Close arterial administration of indomethacin induces vasoconstriction of retinal arterioles in pigs [23]. This is in good agreement with data showing that indomethacin reduces optic nerve head oxygen tension [187]. In healthy humans, systemic administration of indomethacin is associated with a pronounced decrease in choroidal and retinal blood ßow [252]. Whether these effects of indomethacin are, however, related to the effects of COX inhibition is doubtful, because ibuprofen and naproxen do not change retinal or choroidal blood ßow [186]. This hypothesis only recently gained support by the observation that indomethacin, but not ibuprofen, diclofenac, ketoprofen, a parecyclo-oxygenase-2 inhibitor, and lornoxicam affected optic nerve head oxygen tension [171]. Only few data are available for ocular hemodynamic effects of aspirin. In a study involving eight patients with diabetes, an improvement of retinal blood ßow was however observed after 14 days of aspirin treatment [59].

As mentioned above, lipoxygenase and P450 epoxygenase can also convert arachidonic acid. The role of the resulting metabolites such as hydroperoxyeicosatetraenoic acids (HPETEs), HETEs, and epoxyeicosatrienoic acid (EETs) in controlling ocular perfusion is not well characterized. In the newborn pig, however, the P 450 epoxygenase metabolite 20-HETE appears to mediate part of the vasoconstrictor response to hyperoxia [267].

In the literature unoprostone has also been discussed as a prostaglandin analog. Unoprostone isopropyl, however, is a synthetic docosanoid that has been introduced for the treatment of glaucoma. It is a compound with a 22-carbon chain and resembles the naturally occurring oxygenated metabolites of the docosahexaenoic and the docosatetraenoic acids. The latter are 22-carbon polyunsaturated omega-3 fatty acids. In the rabbit, topical unoprostone induces an increase in iris blood ßow as evidenced with two different methods [242] and improves optic nerve head perfusion [172, 228]. In healthy subjects and normal-tension glaucoma patients, laser speckle studies indicates that topical unoprostone is capable of increasing blood ßow to the posterior pole of the eye [121, 129, 147, 236]. A study using laser Doppler ßowmetry does not conÞrm these

results but reported that unoprostone is capable of reversing the vasoconstrictor effects of exogenous ET-1 [194]. A study using pulsatile ocular blood ßow also did not Þnd an effect of topical unoprostone on ocular blood ßow [126]. In patients with normal-tension glaucoma, a 7-day treatment with unoprostone did not affect choroidal or optic nerve blood ßow as assessed by means of laser Doppler ßowmetry [14].

13.4Adrenergic Control

Given that alpha receptor agonists as well as betareceptor blockers have been shown to effectively reduce IOP and are therefore widely used in the therapy of glaucoma, the effect of adrenergic drugs on ocular blood ßow has attracted much interest.

13.5Alpha Receptors

Alpha receptors have been indentiÞed in several ocular tissues, and it is well known today that both alpha-1 and alpha-2 adrenoceptors exist in the human eye. However, the situation is complicated by the fact that for both, alpha-1 and alpha-2 adrenoceptors, several different subtypes exist. In particular, at least three different alpha-1 adrenoceptors have been detected (alpha-1a, alpha-1b, and alpha-1c) [156], and there is compelling evidence that alpha-1 receptors play also an important role in the eye. More speciÞcally, alpha-1a and alpha-1b receptors were found in the pig retina. In the rabbit, alpha-1a and alpha1b receptors were detected in the ciliary body, iris and, retina, whereas in the choroid, only alpha-1a adrenoceptors were detected [255]. In addition, alpha-1 adrenoceptors have also been found in both the glia and the neurons of the rabbit retina [180].

Using the radioligand technique, alpha-2 adrenoceptors have been found in the iris and the ciliary body of rabbits [158]. In human eyes, alpha-2 adrenoceptors have been detected in the iris, the ciliary epithelium, the ciliary muscle, and the choroid [151]. As for the alpha-1 adrenoceptors, in mammals, at least three distinct alpha-2 receptors exist, namely, alpha-2a, alpha-2b, and