Effects of Tetrahydrobiopterin on Blood Pressure

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:

1. 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

2. 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.

3. 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.