The Effects of Nebivolol on the NO-system in Patients With Essential Hypertension (NEBI)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Erling Bjerregaard Pedersen, Regional Hospital Holstebro
ClinicalTrials.gov Identifier:
NCT01679652
First received: September 1, 2012
Last updated: March 1, 2014
Last verified: March 2014
  Purpose

Investigators want investigate the following hypothesis:

  1. Nebivolol increases nitric oxide activity in the systemic circulation and the kidney
  2. The increased activity of nitric oxide during nebivolol treatment can be demonstrated by inhibition of NO synthesis with L-NMMA. We expect increased responses in blood pressure and sodium excretion is expected during nebivolol treatment compared to placebo.

Condition Intervention Phase
Essential Hypertension
Drug: Nebivolol
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effects of Nebivolol on the NO-system in Patients With Essential

Resource links provided by NLM:


Further study details as provided by Regional Hospital Holstebro:

Primary Outcome Measures:
  • Fractional excretion of sodium [ Time Frame: 5 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Blood pressure [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Both ambulatory blood pressure and office and central blood pressure before and during L-NMMA infusion

  • Pulse wave velocity [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    before and during L-NMMA infusion

  • Plasma renin concentration [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    before and during L-NMMA infusion

  • Plasma aldosterone concentration [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Plasma angiotensin II concentration [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Plasma Endothelin concentration [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Plasma brain natriuretic peptide concentration [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Plasma vasopressin concentration [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Glomerular filtration rate [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Urinary excretions of epithelial sodium channels [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Urinary excretions of aquaprorin-2 [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • 24-hour ambulatory blood pressure [ Time Frame: 5 days ] [ Designated as safety issue: No ]
  • Free water clearance [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion

  • Urine flow [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Before and during L-NMMA infusion


Enrollment: 25
Study Start Date: August 2012
Study Completion Date: September 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nebivolol
Tablet Nebivolol 5 mg (oral use) for 5 days
Drug: Nebivolol
Tablet i blinded in capsula
Other Name: Tradename in Denmark: Hypoloc
Placebo Comparator: Placebo
Inactive placebo given as tablet for 5 days
Drug: placebo

Detailed Description:

Beta-blockers are no longer recommended as first line treatment in essential hypertension. Evidence mainly based on clinical trails with the non-vasodilating beta-blockers atenolol and propanolol points towards that beta-blockers have an increased risk of stroke compared to ACE-inhibitors, calcium channel blockers and thiazides. However, this Nebivolol is a third generation beta-blocker with vasodilating properties. Nebivolol decreases peripheral blood pressure to the same extend as other beta-blockers but in contrast to atenolol nebivolol also reduces central blood pressure. Furthermore nebivolol increases nitric oxide (NO) availability in forearm vessels, maybe through activation of beta-3 receptors. The nitric oxide system plays a central role in both renal sodium and water handling and regulation of vascular tone and blood pressure. It has not been investigated if nebivolol changes NO availability in the kidney.

Investigators want investigate the following hypothesis:

  1. Nebivolol increases nitric oxide activity in the systemic circulation and the kidney
  2. The increased activity of nitric oxide during nebivolol treatment can be demonstrated by inhibition of NO synthesis with L-NMMA. Investigators expect increased responses in blood pressure and sodium excretion is expected during nebivolol treatment compared to placebo.

Purpose The purpose of this study is to investigate the effects of nebivolol on renal handling of sodium and water (Glomerular filtration rate, urine production, free water clearance, excretion of proteins from epithelial sodium channels (u-ENaCαβγ) and aquaporin channels (u-AQP2) and sodium and potassium excretion), plasma concentrations of vasoactive hormones (renin, angiotensin II, aldosterone, vasopressin, atrial natriuretic peptide, brain natriuretic peptide and endothelin), central blood pressure, pulse wave velocity (PWV) and augmentation index, under basal conditions and during inhibition of nitric oxide synthesis in patients with essential hypertension.

Design 25 patients with essential hypertension are recruited in this randomised, cross over, placebo-controlled, double blinded study with two treatment periods (nebivolol/placebo). Each subject will attend to two examination days. Four days prior to each examination days and on the morning of each examination day subjects are given either nebivolol 5 mg pr. day or placebo. During treatment periods subject are given a standardized diet. On the examination days subject are given L-NMMA, a nitric oxide synthase inhibitor, and renal function, central hemodynamic and vasoactive hormones are evaluated during basal conditions and during inhibition of nitric oxide synthesis.

Perspectives This study is expected to contribute to increasing the knowledge about the mechanisms involved in the development and progression of cardiovascular disease. Beta-blockers are not recommended as first line treatment in essential hypertension but the results from this study may influence clinical treatment of essential hypertension in the future.

  Eligibility

Ages Eligible for Study:   40 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Increased blood pressure (above 135 mmHg systolic or 85 mmHg diastolic in day time in 24 hour blood pressure measurement taking 5 or 10 mg amlodipine
  • Men and women
  • age 40 - 70 years
  • informed consent

Exclusion Criteria:

  • diabetes mellitus
  • glomerular filtration rate < 30 ml/min
  • albuminuria > 1,5 g/l
  • renogram which suggests secondary hypertension
  • clinical signs of pheochromocytoma or increased p-metanephrines
  • clinical important sign og heart, lung, liver, thyroid or neoplastic diseases
  • clinical important deviations in routine blood samples or ECG
  • drug or alcohol abuse
  • pregnancy or nursery
  • intolerance to nebivolol
  • blood donation with a month of the first examination day
  • inacceptable increase in blood pressure durin L-NMMA infusion (200/120)
  • inacceptable side effects to amlodipine
  • blood pressure increase above 170/105 on highest dose amlodipine (10 mg)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01679652

Locations
Denmark
Department of Medical Research, Holstebro Hospital
Holstebro, Denmark, 7500
Sponsors and Collaborators
Erling Bjerregaard Pedersen
Investigators
Study Chair: Erling B Pedersen, MD Department of medical Research, Holstebro Hospital
Principal Investigator: Frank H Mose, MD Department of Medical Research, Holstebro Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: Erling Bjerregaard Pedersen, MD, Regional Hospital Holstebro
ClinicalTrials.gov Identifier: NCT01679652     History of Changes
Other Study ID Numbers: FHC-1-2012
Study First Received: September 1, 2012
Last Updated: March 1, 2014
Health Authority: Denmark: The Regional Committee on Biomedical Research Ethics
Denmark: Danish Dataprotection Agency

Keywords provided by Regional Hospital Holstebro:
Essential hypertension
Nitric oxide
Nebivolol
Fractional excretion of sodium

Additional relevant MeSH terms:
Hypertension
Cardiovascular Diseases
Vascular Diseases
Nebivolol
Adrenergic Agents
Adrenergic Antagonists
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Antihypertensive Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 21, 2014