Reversal of endothelin-1—induced ocular hemodynamic effects by low-dose nifedipine in humans

l?lFIARMACODYNAPvlICS AND DRUG ACTION

Reversal of endothelin- l-induced ocular hemodynamic effects by low-dose nifedipine in humans

Backgroztnd and purpose: There is evidence that calcium channel blockers may be useful in patients with normal tension glaucoma and vasospastic reactions. We therefore hypothesized that calcium channel blockers may increase ocular blood flow and that there may be a functional antagonism between endothelin-1 (ET-l) and calcium channel blockers in the ocular vasculature. Methods: This was a randomized, double-blind, three-way crossover study with respect to ET-1 infusions (placebo, 2 ng/kg/min ET-l, and 4 @kg/mm ET-l) and a randomized double-blind study in two parallel groups with respect to nifedipine (placebo or 5 mg nifedipine). Ocular hemodynamics in the 12 healthy subjects participating in the study was assessed by laser interferometric measurement of fundus pulsation amplitude (FPA) in the optic disc and two-dimensional soumin g laser Doppler flowmetry in the optic disc. I&&s: ET-1 caused a dose-dependent decrease in PPA and flow. With a dose of 4 ng/kg/min a decrease of -18% f 5% (p < 0.001) and -17% * 5% (p = 0.023) on FPA and flow, respectively, were observed. This effect was completely reversed by nifedipine compared with placebo (FPA, p < 0.001; flow, p = 0.011). However, nifedipine did not affect ocular hemodynamics after placebo infusion. Conchsions: These results show that nifedipine does not increase optic nerve head blood flow during baseline conditions but reverses ET-l-induced constriction in ocular vasculature at doses that do not at&t systemic hemodynamics. This supports the close relation of the therapeutic effect of calcium channel blockers in patients with normal tension glaucoma to the endothelin system. Moreover, the present study provides a strong rationale for a study of low dose nifedipine as a supplementary medication in glaucoma patients. (Clin Pharmacol Ther 1998;63:54-63.)

Karin Strenn, MD, Bettina Matulla, MD, Michael Wolzt, MD, Oliver Findl, MD, Maria-Csilla Bekes, Ulla Lamsfuss, Ursula Graselli, RN, Georg Rainer, MD, Rupert Menapace, MD, Hans-Georg Eichler, MD, and Leopold Schmetterer, MD Vienna, Austria

There is evidence that systemic administration of calcium channel blockers may improve the visual field in patients with normal tension glaucoma.1‘3

From the Department of Clinical Pharmacology, the Department of Ophthalmology B, and the Institute of Medical Physics, University of Vienna.

Received for publication Nov. 26, 1996; accepted Sept. 19, 1997. Reprint requests: Leo@d Schmetterer, MD, Department of Clinical

Pharmacology, Wghringer Giirtel18-20, A-1090 Vienna, Austria. Copyright 0 1998 by Mosby, Inc. 0009-9236/98/$5.00 + 0 13/l/86327

The mechanism behind this therapeutic effect is not yet completely understood. However, recent experiments have shown that intravenous nicardipine increases optic nerve head blood flow in cats.4 There- fore the therapeutic value of calcium channel blockers is compatible with the vascular theory of glaucoma, which maintains that a compromised perfusion of the optic nerve head may contribute to the development of visual field damage. This concept is supported by the observation of reduced blood flow velocities in larger ocular arteries536 and optic nerve

54

CLINICAL PHARMA COLOGY & THERAPEUTICS VOLUME 63, NUMBER 1 Strenn et al. 55

head microcirculation’ in open angle and normal tension glaucoma.

Recent investigations have shown that endothelin-1 (ET-l) plays a role in the pathogenesis of normal tension glaucoma and contributes to ocular hypoperfusion in these patients.’ Vasoconstric- tor responses to ET-l were shown in pig’ and hu- mani’ isolated ophthalmic arteries and in porcine ciliary arteries. l1 ET-l has also been suggested to play a role in retinal blood flow autoregulation12T13 and in the control of optic nerve head and choroidal blood flo~.‘,r~-‘~

The ET-l-induced contraction of retinal arteries is dependent on the influx of extracellular Ca2+ through membrane potential-operated calcium channels.11~17 We therefore hypothesized that calcium channel blockers may increase ocular blood flow and that there may be a functional antagonism between ET-l and calcium channel blockers in the ocular vasculature. A low dose of nifedipine, which provokes no systemic hemodynamic effect, was used to test this hypothesis. Ocular hemodynamic parameters were assessed with laser interferometric measurement of fundus pulsations in the optic disc18,19 and scanning laser Doppler flowmetry.20,21

