlanta, GA, USA Tetrahydrobiopterin (BH4) is a cofactor for the nitric after 5 weeks and persisted for the 8-week study period. oxide (NO) synthase enzymes, such that its insuffi- Study 2: subjects given 400 mg BH4 had decreased ciency results in uncoupling of the enzyme, leading to systolic (P ¼ 0.03) and mean BP (P ¼ 0.04), with a peak release of superoxide rather than NO in disease decline of 16±19 mm Hg (P ¼ 0.04) at 3 weeks. BP states, including hypertension. We hypothesized that returned to baseline 4 weeks after discontinuation. oral BH4 will reduce arterial blood pressure (BP) and Significant improvement in endothelial function was improve endothelial function in hypertensive subjects. observed in Study 1 subjects and those receiving Oral BH4 was given to subjects with poorly controlled 400 mg BH4. There was no significant change in subjects hypertension (BP 4135/85 mm Hg) and weekly measure- given the 200 mg dose. This pilot investigation indicates ments of BP and endothelial function made. In Study 1, 5 that oral BH4 at a daily dose of 400 mg or higher has À1 À1 or 10 mg kg day of BH4 (n ¼ 8) was administered a significant and sustained antihypertensive effect orally for 8 weeks, and in Study 2, 200 and 400 mg of in subjects with poorly controlled hypertension, an BH4 (n ¼ 16) was given in divided doses for 4 weeks. effect that is associated with improved endothelial NO Study 1: significant reductions in systolic (P ¼ 0.005) bioavailability. and mean BP (P ¼ 0.01) were observed with both doses Journal of Human Hypertension (2008) 22, 401–407; of BH4. Systolic BP was 15±15 mm Hg (P ¼ 0.04) lower doi:10.1038/sj.jhh.1002329; published online 6 March 2008 Keywords: tetrahydrobiopterin; endothelium; oxidative stress Introduction Nitric oxide is synthesized in the vascular endothelium by endothelial NO synthase (eNOS) Nitric oxide (NO) is a potent endothelium-derived and tetrahydrobiopterin (BH ) is an essential cofac- vasodilator that regulates blood pressure (BP) and 4 1–6 tor for eNOS. During NO catalysis, oxygen is bound regional blood flow. Decreases in NO production by the ferrous heme in the oxygenase domain of or bioavailability impair endothelium-dependent eNOS. BH4 plays a crucial role in donating an dilation that can be both a consequence as well as electron that leads to scission of the O–O bond, a cause of hypertension. Among other protective leading to formation of an iron–oxy complex that roles of the endothelium, mediated in part by NO, participates in the hydroxylation of L-arginine, are the inhibition of vascular smooth muscle cell leading to formation of NO. In the absence of BH4, proliferation and growth, and inhibition of pro- the Fe2 þ O–O complex dissociates to release inflammatory cytokine expression, platelet aggrega- superoxide (OKÀ). This phenomenon is referred to tion and oxidative modification of low-density 2 7 as eNOS uncoupling. Accumulating evidence sug- lipoprotein. Importantly, the presence of endothe- gests that hypertension increases vascular produc- lial dysfunction heralds increased risk of future tion of reactive oxygen species, which can serve to adverse cardiovascular events in patients including oxidize BH and lead to eNOS uncoupling.9,10 Our those with hypertension.8 4 previous experimental studies have shown that BH4 is oxidized to dihydrobiopterin in the vasculature of the deoxycorticosterone acetate salt hypertensive mouse, and supplementation with oral BH4 can Correspondence: Dr AA Quyyumi, Division of Cardiology, Emory reduce BP and improve oxidative stress in this University, 1364 Clifton Road, Ste D403C, Atlanta, GA 30322, model.11 USA. Several studies have assessed the effects of BH on E-mail: [email protected] 4 Received 25 July 2007; revised 21 November 2007; accepted 1 endothelial function. Sepiapterin, a substrate for December 2007; published online 6 March 2008 BH4 synthesis, improved endothelium-dependent Tetrahydrobiopterin for hypertension M Porkert et al 402 vasodilation in coronary arterioles obtained from uncontrolled hypertension (BP 4180 mm Hg systo- patients undergoing coronary artery bypass graft lic and/or 110 mm Hg diastolic), renal or hepatic 12 surgery (CABG). Acute infusion of BH4 improved dysfunction, and bleeding disorders. All subjects endothelial function in angiographically normal- gave informed consent and the study was approved appearing segments of coronary arteries in subjects by the Emory University Investigational Review with coronary artery disease or hypercholesterolae- Board. mia.13,14 A similar improvement was observed in the forearm circulation of diabetics