Susanne Dallinger

Assessment of optic disk blood flow in patients with open-angle glaucoma

PURPOSE To characterize optic disk blood flow in patients with open-angle glaucoma compared with age-matched healthy control subjects. METHODS In this prospective cross-sectional study, 90 eyes of 90 patients with open-angle glaucoma and 61 eyes of 61 age-matched healthy control subjects were evaluated. Flow in the optic disk cup and the neuroretinal rim were assessed with scanning laser Doppler flowmetry. Fundus pulsation amplitude in the cup and the macula were assessed with laser interferometry. Visual field mean deviation was measured with the Humphrey 30 to 2 program. RESULTS Flow in the neuroretinal rim (-18%, P =.002), and in the cup (-46%, P <.001) and fundus pulsation amplitude in the cup (-33%, P <.001) and in the macula (-24%, P <.001) were significantly lower in patients with open-angle glaucoma compared with healthy control subjects. A significant association between blood flow measurements in the cup and fundus pulsation amplitudes in the cup was observed in both study cohorts. A significant association was also observed between the mean defect from visual field testing and ocular hemodynamic parameters. CONCLUSIONS Reduced optic disk perfusion in patients with open-angle glaucoma is evidenced from two independent methods in the present study. Moreover, our data indicate that reduced ocular blood flow in these patients is linked to visual field changes. It remains to be established whether compromised optic disk and choroidal blood flow contributes to optic disk damage in glaucomatous eyes or is a secondary functional phenomenon.

A comparison between laser interferometric measurement of fundus pulsation and pneumotonometric measurement of pulsatile ocular blood flow. 1. Baseline considerations

Purpose Several methods have been proposed for the investigation of the human choroidal circulation. The aim of the present study was to compare laser interferometric measurements of cardiac synchronous fundus pulsations with pneumotonometric measurements of intraocular pressure pulse and pulsatile ocular blood flow in humans.Methods The association between fundus pulsation amplitude as assessed with laser interferometry and pulse amplitude (PA) and pulsatile ocular blood flow (POBF) as assessed with pneumotonometry was investigated in 28 healthy subjects. Additionally, we investigated the distribution of fundus pulsation amplitude (FPA) in a region of -15° to + 15° around the macula (n = 18) and the influence of accommodation paralysis with cyclopentolate on FPA (n = 10).Results There was a high association between FPA and PA (r = 0.86, p < 0.001) and FPA and POBF (r = 0.70, p < 0.001). Fundus pulsations in the macula were significantly smaller than in the optic disc, but significantly larger than those in peripheral regions of the retina. Administration of cyclopentolate did not influence FPA.Conclusions On the basis of the strong correlation between laser interferometric measurements of FPA and pneumotonometric measurements of PA and POBF, we conclude that the FPA is a valid index of pulsatile choroidal perfusion in humans.

Acetazolamide-induced cerebral and ocular vasodilation in humans is independent of nitric oxide

Acetazolamide, a carbonic anhydrase inhibitor, is used orally in the treatment of primary and secondary open-angle glaucoma and induces ocular and cerebral vasodilation. Several in vitro studies have shown that carbonic anhydrase pharmacology and the L-arginine-nitric oxide (NO) pathway are closely related. We investigated the role of NO in acetazolamide-induced vasodilation on cerebral and ocular vessels in 12 healthy subjects in the presence or absence of NG-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, and in the presence or absence of L-arginine, the precursor of NO. Acetazolamide was administered after pretreatment with either L-NMMA or placebo and either L-arginine or placebo. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. In addition, mean blood flow velocity (MFV) in the middle cerebral artery (MCA) and ophthalmic artery (OA) was measured with Doppler sonography. Acetazolamide increased ocular fundus pulsation amplitude (FPA; +27%, P < 0.001) and MFV in the MCA (+38%, P < 0.001) and in the OA (+19%, P = 0.003). Administration of L-NMMA alone reduced FPA (-21%, P < 0.001) and MFV in the MCA (-11%, P = 0. 030) but did not change MFV in the OA. All hemodynamic effects of L-NMMA were reversed by L-arginine. However, neither L-NMMA nor L-arginine altered acetazolamide-induced changes in cerebral or ocular hemodynamic parameters. The present data indicate that acetazolamide-induced hemodynamic changes are not mediated by NO. Which mediators other than NO are involved in the hemodynamic effects as induced by carbonic anhydrase inhibitors remains to be elucidated.Acetazolamide, a carbonic anhydrase inhibitor, is used orally in the treatment of primary and secondary open-angle glaucoma and induces ocular and cerebral vasodilation. Several in vitro studies have shown that carbonic anhydrase pharmacology and thel-arginine-nitric oxide (NO) pathway are closely related. We investigated the role of NO in acetazolamide-induced vasodilation on cerebral and ocular vessels in 12 healthy subjects in the presence or absence of N G-monomethyl-l-arginine (l-NMMA), a NO synthase inhibitor, and in the presence or absence ofl-arginine, the precursor of NO. Acetazolamide was administered after pretreatment with eitherl-NMMA or placebo and eitherl-arginine or placebo. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. In addition, mean blood flow velocity (MFV) in the middle cerebral artery (MCA) and ophthalmic artery (OA) was measured with Doppler sonography. Acetazolamide increased ocular fundus pulsation amplitude (FPA; +27%, P < 0.001) and MFV in the MCA (+38%, P < 0.001) and in the OA (+19%, P = 0.003). Administration of l-NMMA alone reduced FPA (-21%, P < 0.001) and MFV in the MCA (-11%, P = 0.030) but did not change MFV in the OA. All hemodynamic effects ofl-NMMA were reversed byl-arginine. However, neitherl-NMMA norl-arginine altered acetazolamide-induced changes in cerebral or ocular hemodynamic parameters. The present data indicate that acetazolamide-induced hemodynamic changes are not mediated by NO. Which mediators other than NO are involved in the hemodynamic effects as induced by carbonic anhydrase inhibitors remains to be elucidated.

