is also supported by another experiment from the same group. In this experiment, the vasoconstrictor response of the retinal circulation to administration of serotonin was examined in a primate model [58]. Monkeys with arteriosclerotic lesions, induced by an atherogenic diet, showed a pronounced vasoconstrictor response to serotonin. However, after an 18-month normal diet, the monkeys showed regression of the atherosclerotic lesions, which also led to an abolished response to serotonin [58].

Hayreh et al. have studied the effect of exogenously administered serotonin on the ocular circulation in a monkey model [101]. For this purpose, serotonin in a dose of 40 mg/kg/min was administered intravenously in 18 arteriosclerotic and 5 normal cynomolgus monkeys. To evaluate changes in the ocular fundus, fundus photography and ßuoroscein angiography was performed under basal condition and during serotonin infusion. Whereas the authors observed no changes in normal monkeys, serotonin produced a transient occlusion or delayed Þlling of both the central retinal artery and the posterior ciliary artery in

arteriosclerotic animals [101]. Based on these results, the authors have speculated that ischemic episodes in the eye such as amaurosis fugax or retinal arterial occlusions could be due to vasospasm induced by serotonin released by platelet aggregation in atherosclerotic vessels [100]. However, the study also revealed a marked interindividual as well as interocular variability in the rate and site of susceptibility to vasospasm, not related to generally accepted risk factors for atherosclerosis such as cholesterol. Thus, the hypothesis that serotonin is involved in ischemic events in the eye has to be proven in further experiments.

13.7Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) are a class of drugs that suppress the activity of carbonic anhydrase, an enzyme necessary to catalyze the rapid conversion of carbon dioxide to bicarbonate and protons. Given that this reaction is ubiquitous throughout the body, several isoforms of the CA (Fig. 13.10) can be found, from which CA-I,

H2O + CO2 HCO3¯ + H+

Fig. 13.11 The reaction catalyzed by carbonic anhydrase

CA-II, and CA-IV are considered to be most important ones in the human eye. Today, CAIs are widely used to decrease intraocular pressure. The use of CAIs to lower intraocular pressure is based on the Þnding made 50 years ago that the inhibition of CA leads to a pronounced reduction in aqueous humor production and thus in a decrease in intraocular pressure [15]. This has been explained by the fact that aqueous humor secretion depends on the production of bicarbonate (HCO3−), catalyzed by carbonic anhydrase II, which is located in the ciliary epithelium. CA induces the conversion of CO2 to H2CO3, which in turn dissociates into HCO3− and H+ (Fig. 13.11). Consequently, inhibition of CA leads to decreased production of bicarbonate and to decreased intraocular pressure.

However, blockade of CA has also additional impact on the vasculature. In particular, the shift of the equilibrium from bicarbonate to CO2 due to carboanhydrase inhibition may lead to increased tissue pCO2 and to lower tissue pH. This is of special importance because local pCO2 and tissue pH play a role in local blood ßow regulation. Based on these theoretical considerations, it has been hypothesized that inhibition of carboanhydrase may lead to vasodilatation and increased blood ßow. Consequently, many studies have focused on the effect of systemic and local CAIs on ocular blood ßow.

13.8Acetazolamide

The Þrst CAI widely used in ophthalmology was acetazolamide. However, beside its strong intraocular pressure lowering effect, the chronic treatment is accompanied by considerable side effects such as paresthesias, malaise, or hypokalemia in the majority of patients [188]. The obvious approach to limit the systemic side effects by topical administration of the drug was precluded by the fact that both topical administration and the

subconjunctival injection of acetazolamide failed to lower the IOP of rabbits [62, 75].

First evidence of an effect on ocular blood ßow caused by systemic administration of acetazolamide was derived from animal experiments in a model of ocular hypertensive rabbits. By the means of the microsphere method, it was observed that administration of acetazolamide leads to a pronounced increase in retinal and choroidal blood ßow [36]. These preliminary results have been conÞrmed by several other studies in different species, including humans. Rassam et al. investigated the effect of intravenously administered acetazolamide on ocular blood ßow in healthy subjects [199]. Acetazolamide was administered intravenously at a dose of 500 mg, and retinal blood ßow was calculated based on measurements of red cell velocity using laser Doppler velocimetry and vessel diameter measurement using computerized digital image analysis of fundus photographs. The data indicate a signiÞcant increase in both retinal blood ßow and retinal vessel diameters 60 min after drug injection [199].

To assess perimacular retinal blood ßow, Grunwald et al. have measured leukocyte ßow with the blue-Þeld system before and after ingestion of 500 mg acetazolamide in a randomized, placebo-controlled study [80]. However, the authors did not Þnd a signiÞcant change in leukocyte ßow after drug administration.

Differing results for the effect of acetazolamide on retrobulbar blood ßow as assessed by the color Doppler technique have been reported. Harris et al. did not Þnd a signiÞcant effect of 1,000 mg of acetazolamide administered orally on peak systolic, end-diastolic velocities or resistance index in the ophthalmic or central retinal arteries [95]. These results are in contrast to the Þndings of Dallinger et al., who also focused on the effects of acetazolamide on retrobulbar blood ßow [40]. This study indicated that intravenous administration of acetazolamide increases mean blood ßow velocity in the middle cerebral artery and ophthalmic artery in a dose dependent manner [40] (Fig. 13.12).

