Nebivolol in the Supine Hypertension of Autonomic Failure

Condition(s) targeted: Hypertension; Pure Autonomic Failure; Multiple System Atrophy

Intervention: Placebo (Drug); Nebivolol 5 mg (Drug); metoprolol tartrate 50 mg (Drug); Sildenafil25 mg (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: Vanderbilt University

Official(s) and/or principal investigator(s):
Italo Biaggioni, MD, Principal Investigator, Affiliation: Vanderbilt University

Overall contact:
Bonnie K Black, RN, Phone: 615-322-3304, Email: adcresearch@vanderbilt.edu

The purpose of this study is to evaluate the effect of the antihypertensive drug, nebivolol (Bystolic), compared to metoprolol (Lopressor) and sildenafil (Viagra) on blood pressure in patients with autonomic failure and supine hypertension.

Official title: Effect of Nebivolol on Blood Pressure in a Model of Hypertension Sensitive to Potentiation of Nitric Oxide Bioactivity

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator)

Primary outcome: The fall in systolic blood pressure, measured from 8 pm to 8 am, after a single dose of nebivolol

Secondary outcome:

Urinary volume

SBP and DBP 1 minute post standing the following morning

The mean score of Item 1 of the Orthostatic Hypotension Symptom Assessment (OHSA) taken after standing morning following the study

Detailed description: 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).

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

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).

Bonnie K Black, RN, Phone: 615-322-3304, Email: adcresearch@vanderbilt.edu

Vanderbilt University, Nashville, Tennessee 37232, United States; Recruiting
Italo Biaggioni, MD, Principal Investigator
David Robertson, MD, Sub-Investigator
Satish Raj, MD, Sub-Investigator
Andre Diedrich, MD, PhD, Sub-Investigator
Alfredo Gamboa, MD, Sub-Investigator
Cyndya Shibao, MD, Sub-Investigator
Bonnie Black, RN, Sub-Investigator
Luis Okamoto, MD, Sub-Investigator
Hossam Mustafa, MD, Sub-Investigator
Cindy Dorminy, MEd, LPN, Sub-Investigator
Amy Arnold, PhD, Sub-Investigator

Autonomic Dysfunction Center. Vanderbilt University

Related publications:

Biaggioni I, Garcia F, Inagami T, Haile V. Hyporeninemic normoaldosteronism in severe autonomic failure. J Clin Endocrinol Metab. 1993 Mar;76(3):580-6.

Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, Wooding SJ, Ritter JM. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995 Sep;274(3):1067-71.

Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, Raj SR, Robertson D, Biaggioni I. Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure. Hypertension. 2008 Jun;51(6):1531-6. Epub 2008 Apr 21.

Gupta S, Wright HM. Nebivolol: a highly selective beta1-adrenergic receptor blocker that causes vasodilation by increasing nitric oxide. Cardiovasc Ther. 2008 Fall;26(3):189-202. Review.

Shannon J, Jordan J, Costa F, Robertson RM, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension. 1997 Nov;30(5):1062-7.

Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001 Jul 31;104(5):511-4.

Starting date: January 2010
Last updated: May 10, 2012