and smokers.15–17 These studies have used either parenteral infusion Study design of BH4 or a single oral dose, and it has not been Both studies were designed as pilot investigations to shown that chronic oral administration of BH4 could (a) evaluate the effects of BH4 on BP and vascular cause a sustained improvement in endothelial function, (b) the dose–response of this effect. For function. Moreover, no prior study has examined this reason, they were not placebo controlled, but the effect of BH4 in subjects with hypertension. We included a withdrawal phase. After screening, hypothesized that chronic oral therapy with BH4 in suitable subjects were admitted to the Emory hypertensive patients will result in reduction of University General Clinical Research Center. All arterial BP as a result of improvement in endothelial BP and heart rate measurements were made after dysfunction. For this purpose, we conducted two having the patient rest in a seated position for at pilot studies where (a) the duration of action of oral least 10 min, by coordinators unaware of study BH4 and (b) its dose–response were studied in stage. Mean BP was calculated as: (systolic hypertensive subjects. BP þ 2  diastolic BP)/3. Tetrahydrobiopterin (Schircks Laboratories, Jona, Switzerland) was compounded with an equivalent Methods amount of vitamin C to ensure stability of the drug. Patient selection Subjects were advised to keep the pills in a Subjects between the ages of 18 and 75 years were refrigerator. recruited if they had uncontrolled hypertension on traditional stable antihypertensive therapy (BP X135/85) or newly diagnosed hypertension (BP Study 1: investigation of the time of onset and duration X140/90). Patients were continued on their current of action of oral BH4 antihypertensive therapy throughout the study. Eight hypertensive subjects (Table 1) were assigned Exclusion criteria included female subjects with to either 5 mg kgÀ1 dayÀ1 (n ¼ 4) or 10 mg kgÀ1 dayÀ1 childbearing potential, history of recently sympto- (n ¼ 4) of BH4, given in two divided doses orally for matic coronary or peripheral vascular disease, 8 weeks. This regimen was based on BH4 dosing in known secondary causes for hypertension, severe phenylketonuria. Weekly BP measurements were Table 1 Baseline characteristics Study 1 (n ¼ 8) Study 2 (n ¼ 16) 400 mg (n ¼ 8) 200 mg (n ¼ 8) Age (years) 60.5±11 (48–74) 57±9 (43–72) 62±8 (45–69) Males 3 4 2 Mean number of antihypertensive medications 1.4±0.9 (0–3) 2.0±1.9 (0–6) 1.9±1.0 (1–3) Treated with ACE-I or ARB 4 4 7 Treated with diuretics 3 6 2 Treated with calcium antagonists 2 3 3 Treated with beta blockade 2 2 3 Treated with statins 2 3 3 Systolic blood pressure (mm Hg) 144±6.6 (138–154) 149±10.3 (140–171) 154±12.3 (137–178) Diastolic blood pressure (mm Hg) 81±14.4 (54–100) 88±11.1 (73–108) 79±13.0 (51–92) Mean arterial pressure (mm Hg) 102±9.7 (82–115) 109±10.0 (96–129) 104±9.6 (88–118) Past medical history Coronary artery disease 0 0 2 High cholesterol (4240 mg per 100 ml) 2 5 4 Diabetes 0 2 1 Current tobacco 0 1 1 Former tobacco 2 3 3 Abbreviations: ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker. Continuous values are represented as mean±s.d. with range in parentheses. Journal of Human Hypertension Tetrahydrobiopterin for hypertension M Porkert et al 403 Study 1 after discontinuation of therapy. In Study 2, it was measured at the end of the 2-week vitamin C run-in BH4 period, after 4 weeks of BH4 therapy and 4 weeks after discontinuation of BH4. The technique has been described in detail previously.18 Briefly, stu- 0 1 2 3 4 5 6 7 8 9 14 Weeks dies were performed in a temperature-controlled BP room, and brachial diameter was measured above the antecubital fossa in the non-dominant arm using FMD an 11 MHz high resolution ultrasound transducer (Acuson Inc., Malvern, PA, USA). Flow-mediated vasodilation (FMD) was determined by inflating a BP cuff on the forearm to 4200 mm Hg for 5 min, Study 2 deflating rapidly, and recording brachial diameter at 1 min after onset of hyperaemia. Three diameter measurements were averaged on end-diastolic Vitamin C BH4 frames each time. FMD was calculated as: (average diameter with hyperaemiaÀaverage baseline dia- meter)/average baseline diameter  100. Endothe- -1 -2 0 1 2 3 4 5 8 Weeks lium-independent vasodilator response was measured as brachial artery diameter change 5 min BP after 0.4 mg sublingual nitroglycerin using the formula: (average diameter post nitroglycerinÀ FMD average baseline diameter)/average baseline Figure 1 Protocol for Studies 1 and 2.
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