Is the ocular L-arginine/nitric oxid pathway altered in patients with open angle glaucoma? Studies on the nitric oxid dependence of optic nerve head blood flow in man

Glaucoma is one of the most common causes of blindness in the industrialized nations. Recent investigations show that the most widely used indicator for glaucoma, the intraocular pressure is not necessarily an adequate measure of clinical severity: some eyes with high intraocular pressure do not develop glaucoma and some patients suffering from glaucoma have normal intraocular pressure. Hence factors other than intraocular pressure are likely involved in the pathogenesis of glaucoma. Several investigators have shown that ocular blood flow is reduced in patients with glaucoma. Systemic hypotension has been identified as a risk factor for the disease. These results indicate that vascular factors are involved in the pathogenesis of glaucoma. Nevertheless the current treatment of glaucoma aims to decrease intraocular pressure without paying to much attention to ocular blood flow. However, recent investigations show that most available topical antiglaucoma drugs reduce ocular blood flow. Nevertheless the pathophysiology of open angle glaucoma remains unclear. lt has been speculated that altered ocular blood flow in glaucoma patients is linked to an altered ocular endothelial function and it may well be that glaucoma is associated with an altered L-arginine/nitric oxide (NO) system. Systemic infusion of nitric oxide inhibitors reduces choroidal blood flow in cats, dogs, and humans. The effect of NO synthase inhibition on optic nerve head blood flow has not yet been investigated. As mentioned above there is considerable effort in the therapy of glaucoma in the last decade. Nevertheless intensive research activities are directed to new classes of antiglaucoma drugs. Nitrates are potentially interesting for the management of the disease. Firstly there is evidence that they reduce intraocular pressure. Secondly retrospective studies have shown that systemic administration of nitrates preserve visual function in glaucoma patients, which may partially be attributed to the neuro-protective action of these drugs. Thirdly nitrates increase optic nerve head blood flow, but not choroidal blood flow in healthy subjects. These results indicate that the L- arginine/NO system may be a target system for glaucoma therapy. However, additional information on the pathophysiology of the disease is required to more specifically direct research activities for future therapeutic regimen. We will therefore investigate the effects of two different doses of L-NMMA on optic disc blood flow. L-arginine will be co-administered to L-NMMA in 50% of the subjects under study, because some reasonable doubts concerning the specificity of L-NMMA as an inhibitor of NO-synthase have been raised. Based on the results of this pilot study we will select a dose of L-NMMA for the study in glaucoma patients. This dose should reduce optic nerve head blood flow in healthy subjects by approximately 15-20%. We will then compare the response in optic nerve head blood flow in glaucoma patients and healthy subjects. The aim of the study is to investigate the NO-dependence of choroidal and optic nerve head blood flow and to investigate whether the L-arginine/NO pathway is altered in patients with open angle glaucoma. Study medication: Pilot study: N-monomethyl-L-arginine (L-NMMA, Clinalfa AG, Läufelfingen, Switzerland) 3.0 or 6.0 mg/kg i.v for 5 min, followed by 30 or 60 g/kg/min, respectively, i.v. for 55 min. L-arginine (Clinalfa AG, Läufelfingen, Switzerland), 1 g/min infused intravenously over 30 minutes Physioiogic saline solution Glaucoma patient study: N-monomethyl-L-arginine (L-NMMA, Clinalfa AG, Läufelfingen, Switzerland), dose to be selected depending on the results of the pilot study Main outcome variables and methods: Optic disc blood flow and choroidal blood flow will be measured by laser Doppler flowmetry. Risk/benefit assessment: The role of NO in the physiology and pathophysiology of ocular blood flow has to be further elucidated before therapeutic regimen in ocular vascular disease can be directed to the L-arginine/NO pathway. In the present study drug effects will be assessed by non-invasive methods. L-NMMA, and L-arginine are well tolerated. L-NMMA has been used repeatedly to inhibit endogenous production in a number of studies. Administration of L-NMMA may cause mild and transient elevations of blood pressure and decreases of heart rate. L-Arginine my cause mild transient vasodilation without systemic effects and has been used repeatedly with the same dosage. Hence the risk/benefit ratio appears acceptable.