Optic nerve head autoregulation

Glaucoma is an optic neuropathy of unknown etiology. Increase intraocular pressure is the most important risk factor for the disease. A variety of large scale clinical outcome trials have shown that reducing intraocular pressure leads to reduced progression of visual field loss. However, some patients progress despite adequate reduction in intraocular pressure. It has been hypothesized that vascular factors may be involved in the pathogenesis of glaucoma as well. This hypothesis has gained support by the results of several large scale studies showing that reduced ocular perfusion pressure is a risk factor for the prevalence, incidence and progression of the disease. This reduced ocular perfusion pressure may well be associated with optic nerve head ischemia. In principle increased intraocular pressure could also play a role in this context, because venous pressure in the eye almost equals intraocular pressure. Hence, any increase in intraocular pressure is associated with a decrease of ocular perfusion pressure. Whether this is, however, associated with a reduction of optic nerve head blood flow is unclear, because optic nerve head perfusion is autoregulated. In the present project we therefore aim to investigate the mechanisms of optic nerve head blood flow autoregulation in detail. Little is known about optic nerve head blood flow autoregulation in humans. A few pilot studies have been published indicating some degree of autoregulation in optic nerve head blood flow. In the present grant application we propose a number of experiments to elucidate optic nerve head autoregulation in more detail. We have already successfully done such studies for choroidal blood flow regulation, which were sponsored by the Austrian Science Foundation. In the present project four specific hypotheses are tested: Hypothesis 1: Inhibition of nitric oxide synthase modifies the response of optic nerve head blood flow to an exercise-induced increase in systemic blood pressure; Hypothesis 2: Inhibition of nitric oxide synthase modifies the response of optic nerve head blood flow to an experimental increase in intraocular pressure induced with the suction cup method; Hypothesis 3: Blockade of the endothelinA receptor subtype modifies the response of optic nerve head blood flow to an exercise-induced increase in systemic blood pressure; Hypothesis 4: Optic nerve head blood flow is more effectively regulated during exercise-induced changes in systemic blood pressure than during intraocular pressure changes induced with a suction cup. Testing these hypotheses should provide information on the degree and mechanisms of optic nerve head autoregulation to enhance our understanding of the potential involvement of autoregulatory deficits in the pathogenesis of glaucoma.

In the present project blood flow regulation of the optic nerve head and its potential influencing factors were investigated. Our results confirm that the optic nerve head shows autoregulatory behaviour during both an increase and a decrease in ocular perfusion pressure. Additionally, our data show that optic nerve head blood flow is better regulated during changes in blood pressure than during an increase in intraocular pressure. Optic nerve head blood flow regulation is complex and differs from that of the choroid. During isometric exercise, the choroid regulates its blood flow better than the optic nerve head while the opposite is the case during artificial increase in intraocular pressure. Furthermore, endothelin-1 seems to play a role in the autoregulatory process of blood flow during isometric exercise. These data indicate that the endothelin system is a potential treatment target for eye diseases with abnormal autoregulation. In contrast, nitric oxide does not seem to be involved in the regulatory processes during experimental manipulation in ocular perfusion pressure. Nitric oxide, however is an important regulator of basal vascular tone in the optic nerve head. The influence of a certain genetic variation, which is associated with age related macular degeneration, on choroidal blood flow regulation was investigated in an additional experiment. Our data indicate that the regulation of choroidal blood flow is abnormal in homozygous rs1061170 risk allele carriers. The results suggest that early onset of altered choroidal blood flow regulation in individuals homozygous for the high risk allele of a complement factor H polymorphism may be associated with vascular deficiencies and age related macular degeneration.