The Effect of Nebivolol on Endothelial Dysfunction in African Americans With Hypertension

Study Overview
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Brief Summary
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High blood pressure (hypertension) is called the silent killer because many people do not know they have it, and do not know when it is well controlled. Unfortunately, over time uncontrolled hypertension can cause irreversible organ damage that can lead to heart attack, stroke, heart failure, and kidney failure. If a person cannot control their blood pressure with diet and exercise, doctors often prescribe medications to help control the blood pressure. Nebivolol is a medication that has been recently approved by the FDA for the treatment of hypertension. Our study will investigate whether treatment with nebivolol, as compared to another medication called metoprolol, in African Americans with hypertension will be more effective in protecting blood vessels against the harmful effects of high blood pressure. Over time high blood pressure causes hardening of the arteries (atherosclerosis) which leads to narrowing of the blood vessels and reduces blood flow to our organs. Arteries also relax and contract naturally, which further changes the blood supply. When arteries are narrowed, exercise can bring on a condition in which the blood supply is inadequate, and this might result in the sensation of pain. Cells lining our blood vessels produce a variety of substances that normally cause arteries to relax. Two of these substances are called nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). We are trying to determine the nature of these substances in African Americans with high blood pressure and how it is affected by nebivolol and metoprolol. One way to determine this is to inject drugs such as L-NMMA (N(G)-monomethyl-L-arginine) or TEA (tetraethylammonium chloride), which block the production of NO and EDHF respectively, and then study what happens to the blood flow at rest and during exercise. It is our thought that nebivolol, in comparison to metoprolol, will increase the substances that naturally cause arteries to relax and improve blood supply.

Official Title
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The Effect of Nebivolol on Endothelial Dysfunction in African Americans With Hypertension

Conditions
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High Blood Pressure

Intervention / Treatment
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* Drug: Nebivolol
* Drug: Metoprolol XL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or post-menopausal females aged 18-80 years. Subjects self-identified as black or African-American. Diagnosis of hypertension. Patients on current anti-hypertensive therapy that does not include beta blockade should have BP >135/85. Patients on anti-hypertensive therapy including beta blockers will have their beta blockers discontinued gradually over 2 weeks before enrolment. Concomitant therapy: Patients will be allowed to be on concomitant therapy with aspirin, statins, thiazide diuretics, calcium antagonists (for treatment of hypertension), clonidine, or vasodilators. Patients will be on stable medical therapy for at least 2 months before recruitment. Patients with previous treatment with beta adrenergic blockers (metoprolol, propranolol, atenolol, and labetalol) will also be eligible to participate, but will be randomized to the study beta blocker. Exclusion Criteria: Initiation or change in dose of statin or other anti-hypertensive therapy within 2 months before the study Inability to return to Emory for follow-up testing Age < 21 or >80 years Premenopausal females with potential for pregnancy Acute infection in previous 2 weeks On angiotensin antagonists (ACE inhibitors or ARBs) History of substance abuse Current neoplasm Chronic renal failure [creatinine > 2.5 mg/dL] or liver failure (liver enzymes >2X normal) Acute coronary syndrome, Class IV heart failure, CVA, coronary intervention within 2 months Known aortic stenosis, hypertrophic cardiomyopathy. Inability to give informed consent

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nebivolol followed by Metoprolol XL<br>Subjects are randomized to Nebivolol 5mg and titrate to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration subjects will cross over to Metoprolol XL 50mg and titrate to Metoprolol XL 100mg two weeks after cross over. | Drug: Nebivolol<br>* Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then cross over to take 10 weeks of the comparator drug.<br>Drug: Metoprolol XL<br>* Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then cross over to take 10 weeks of the comparator drug.<br>|
| Active Comparator: Metoprolol XL followed by Nebivolol<br>Subjects are randomized to Metoprolol XL 50mg and titrate to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration subjects will cross over to Nebivolol 5mg and titrate to Nebivolol 10mg two weeks after cross over. | Drug: Nebivolol<br>* Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then cross over to take 10 weeks of the comparator drug.<br>Drug: Metoprolol XL<br>* Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then cross over to take 10 weeks of the comparator drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute. | 12 weeks | 
| Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurotransmitter Agents, Metoprolol, Nebivolol, Nitric Oxide, Adrenergic beta-Antagonists, Antihypertensive Agents, Vasodilator Agents, Anti-Arrhythmia Agents, Sympatholytics, Vascular Resistance, Cardiovascular Diseases, Metoprolol succinate, Therapeutic Uses, Vascular Diseases, Cardiovascular Agents, Endothelium-Dependent Relaxing Factors