Role of Nitric Oxide in the Control of Ocular Blood Flow
Introduction
For a long time it was assumed that acetylcholine exerts its vasodilator effects on blood vessels via a direct mechanism. However, in 1980 (Furchgott and Zawadzki (1980) observed in their famous experiments that acetylcholine-induced vasodilation is dependent on the presence or absence of the vascular endothelium. From these experiments it was obvious that the endothelium produces a vasodilator, which was initially called “endothelial derived relaxing factor” (EDRF), playing a key role in the effects of acetylcholine on vascular tone. However, in the subsequent years a number of scientists failed to identify the molecular structure of the EDRF, although considerable effort was put to this question. Even without knowing the molecular structure of EDRF it was possible to identify cyclic GMP as a second messenger (Rapoport et al., 1983). Some years later nitric oxide (NO) or a closely related compound was identified as the ERDF (Palmer et al., 1987; Ignarro et al., 1987). Soon thereafter it was recognized that the vascular endothelium synthesizes NO from the amino acid l-arginine with the stoichiometric formation of citrulline (Palmer et al., 1988; Palmer and Moncada, 1989). Since then numerous investigators tried to elucidate the physiological and pathophysiological roles of NO in the human body with a continuously growing number of NO-related articles appearing every year. This is also true for the role of NO in the eye where NO is implicated in the pathogenesis of diseases such as glaucoma and diabetic retinopathy. Whereas several overview articles have been published that cover certain aspects of this topic (Haefliger et al (1994a), Haefliger et al (1999), Haefliger et al (2001); Brown and Jampol, 1996; Goldstein et al., 1996; Becquet et al., 1997; Schmetterer and Wolzt, 1999; Koss, 1999; Hardy et al., 2000) the present review focuses on the role of NO in the regulation of ocular perfusion with special emphasis to currently available data in humans.
Section snippets
Biosynthesis of NO
Nitric oxide is synthesized by three distinct isoforms of nitric oxide synthase (NOS). These isoforms are the products of three different genes. NOS oxidizes the guanidine group of l-arginine in a process that involves five electrons. The three isoforms of NOS are classified as follows: neuronal NOS (NOS1), calcium calmodulin independent or “inducible” NOS (NOS2) and endothelial NOS (NOS3). Previously the NO synthases were classified as inducible and constitutive, but recent experiments have
Identification
In the recent years the NO pathway has been investigated in all ocular tissues. All types of NO-synthase were identified in animal and human eyes. A variety of different approaches exist to analyze the existence of NO-synthase in biological specimen. These divide into immunological, histochemical, radioactive and molecular biology based techniques. All of these techniques have been used to gain insight into the local distribution of NO-synthase in the eye.
A widely used method for the
Role of NO in the maintenance of basal choroidal blood flow
There are several factors, which hamper the extrapolation of animal studies for the situation in humans. It is well known that the human eye has a specific angioarchitecture, which is not well reflected in most other species. In addition, numerous species differences have been reported with respect to the role of NO in the ocular vasculature. The fact that histamine causes vasodilatation in some ocular vessels, whereas it induces vasoconstriction in others has been discussed in detail above. It
The roles of NO in primary open angle glaucoma
Considering the multifactorial pathogenesis of glaucoma, NO may represent one of the possible links between altered blood flow, elevated intraocular pressure and apoptosis, phenomena that are suggested to be underlying mechanisms of glaucomatous damage.
NO in ocular retinal ischemia and reperfusion
There is evidence that NO plays a key role in ischemic neurodegeneration (Samdani et al., 1997). In ischemia excessive activation of NOS1 due to NMDA receptor activation by excitotoxic amino acids promotes early neuronal injury after ischemic onset. NO formation is thereafter sustained by NOS2 activation, which is responsible for the delayed neuronal cell death in reperfusion injury. Excessive NO induces enzyme activation and DNA degeneration, inhibition of mitochondrial respiration due to its
Conclusions
Over the last decade it was recognized that NO is among the most important regulators of ocular perfusion. This has been shown in numerous in vitro and animal studies, but also in an increasing number of human studies. This provides us with the hope that ocular perfusion abnormalities as seen in ocular vascular disease may be treated via the l-arginine/NO-pathway. However, NO exerts a wide variety of biological actions, which makes a selective intervention difficult. Moreover, the role of
Uncited References
Hayreh, 1999.
Acknowledgments
Part of the experimental work done by the authors was funded by a grant from the “Österreichischer Fonds zur Förderung der Wissenschaftlichen Forschung” (Grant Nr. P 13050). The authors thank Prof. Dr. Wolzt for many helpful suggestions and Dr. Luksch and Dr. Frank for help in preparing the manuscript.
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