Effects of Tetrahydrobiopterin on Blood Pressure
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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
    

Detailed description: 
      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.
    

Intervention name(s): Tetrahydrobiopterin; Tetrahydrobiopterin
Intervention type(s): Drug; Drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Oxidative Stress; Endothelium