the Heidelberg retina ßowmeter has been investigated in patients with primary open-angle glaucoma and compared to a healthy control group [141]. A treatment period of 3 weeks was scheduled for both groups. The authors did not Þnd a change in optic nerve head blood ßow data after treatment with timolol.

Several studies investigating pulsatile choroidal blood ßow in patients with glaucoma or ocular hypertensives found unchanged POBF after treatment with timolol. Morsman et al. randomized 33 ocular hypertensive patients to receive either timolol, levobunolol, or betaxolol in one eye [161]. Although the authors found a tendency toward a decreased puslatile choroidal blood ßow, this effect did not reach statistical signiÞcance. These results are in good agreement with the data of another group investigating pulsatile ocular blood ßow in patients with chronic open-angle glaucoma [245].

Although several reports also focused on the effect of timolol on retrobulbar blood ßow, the majority of the studies did not Þnd a signiÞcant change in retrobulbar hemodynamics caused by timolol treatment. Harris et al. did not Þnd a timolol effect of on retrobulbar ßow velocities as determined by color Doppler imaging in patients with normal-tension glaucoma [93]. This is in keeping with the results of several other reports that failed to Þnd substantial hemodynamic changes in the retrobulbar vessels after timolol treatment [55, 92, 167].

In contrast, treatment with timolol was found to decrease vascular resistance in a group of glaucoma patients, whereas no change was found in the ocular hypertensive group [17]. No change was observed in blood ßow velocities in the ophthalmic artery after treatment. The authors have speculated that the different timolol effect between the glaucoma group and the ocular hypertensive group may be related to a potentially defective autoregulation in the ocular hypertensive group [17].

13.6.6 Betaxolol

In contrast to timolol, betaxolol is a selective beta-1 receptor blocker, originally developed to reduce systemic side effects such as bronchospasm. As for timolol, much effort has been

spent to investigate the hemodynamic effects of betaxolol. In a rabbit model, 30 days of repeated application of betaxolol 0.5% did not produce any observable effect in optic nerve head blood ßow [178]. In contrast, Araie and colleagues have found a small but signiÞcant increase in tissue blood velocity in the iris and optic nerve head as measured with the laser speckle technique [6]. Instead of measuring only static choroidal blood ßow, Kiel and Patel focused on the choroidal pressure-ßow relationship measured before and after topical treatment with betaxolol [120]. Betaxolol did not induce a change in baseline choroidal blood ßow or in the pressure ßow relationship in this rabbit model.

13.6.7 Human Studies

Various methods have been used to investigate the effects of betaxolol on ocular blood ßow in humans. Perimacular hemodynamic parameters have been studied after a single administration of betaxolol in normal subjects [92]. Two hours after topical administration of the drug, no change in perimacular leukocyte velocity or density was observed. Data obtained with the Heidelberg retina ßowmeter focused on topical treatment with either timolol or betaxolol on optic nerve head blood ßow. In contrast to timolol, which showed a slight decrease in optic nerve head blood ßow, betaxolol did not show any effect on HRF parameters [87]. Similarly, Schmetterer et al. did not observe an effect of a single topical dose of betaxolol on pulstile choroidal blood ßow in healthy volunteers [209].

In contrast to a single topical instillation, longterm betaxolol instillation revealed different effects. The effect of topical betaxolol on tissue circulation in the human optic nerve head has been investigated using the laser speckle technique [235]. The authors report a small but signiÞcant increase in tissue blood velocity in the human optic nerve head after topical instillation of betaxolol twice daily for 3 weeks. However, whether this increase is of clinical relevance has yet to be shown.

In addition, several studies have focused on the effect of topical betaxolol in patients with glaucoma or ocular hypertension. Again the data

reported about betaxolol and its effect on ocular blood ßow are not consistent. Steigerwalt et al. investigated the effect of betaxolol in patients with ocular hypertension [220]. The authors show that topical betaxolol as well as topical carteolol and timolol led to an increase in the ßow velocity of the central retinal artery, indicating but not Þnally proving an increase in blood ßow [220].

However, given that data about long-term treatment may be more relevant for glaucoma patients, several studies have focused on the hemodynamic effects of long-term betaxolol treatment. Carenini et al. have investigated whether a 12-month treatment with either topical timolol or betaxolol may inßuence pulsatile ocular blood ßow in patients with primary open-angle glaucoma [27]. Although treatment with betaxolol and timolol showed similar reductions of the IOP, timolol decreased pulsatile ocular blood ßow over the 12-month observation period, whereas no change was observed in betaxolol-treated patients.

Using the color Doppler imaging technique, a 1-month drug treatment with either timolol or betaxolol was tested in a double-masked two-way crossover design in patients with normal-tension glaucoma [93]. The authors found a decrease in resistance index after betaxolol treatment, whereas no effect was observed in the timolol group. However, whether a decrease in resistance index as found in the latter study can really be interpreted as an increase in blood ßow remains unclear.

The effect of betaxolol was also investigated in a selected group of glaucoma patients, namely in patients who exhibited ocular vasospasm [55]. Patients were evaluated for blood ßow velocity of the retrobulbar vessels using color Doppler imaging and resistance indices were calculated for the ophthalmica artery, the central retinal, and temporal posterior ciliary arteries. Measurements were done before and after a 4-week treatment with either timolol or betaxolol. Treatment with timolol did not induce a change in hemodynamic parameters. Surprisingly, the authors found that after betaxolol treatment resistance index signiÞcantly decreased in the ophthalmic artery, whereas an increase in resistance index was observed in both the central retinal and temporal posterior ciliary arteries. Whether these data can be applied

correspondingly to a typical glaucoma patient without signs of vasospasm remains unclear.