MATERLAL AND METHODS Subjects. After the study protocol had been ap-

proved by the Ethics Committee of Vienna Univer- sity School of Medicine and written informed con- sent was obtained, 12 healthy male, nonsmoking drug-free volunteers between 20 and 32 years old (mean + 1 SD, 26.6 ? 3.6 years) were studied. Each subject passed a screening examination that included medical history and physical examination, 1Zlead electrocardiogram, complete blood cell count with differential, urine drug screen, serum electrolytes, bilirubin, BUN, creatinine, cholesterol, triglycerides, y-glutamyltransferase, glucose, lactate dehydrogenase, AST, ALT, total protein, activated partial thromboplastin time, thrombin time, hepati- tis A, B, and C serologic tests and HIV antibody tests, and an ophthalmic examination. All subjects included had normal ophthalmic findings with ametropia <3 diopters. Subjects were excluded if any abnormality was found as part of the pretreat- ment screening unless the investigators considered an abnormality to be clinically irrelevant.

Study protocol. This was a randomized, double- blind, balanced, three-way crossover study design with respect to ET-1 infusions and a randomized double-blind study design in two parallel groups

with respect to nifedipine. Each subject received intravenous placebo, 2 ng/kg/min ET-l, or 4 @kg/ min ET-1 infusions on 3 study days. Six subjects were randomized into the oral placebo group (group A) and six subjects into the nifedipine group (group B). ET-l treatment sequence was assigned by balanced randomization.

On all trial days subjects arrived after an over- night fast and 7 to 8 hours of sleep. After a 20- minute resting period in a sitting position, baseline measurements of laser interferometry, laser Dopp- ler flowmetry and blood pressure were performed. Thereafter, ET-l or placebo were administered for 30 minutes. Measurements were performed during the last 10 minutes of the infusion. Sixty minutes after the start of infusion, nifedipine or placebo were administered and measurements were re- peated 90,150,210, and 270 minutes after the end of infusion. Hemodynamic measurements were performed in a predetermined order (laser interferometry, laser Doppler flowmetry, blood pressure, and pulse rate) and took approximately 10 minutes per time point. The washout period between the 3 study days was at least 5 days.

Study medication. ET-1 (Clinalfa AG, Laufelfin- gen, Switzerland) was administered as an intravenous infusion over 30 minutes in doses of 2 and 4 ng/kg/min. Physiologic saline solution was infused intravenously over 30 minutes as placebo (intravenous placebo). Nifedipine (Adalat, Bayer, Vienna, Austria) was administered orally in a dose of 5 mg. Placebo tablets were identical in appearance and taste to maintain double-blind conditions (oral placebo).

Study methods. Systolic and diastolic blood pres- sures were measured by an automated oscillometric device (Hewlett-Packard CMS patient monitor, Hewlett-Packard, Palo Alto, Calif.). Mean arterial pressure was calculated as follows: % diastolic blood pressure plus % systolic blood pressure. Pulse rate was registered automatically from a finger pulse- oxymetric device (Hewlett-Packard CMS patient monitor).

Pulse synchronous pulsations of the eye fundus were assessed by laser interferometry on the subject’s right eye. The method is described in detail by Schmetterer et al.” In brief, the eye is illuminated by the beam of a single-mode laser diode with a wavelength (1) of 783 nm. The light is reflected at both the front side of the cornea and the retina. The two re-emitted waves produce interference fringes from which the distance changes between cornea

56 Strenn et al. CLINICAL PHARMACOLOGY&THERAPEUTICS

JANUARY 1998

Table I. Baseline hemodynamic parameters of the 3 study days in the placebo group (group A) and in the nifedipine group (group B)

Group A Group B

Day 1 Day 2 Day 3 Day 1 Day 2 Day 3

Fundus pulsation amplitude (pm) 8.2 2 2.0 8.6 k 2.3 8.7 + 2.6 6.3 2 1.2* 6.2 + 1.3* 6.2 2 l.l* Optic disc flow (relative units) 248 +- 45 227 2 55 232 + 33 245 ? 26 235 k 31 247 2 25 Mean arterial (mm Hg) pressure 84 ” 5 85 + 4 88 2 5 86 + 9 86 k 15 86 ? 16 Pulse rate (Urnin) 73 2 8 69 ?I 6 76 +- 6 77 + 9 77 k 6 78 + 10

Results are presented as mean values 5 SD. *Indicates significant differences behveen the hvo study groups.

