Role of Endothelin- and Nitric Oxide-system in the Regulation of Optic Nerve Head Blood Flow During Changes in Ocular Perfusion Pressure

Study Overview
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Brief Summary
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Autoregulation is the ability of a vascular bed to maintain blood flow despite changes in perfusion pressure. The existence of an effective autoregulation in the optic nerve circulation has been shown in animals and humans. The exact mechanism behind this autoregulation is still unknown. The motive for the investigation of optic nerve head (ONH) blood flow autoregulation is to enhance the understanding of pathologic eye conditions associated with ocular vascular disorders. To clarify the regulatory mechanisms of ONH microcirculation is of critical importance to understand the pathophysiology of glaucoma because there is evidence that glaucoma is associated with optic nerve head ischemia. Several studies indicate that a disturbed autoregulation might contribute to glaucomatous optic neuropathy. Previous findings suggest endothelial dysfunction in glaucomatous optic neuropathy, in particular alterations in endothelin- and nitric oxide- system, which both play an important role in local regulation of vascular tone. In the present study, changes in ocular perfusion pressure will be performed during administration of drugs, which may potentially alter the pressure-flow relationship. These drugs include endothelin-1 and the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA).

Official Title
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Role of endothelin-and Nitric Oxide-system in the Regulation of Optic Nerve Head Blood Flow During Changes in Ocular Perfusion Pressure

Conditions
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Ocular Physiology, Optic Disk, Regional Blood Flow

Intervention / Treatment
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* Drug: NG-monomethyl-L-arginine (L-NMMA)
* Drug: Endothelin-1 (ET-1)
* Drug: Physiologic saline solution (placebo control)
* Device: Laser Doppler flowmetry
* Device: Goldmann applanation tonometer
* Device: HP-CMS patient monitor
* Procedure: Suction cup method


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged between 18 and 35 years, nonsmokers Body mass index between 15th and 85th percentile (Must et al. 1991) Normal findings in the medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant Normal laboratory values unless the investigator considers an abnormality to be clinically irrelevant Normal ophthalmic findings, ametropy < 1 Dpt Exclusion Criteria: Regular use of medication, abuse of alcoholic beverages, participation in a clinical trial in the 3 weeks preceding the study Treatment in the previous 3 weeks with any drug Symptoms of a clinically relevant illness in the 3 weeks before the first study day History of hypersensitivity to the trial drug or to drugs with a similar chemical structure History or presence of systemic or pulmonary hypertension, or other cardiac or pulmonary diseases History or presence of gastrointestinal, liver or kidney disease, or other conditions known to interfere with, distribution, metabolism or excretion of study drugs Blood donation during the previous 3 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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

| Intervention/Treatment |
| --- |
|Drug: NG-monomethyl-L-arginine (L-NMMA)|bolus 6 mg/kg over 5 minutes followed by a continuous intravenous infusion of 60 µg/kg/min over 12 minutes; twice on 1 study day|
|Drug: Endothelin-1 (ET-1)|5 ng/kg/min intravenous infusion over 17 minutes; twice on 1 study day|
|Drug: Physiologic saline solution (placebo control)|intravenous infusion over 20 minutes; twice on 1 study day|
|Device: Laser Doppler flowmetry|blood flow measurements at the temporal neuroretinal rim of the optic nerve head|
|Device: Goldmann applanation tonometer|Intraocular pressure measurements|
|Device: HP-CMS patient monitor|blood pressure and pulse rate measurements|
|Procedure: Suction cup method|The IOP will be raised by an 11 mm diameter, standardized suction cup placed on the temporal sclera with the anterior edge at least 1 mm from the limbus.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ONH pressure-flow relationship |  | up to 3 study days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelin-1, L-NG-Monomethyl Arginine, Optic Nerve Head blood flow