Effects of Tetrahydrobiopterin on Blood Pressure

Hypertension

Oxidative Stress, Endothelium

Tetrahydrobiopterin (BH4) 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 BH4 will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH4 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 BH4 (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH4 (n=16) was given in divided doses for 4 weeks

Problem of Interest: Blood vessels are lined by a single layer of cells called the endothelium. These cells actively release substances that influence a variety of functions including blood flow in the arteries. Nitric oxide (NO) is among the most important of these substances. Decrease in NO reduces blood vessel size and increases blood pressure (BP). Subjects with hypertension (high blood pressure) and those with a strong family history of hypertension but without high blood pressure also exhibit endothelial dysfunction and decreased NO activity. This abnormality predisposes individuals with high blood pressure to an increased long term risk of adverse cardiovascular events such as heart attack and stroke. NO is produced in cells by a reaction mediated by the enzyme endothelial nitric oxide synthase (eNOS). Experimental studies performed at Emory University have shown that tetrahydrobiopterin (BH4), a naturally produced substance, is an essential factor for eNOS to be normally active, because in the event of BH4 deficiency, eNOS switches from producing NO to generating oxygen free radicals that increase oxidant stress in blood vessels leading to vascular damage. Moreover, studies have shown that administration of BH4 to animals with hypertension decreases blood pressure. A recently completed study performed by the researchers at Emory University showed that BH4 pills given twice a day to 8 patients with poorly controlled high blood pressure for eight weeks improved endothelial function and decreased blood pressure without any significant side effects. After stopping BH4, the blood pressure and endothelial function returned to baseline. Hypertension has also been linked with diastolic heart failure, a condition where the squeeze of the heart is normal but it relaxes abnormally causing shortness of breath, edema and fatigue. Up to one half of cases of heart failure are caused by diastolic heart failure. Recent evidence shows that the lining cells of the heart also produce NO and that this promotes relaxation of the heart. In addition, studies here at Emory have shown that in animals with high blood pressure, NO production in the heart is reduced compared to normals. How problem will be studied: The study will consist of three parts: We, the researchers at Emory University, will recruit patients with hypertension and randomize them to various doses of BH4 to find out what the lowest dose is that produces a significant response This dose will then be used in patients with hypertension who will be randomized to BH4 or a placebo. Patients will be followed for blood pressure response and for markers of endothelial function using ultrasound and for markers of inflammation using blood samples. Patients from part 2 with evidence of abnormal heart relaxation on echocardiogram will have repeat echocardiograms after drug administration to study the effects of BH4 on heart relaxation. Advancement in Scientific Knowledge This study will advance scientific knowledge by looking at the effects of BH4, a naturally occurring substance without known major side effects, on blood pressure. We will also examine the effect of BH4 on NO and relaxation of the heart muscle. Improvement in blood pressure with BH4 will allow this to be an option for treatment of high blood pressure and potentially reducing the complications associated with this condition. Standard of care: Currently the standard of care for patients with high blood pressure includes treatment with Food and Drug Administration (FDA) approved medications such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics and calcium-channel blockers to a goal BP of less than 135/85.

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