and retina during a cardiac cycle can be calculated. Distance changes between cornea and retina lead to a corresponding variation of the interference order [AN(t)]. This change in interference order can be evaluated by counting the fringes moving inward and outward during the cardiac cycle. Changes in optical distance [AL(t)], corresponding to the cornea-retina distance changes, can then be calculated by the following:

AL(t) = AN(t) . A/2

The maximum distance change is called fundus pulsation amplitude (FPA) and estimates the local pulsatile blood flow at the selected measurement point. l8 The short-term and day-to-day variability of the method is small, which allows detection of even small changes in local pulsatile blood flow after pharmacologic stimulation.22 In contrast to systems that record ocular pressure pulse,23,24 information on the ocular circulation may be obtained with high topical resolution. Fundus pulsation measurements were performed in the optic disc in regions without surface vessels and were located temporally between the outer margin of the pallor and the margin of the optic nerve head.

Optic nerve head microcirculation was assessed with a commercially available scanning laser Doppler flowmeter (Heidelberg Retina Flowme- ter, Heidelberg Engineering, Heidelberg, Germa- ny). 20,21 This system combines laser Doppler flowmetry with laser scanning tomography. In brief, the vascularized tissue is illuminated by coherent laser light. Scattering on moving red blood cells leads to a frequency shift in the scattered light. In contrast, static scatterers in tissue do not change light frequency but lead to randomization of light directions that impinge on red blood cells. This light diffusing in vascularized tissue leads to a broadening of the spectrum of scattered light, from which mean red blood cell velocity, the

blood volume, and the blood flow (termed flow) can be calculated. These parameters are calculated from the backscattered light for each point during the scanning process, and a two- dimensional map of retinal perfusion is created. Therefore these parameters may be quantified in relative units for any image point. In this study a 20 x 20 pixel area was chosen for calculation of optic disc hemodynamic parameters.

Stutisticul analysis. Statistical analysis was done with use of the Statistica software package (release 4.5, StatSoft Inc., Tulsa, Okla.). A Wilcoxon signed- rank test was used to compare the baseline values between the two study groups. The effects of the study drugs were assessed with Friedman ANOVA and Wilcoxon signed-rank tests for post hoc com- parisons. The significance of hemodynamic effects of ET-l were calculated versus baseline and versus intravenous placebo. The hemodynamic effect of nifedipine alone was assessed from the placebo study day of this group versus baseline. The treatment effect of nifedipine on ET-l-induced changes was estimated by comparison with the oral placebo study group. To compare the ET-l-induced effects in the two study groups, a Wilcoxon signed-rank test was performed.

RESULTS Baseline hemodynamic parameters of the two

study groups are presented in Table I. FPA in the optic disc was significantly higher in group A than in group B @ = 0.022). The other parameters under study were not significantly different between the two study groups.

The effect of ET-l on FPA and flow in the optic disc is shown in Fig. 1. These data are taken from the oral placebo group (group A). The ET-l- induced reduction in ocular hemodynamic parameters was dose dependent and long lasting. The 2 ng/kg/min dose significantly reduced FPA versus

CLINICAL PHARMACOLOGY &THERAPEUTICS VOLUME 63, NUMBER 1 Strews et al. 57

3 90 0

ii

80

70

B * . 1 - -L

II- 0 30 90 120 150 180 210 240 270

minutes Fig. 1. Effect of endothelin-1 (open triangles, 2 nglkglmin ET-l; solid triangles, 4 ngkglmin ET-l) or placebo (no symbols) on fundus pulsation amplitude (FPA) and optic disc flow (flow). Horizontal arrow indicates the 30-minute infusion period. Data are presented as mean values k SD. Asterisks indicate significant ET-l-induced effects versus placebo as calculated by Friedman ANOVA.

58 Strenn et al. CLINICAL PHARMACOLOGY &THERAPEUTICS

JANUARY 1998

baseline 0, < 0.001; at 30 minutes: -13% + 5%) and versus placebo (p = 0.008). The effect on flow was significant versus baseline (JJ = 0.012; at 30 minutes: -10% ? 7%) but not versus placebo. The effect of 4 ng&/min ET-l on FPA was more pronounced (p < 0.001 versus placebo and versus baseline; at 30 minutes: -18% + 7%). This dose also caused a significant drop in optic disc flow (p = 0.005 versus placebo,p = 0.023 versus baseline; at 30 minutes: -17% + 5%). Neither ET-l nor placebo caused any significant change on systemic hemodynamic parameters.