Effects of Acetazolamide on Choroidal Blood Flow

BACKGROUND AND PURPOSE The acetazolamide provocation test is commonly used to study cerebrovascular vasomotor reactivity. On the basis of the effect of a carbonic anhydrase inhibitor in the central nervous system, we hypothesized that acetazolamide may also increase blood flow in the human choroid. METHODS In a placebo-controlled, randomized, double-blind, three-way crossover design, acetazolamide (500 mg or 1000 mg i.v.) or placebo was administered to nine healthy subjects. The effect of acetazolamide was studied at 15-minute intervals for 90 minutes. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. In addition, mean blood flow velocity and resistive index in the ophthalmic artery were measured with Doppler sonography. In a second study in six healthy subjects, we assessed the effect of acetazolamide (1000 mg i.v.) on intraocular pressure. RESULTS Acetazolamide increased fundus pulsation amplitude in a dose-dependent manner (1000 mg: +33%; 500 mg: +20%; P<0.001, ANOVA). The effect of acetazolamide on MFV (1000 mg: +18%; 500 mg: +8%; P=0.003, ANOVA) and RI (1000 mg: -4%; 500 mg: -2%; P=0.006, ANOVA) was less pronounced but also significant. Acetazolamide did not induce any changes in systemic hemodynamic parameters but significantly decreased intraocular pressure (1000 mg: -37%; P<0.0001). CONCLUSIONS The present data show for the first time that intravenously administered acetazolamide increases choroidal blood flow in humans. This phenomenon therefore indicates that the acetazolamide provocation test may qualify as a tool to investigate ocular vasomotor reactivity in a variety of ocular diseases. Moreover, the increase in choroidal blood flow after carbonic anhydrase inhibition can be expected to contribute to the therapeutic efficacy of carbonic anhydrase inhibitors in glaucoma.

Systemic and renal effects of an ETA receptor subtype‐specific antagonist in healthy subjects

Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ‐123, a specific ETA receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET‐1. The study was performed in a balanced, randomized, placebo‐controlled, double blind 4 way cross‐over design in 10 healthy male subjects. Subjects received co‐infusions of ET‐1 (2.5 ng kg−1 min−1 for 120 min) or placebo and BQ‐123 (15 μg min−1 for 60 min and subsequently 60 μg min−1 for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para‐aminohippurate (PAH) and the inulin plasma clearance method, respectively. BQ‐123 alone had no renal or systemic haemodynamic effect. ET‐1 significantly reduced RPF (−24%, P<0.001) and GFR (−12%, P=0.034). These effects were abolished by co‐infusion of either dose of BQ‐123 (RPF: P=0.0012; GFR: P=0.020). BQ‐123 reversed the renal haemodynamic effects induced by exogenous ET‐1 in vivo. This indicates that vasoconstriction in the kidney provoked by ET‐1 is predominantly mediated by the ETA receptor subtype.

Ocular haemodynamics and colour contrast sensitivity in patients with type 1 diabetes

BACKGROUND There is evidence that altered ocular blood flow is involved in the development and progression of diabetic retinopathy. However, the nature of these perfusion abnormalities is still a matter of controversy. Ocular haemodynamics were characterised with two recently introduced methods. METHODS The cross sectional study was performed in 59 patients with type 1 diabetes with a diabetes duration between 12 and 17 years and an age less than 32 years and a group of 25 age matched healthy controls. Scanning laser Doppler flowmetry and laser interferometric measurement of fundus pulsation amplitude were used to assess retinal and pulsatile choroidal blood flow, respectively. In addition, colour contrast sensitivity along the tritan axis was determined. RESULTS Fundus pulsation amplitude, but not retinal blood flow, increased with the progression of diabetic retinopathy. Retinal blood flow was influenced by plasma glucose levels (r = 0.32), whereas fundus pulsation amplitude was associated with HbA1c(r = 0.30). In addition, a negative correlation between the colour contrast sensitivity along the tritan axis and retinal blood flow was observed. CONCLUSIONS The present study indicates that pulsatile choroidal blood flow increases with the progression of diabetic retinopathy. Increased retinal blood flow appears to be related to loss of colour sensitivity in patents with type 1 diabetes.