These results have been conÞrmed by another study of the same group [122] who found an

Percent change from baseline

O O

S

S O

O

S

NH2

NH

studies used intravenously administration of the study drug, which in turn may lead to higher plasma drug concentrations.

The work of Dallinger et al. also indicates that acetazolamide increases fundus pulsation amplitude as measured with laser interferometery, which gives an estimate of pulsatile choroidal blood ßow [40]. These results are in keeping with other studies investigating the effect of acetazolamide on choroidal blood ßow [122].

Fig. 13.13 Dorzolamide

increase in blood velocity after administration of the drug. The reason for the differing results is however still unclear but may be related to different routes of drug administration used in the studies. Whereas in the work of Harris et al., acetazolamide was administered orally, the latter

13.9Dorzolamide

Dorzolamide hydrochloride is a water-soluble inhibitor of carbonanhydrase (Fig. 13.13). From a chemical view, it consists of a heterocyclic thienothiopyran resulting in an increased lipophilicity compared to acetazolamide [188]. Because of its better penetration through the cornea, dorzolamide is used as a topical CA-inhibitor to lower intraocular pressure. Topical dorzolamide leads to

a pronounced decrease in intraocular pressure [215] due to a strong reduction in aqueous humor production [107].

The hemodynamic effect of dorzolamide was the focus of a several studies in healthy subjects and glaucoma patients that reached differing conclusions about the ability of dorzolamide to increase ocular hemodynamics, but most studies indicate vasodilator effects. The reason for the differing results is still a matter of controversy. This may be related to the variety of methods used for assessing blood ßow and the differences in the ocular vascular beds under study. Furthermore, given that dorzolamide is mainly used in glaucoma patients, a large number of studies have been performed in glaucoma patients. However, it has to be considered that glaucoma is a multifactorial disease and drug effects may be different depending on the type of glaucoma.

13.10 Retrobulbar Blood Flow

As one of the Þrst studies in humans, Harris et al. investigated the effect of topical dorzolamide blood velocity in four retrobulbar vessels (nasal and temporal posterior ciliary, central retinal and ophthalmic artery) and on retinal arteriovenous passage time with SLO [94]. For this purpose, two drops 2% dorzolamide or placebo were instilled in a group of 11 healthy volunteers and ocular hemodynamic parameters were assessed at baseline and after drug administration in a dou- ble-masked, balanced study. As measured 2 h after drug administration, no difference in retrobulbar hemodynamic parameters was observed. However, the same study revealed accelerated retinal arteriovenous passage of ßuorescein as well as an increase in capillary velocity in the optic nerve head, both variables indicating but not proving an increase in blood ßow [94].

The same group investigated the effect of dorzolamide on ocular hemodynamics in patients with glaucoma. Again, blood ßow velocities in retrobulbar vessels were measured with the CDI technique, as well as retinal arteriovenous passage time and retinal arterial/venous diameters with SLO [96]. Included were 18 patients

with normal-tension glaucoma, treated for 4 weeks with 2% topical dorzolamide after a washout phase and compared to a placebo group. Measurements were made at baseline and 2 and 4 weeks after start with dorzolamide treatment, respectively. In agreement with their previous results, the authors did not Þnd a change in retrobulbar hemodynamic parameters in response to dorzolamide [96]. However, although no changes in retinal vessel diameters were observed, an increased retinal arteriovenous passage time was observed.

Data about the effect of dorzolamide on retrobulbar blood ßow are also available from Matinez et al. The authors have investigated the effect of dorzolamide on 26 patients with openangle glaucoma compared to a control group consisting of 13 normal eyes [150]. All eyes underwent CDI measurements of all major retrobulbar vessels. In keeping with the results of Harris et al., dorzolamide did not change peak systolic velocities of the ophthalmic artery and the central retinal artery. However, in contrast, Martinez et al. found an increase of end-diastolic velocity and a decrease of resistance index [150]. The reason for these differing results is not entirely clear but may be related to the fact that patients with different types of glaucoma have been included in these studies.

Zeitz et al. have investigated retrobulbar blood ßow in patients with normal-tension glaucoma and in patients with primary open-angle glaucoma in two different experiments. In the Þrst experiment, peak systolic and end-diastolic blood ßow velocities in the short posterior ciliary artery were assessed by color Doppler imaging in 42 patients with normal-tension glaucoma [264]. Measurements were done shortly before and after a 1-month treatment with latanoprost, bimatoprost, or dorzolamide. Whereas no changes were observed in the latanoprost and the bimatoprost groups, dorzolamide accelerated peak systolic blood ßow velocities [264]. In the second experiments, CDI measurements were performed in patients with primary open-angle glaucoma. However, in this study, no changes in blood ßow velocities were detected after the application of dorzolamide [265].