Nebivolol in the Supine Hypertension of Autonomic Failure

Nebivolol is distinct among beta-blockers by its ability to increase nitric oxide (NO)
bioactivity. The contribution of this effect to the pharmacological actions of the drug,
however, is difficult to ascertain in normal subjects because of the confounding
contribution of the autonomic nervous system. Autonomic failure patients provide a unique
model of hypertension devoid of autonomic modulation but sensitive to NO mechanisms. We
propose to determine the effect of nebivolol on blood pressure in this patient population.
A decrease in blood pressure will imply increased bioactivity of NO. Comparisons will be
made with placebo, metoprolol (as a negative control) and sildenafil (as a positive
control).

Inclusion Criteria:

- Male or female and aged 18 years or over.

- Clinical diagnosis of orthostatic hypotension associated with Primary Autonomic
Failure (PD, MSA and PAF).

- A documented fall in systolic blood pressure of at least 20 mmHg, or in diastolic
blood pressure of at least 10 mmHg, within 3 minutes after standing.

- Supine hypertension, defined as a systolic blood pressure >150 mm Hg or diastolic
blood pressure > 90 mm Hg.

- Provide written informed consent to participate in the study and understand that they
may withdraw their consent at any time without prejudice to their future medical
care.

Exclusion Criteria:

- Have changed dose, frequency and or type of prescribed medication, within two weeks
of study start.

- Women of childbearing potential who are not using a medically accepted contraception.

- Have, in the investigator's opinion, any significant cardiac, systemic, hepatic, or
renal illness.

- Diabetes mellitus or insipidus.

- In the investigator's opinion, have clinically significant abnormalities on clinical
examination or laboratory testing.

- In the investigator's opinion, are unable to adequately co-operate because of
individual or family situation.

- In the investigator's opinion, are suffering from a mental disorder that interferes
with the diagnosis and/or with the conduct of the study, e.g. schizophrenia, major
depression, dementia.

- Are not able or willing to comply with the study requirements for the duration of the
study.

- Persons on drugs with beta-blocking potential (e.g., amiodarone), persons taking
scheduled or as needed nitrates and persons on drugs with alpha-blocking potential
(e.g. tamsulosin).