Age Dependence of Choroidal Blood Flow

OBJECTIVE: To investigate the age dependence of choroidal blood flow.

Glucose and insulin exert additive ocular and renal vasodilator effects on healthy humans.

Aims/hypothesis. There is evidence that insulin and glucose cause renal and ocular vasodilation. There is, however, currently no data on the effect of combined hyperglycaemia and hyperinsulinaemia on the renal and ocular blood flow seen in diabetic patients on insulin therapy.¶Methods. We carried out two different 3-way cross-over studies in healthy subjects (each, n = 9). In study one, hyperglycaemic clamps (5.6 mmol/l, 11.1 mmol/l, 16.7 mmol/l) were carried out during placebo or insulin (dose 1: 1 mU/kg/min; dose 2: 2 mU/kg/min) infusion. The second study was identical but endogenous insulin secretion was blocked with somatostatin. The renal plasma flow, glomerular filtration rate and pulsatile choroidal blood flow were measured using the paraaminohippurate method, the inulin method and a laser interferometric measurement of fundus pulsation amplitude, respectively.¶Results. Insulin increased renal plasma flow and fundus pulsation amplitude but not the glomerular filtration rate. Hyperglycaemia increased all the renal and ocular parameters studied. Haemodynamic effects of glucose and insulin were additive when somatostatin was co-administered but not under basal conditions.¶Conclusions/interpretation. Glucose and insulin can exert additive vasodilator properties on renal and ocular circulation. To find out whether this observation is related to the increased regional perfusion in diabetes longitudinal studies on patients with Type I (insulin-dependent) diabetes mellitus are needed. [Diabetologia (2001) 44: 95–103]

Effects of peribulbar anesthesia on ocular blood flow in patients undergoing cataract surgery

PURPOSE The effects of extraconal, peribulbar anesthesia on ocular blood flow may be caused by concomitant elevations in intraocular pressure or direct pharmacologic alteration of vascular tone. We quantified the effect on ocular circulation with a new technique for assessment of ocular hemodynamics. METHODS In a prospective study, ocular hemodynamics were measured before and 1 and 5 minutes after peribulbar anesthesia in 22 eyes with age-related cataract. Measurements included fundus pulsation amplitude with a laser interferometric method assessing the pulsatile choroidal blood flow and mean blood flow velocity as well as resistive index in the ophthalmic and central retinal artery with Doppler sonography. Systemic blood pressure and pulse were monitored throughout the period of ocular hemodynamic measurements. RESULTS Fundus pulsation amplitude decreased significantly after peribulbar anesthesia (after 1 minute and 5 minutes: -13% and -8%; P < .001). In the central retinal artery, mean blood flow velocity dropped (-15%; P < .001) and resistive index increased (+3%; P = .02) 1 minute after peribulbar anesthesia compared with baseline. There were no changes in ophthalmic artery hemodynamics. Intraocular pressure was elevated 1 minute after peribulbar anesthesia (+29%; P = .003) but reached baseline values after 5 minutes. CONCLUSION Pulsatile choroidal blood flow and retinal blood flow velocities were reduced after peribulbar anesthesia. These reductions were still present 5 minutes after peribulbar anesthesia, when intraocular pressure had returned to baseline values. This supports the theory of drug-induced vasoconstriction after peribulbar anesthesia. A loss of vision may be a risk of peribulbar anesthesia in patients who have compromised ocular blood flow before surgery.

A comparison between laser interferometric measurement of fundus pulsation and pneumotonometric measurement of pulsatile ocular blood flow. 2. Effects of changes in pCO2 and pO2 and of isoproterenol.

Purpose We have shown in the companion paper that, under baseline conditions, there is a high degree of association between laser interferometrically measured fundus pulsation amplitude (FPA) and pneumotonometrically measured pulse amplitude (PA) and pulsatile ocular blood flow (POBF). The present study investigated the effect of high pCO2, of high pO2 and of isoproterenol on POBF as assessed with laser interferometry and pneumotonometry.Methods Pneumotonometry and laser interferometry were performed in young healthy subjects during breathing of 100% O2 (n = 10; hyperoxia) and of 5% CO2 + 95% air (n = 8; hypercapnia). In addition these parameters were studied during stepwise increasing doses of isoproterenol, a β-receptor agonist (n = 8).Results Inhalation of 5% CO2 + 95% air increased FPA (24 ± 12%, p < 0.001), PA (26 ± 13%, p < 0.001) and POBF (15 ± 8%, p = 0.002). Inhalation of 100% O2 decreased FPA (-5 ± 7%, p = 0.027), but did not change PA or POBF. The effect of 100% O2 inhalation on FPA in the optic disc was more pronounced (-11% to -20%) than in the macula. Isoproterenol caused a dose-dependent increase in FPA, PA and POBF (p < 0.001). The association between the induced changes in FPA and PA or POBF was highly significant.Conclusions The present study shows that FPA can be taken as a valid relative measure of pulsatile choroidal blood flow. Our results in the optic disc indicate that FPA at the neuroretinal rim and at the cup is influenced by retinal and choroidal circulation.