The hemodynamic effect of topical treatment with either timolol, betaxolol, carteolol, or levobunolol drops was investigated using the CDI technique in patients with primary open-angle glaucoma [5]. Retrobulbar ocular blood ßow velocity was measured using the color Doppler imaging method in the ophthalmic artery, central retinal artery, and temporal posterior ciliary arteries. The authors report that in the timolol group, an increase in resistance index values of the posterior ciliary artery was observed. In the betaxolol group, resistance index decreased in the central retinal artery and the posterior ciliary artery, whereas in the carteolol group, there was a signiÞcant decrease only in the central retinal artery. Finally, no change in retrobulbar hemodynamics was observed in the levobunolol group.

13.6.8 Levobunolol

Although not as widely used as timolol or betaxolol, the hemodynamic effects of the nonselective beta-adrenoreceptor antagonist levobunolol have been the focus of several experiments. Arend et al. report that levobunolol, as the other beta-adreno- ceptor blockers tested increased blood velocities in retinal and epipapillary capillaries [7]. In this study, blood velocities were measured by digital image analysis of scanning laser ßuorescein angiograms. None of the drugs tested induced a change in vessel diameters but increased epipapillary and macular papillary blood velocities.

Data about the effect of levobunolol 0.5% is also available from a randomized, double-masked, placebo-controlled study investigating puslatile ocular blood ßow in patients with glaucoma and healthy volunteers [22]. The authors found that pulsatile ocular blood ßow was increased after treatment with levobunolol in both the glaucoma group as well as in the healthy subjects.

In contrast, other reports did not Þnd a hemodynamic effect of levobunolol. Harris et al. failed to Þnd an effect in perimacular blood ßow assessed with the blue-Þeld technique 2 h after topical drug administration [92]. This is also in keeping with a

randomized, placebo-controlled study investigating the effect of levobunolol in healthy subjects by the means of fundus pulsation amplitudes in the macula and the optic disk [209]. The authors report that application of a single drop of levobunolol did not change the measured ocular hemodynamic parameters. These results seem also to hold true for the retinal circulation. Leung et al. have investigated the effect of topical administered levobunolol on retinal blood ßow by a combined measurement of retinal vessel diameters and red blood cell velocity as determined with laser Doppler velocimetry [138]. As with the blue-Þeld technique, there was no statistically signiÞcant effect on calculated volumetric blood ßow rate after administration of levobunolol. The same technique has been used to investigate within 1 week of topical treatment with levobunolol on retinal blood ßow [20]. In contrast to the latter data reported of single instillation, 1 week treatment with levobunolol lead to a slight but statistically signiÞcant increase in volumetric retinal blood ßow.

13.6.9 Carteolol

Carteolol is a non cardio-selective beta-adrener- gic blocking agent. In contrast to other betablockers such as timolol or betaxolol, cartelolol possesses intrinsic sympathomimetic activity, which might at least theoretically provide some reduced potential for systemic effects.

A variety of studies have been performed to study the blood ßow effects of carteolol in animal models as well as in humans. In a rabbit model, topical instillation of carteolol induced a signiÞcant reduction of choroidal and retinal blood ßow [202], whereas intravenous administration of carteolol was found to result in an increase in blood ßow parameters [231].

Yamazaki et al. found an increase in pulsatile ocular blood ßow after installation of carteolol [257]. In contrast to these Þndings, no changes in retinal haemodynmics were reported using the blueÞeld technique to assess white blood cell ßux [92] and combined measurement of red blood cell velocity and retinal vessel diameters [79]. Both studies were performed in healthy subjects.

Steigerwalt et al. have investigated the effect of carteolol 2% on blood ßow velocity of retrobulbar vessel after topical administration of the drug in patients with ocular hypertension [220]. The authors found a signiÞcant increase in blood velocity in the central retinal artery after carteolol administration in this group of patients.

13.6.10 Serotonin

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamino neurotransmitter and an important tissue hormone in several organ systems. However, serotonin also has vasoactive functions. Unfortunately, these vasoactive properties are complex and differ considerably depending on the vascular bed investigated. Given that at least 19 different serotonin receptors have been indentiÞed so far, this complex nature of effects may be in part attributed to the large number of serotonin receptors existing [166]. For example, it has been shown in the heart that serotonin can cause vasodilation of coronary arterial vessels with a diameter smaller than 100 mm while causing constriction of larger coronary artery segments causing a net increase in coronary blood ßow in the healthy heart [136]. The authors have hypothesized that this difference in the effect of serotonin on the vessels can be attributed to the different serotonin receptors involved.

Currently, knowledge of the effects of serotonin in the ocular circulation is sparse. One study investigated the effect of serotonin on the ocular circulation with the microsphere method in a monkey model [57]. In this experiment, exogenous administration of serotonin did not signiÞcantly affect retinal or choroidal blood ßow. However, in contrast, the same experiment showed that in arteriosclerotic monkeys, administration of serotonin induces pronounced vasoconstriction, which in turn lead to a reduction of retinal and choroidal blood ßow [57]. Although the exact reason for this effect remains unclear, the authors hypothesized that this effect can be attributed to a pronounced release of vasoconstrictor components including serotonin and thromboxane by the platelets aggregated in arteriosclerotic plaques. This hypothesis