The effect of nifedipine on ocular and systemic hemodynamic parameters is presented in Fig. 2. In the absence of exogenous ET-l, nifedipine had no effect on ocular and systemic hemodynamic parameters. In contrast, nifedipine significantly affected the ET-l-induced decrease in ocular hemodynamic parameters. The effect of 2 mg/kg/min ET-l on FPA was mitigated in the nifedipine group (p c 0.007), whereas the effect on flow did not reach the level of significance (Fig. 3). Nifed- ipine almost completely abolished the effects of 4 ng/kg/min ET-l on FPA and flow (FPA,p < 0.001; flow, p < 0.011; Fig. 4). The effect of nifedipine was significant even though the decrease in FPA and flow after ET-l infusions alone, that is, im- mediately before nifedipine or oral placebo administration, tended to be higher in the nifedipine group. The effects of nifedipine on systemic hemodynamics were generally small and were non- significant at most time points.

DISCUSSION There is increasing evidence that calcium channel

blockers may be useful in the treatment of patients with normal tension glaucoma with vasospastic reactions and that improvement of visual fields can be obtained in these patients.1”‘25 However, it is not yet entirely clear whether this effect can be attributed to changes in ocular hemodynamics. An increase in ocular blood flow after administration of calcium channel blockers has been observed by sev- eral authors. Retinal and optic disc blood flow were investigated in cats after nicardipine administration with laser Doppler velocimetry and flowmetry, respectively. An increase in optic disc but not in retinal blood flow was observed at doses that caused a significant decrease in blood pressure. An increase in ophthalmic artery blood flow after nifedipine administration was proposed on the basis of Doppler sonographic investigations in some patients with

normal tension glaucoma.26 Moreover, nimodipine3 and nifedipine2’ have been shown to increase pulsatile ocular blood flow in some patients. In this study we did not observe an effect of nifedipine on optic disc blood flow in normal subjects during baseline conditions. This might be explained, at least partially, by the low doses used. However, higher doses of nifedipine reduce systemic blood pressure. Because low systemic blood pressure has been re- ported to be a risk factor in glaucomatous damage,28’29 it does not seem to be advisable to treat glaucoma patients with high-dose calcium channel blockers. Therefore the use of topical verapamil, which increases ocular blood flow fithout concom- itant changes in systemic hemodynamics,30931 has been proposed.

This study confirms our previous findings16 that intravenous ET-l infusions re’duce ocular blood flow in humans, even at doses that do not alter systemic hemodynamics. This is in keeping with previous an- imal experiments8,14”5 and indicates that the ocular vasculature is particularly sensitive to changes in ET-l plasma levels. The effects of ET-l on FPA and flow were dose dependent and long lasting. Even 270 minutes after infusion of ET-l, ocular hemodynamic parameters did not return to baseline levels, although the plasma elimination half-life of ET-l in humans is only 3.6 minutes.32 A protracted effect on the ocular circulation has already been observed in rabbits after intravenous ET-l administration. These findings are compatible with the hypothesis that ET-l plays a role in optic disc ischemia associ- ated with normal tension glaucomas.8,33

The ET-l-induced reduction in ocular blood flow was completely reversed by nifedipine. A functional antagonism between calcium channel blockers and ET-l has already been observed in the human fore- arm. 34 A complete abrogation of ET-l-induced con- tractions by nifedipine has also been observed in vitro in porcine ciliary arteries.” In the present study these functional antagonist effects of nifedipine were observed at the level of ocular circulation, even though both drugs had no relevant systemic hemodynamic effects. The lack of effect of low-dose oral nifedipine on blood pressure and pulse rate is in keeping with previous studies in healthy subjects.35,36

Nifedipine almost completely reversed the ET-l- induced reduction in ocular blood flow, which supports the close relation of the therapeutic effect of nifedipine in patients with normal tension glaucoma to the endothelin system. There is evidence that not

CLINICAL P JXARMACOLOGY & THEBAPEUTICS VOLUME 63, NUMBER 1 Strenn et al. 59

placebo

2 100 IL

80

120

3 ‘100 .g ii 0

5 80 2 . . . .

a

3 120

100

80

120 B E 2

100

2 80 Iii 0 30 90 150 210 270

minutes

Fig. 2. Effect of oral placebo (open bars) or nifedipine (hatched bars) on fundus pulsation amplitude (FPA), optic disc flow (flow), mean arterial pressure (MAP), and pulse rate after placebo infusion. Horizontal arrow indicates the 30-minute placebo infusion period. Vertical arrow indicates the time point of oral placebo or nifedipine administration, Data are presented as mean values 2 SD. Asterisks indicate time points at which significant differences between nifedipine and oral placebo, as calculated with Wilcoxon signed-rank test, were observed.

60 Strenn etal. CLINICAL PHARMACOLOGY & THERAPEUTICS

JANUARY 1998

120

80

ET-l

120

g 100 .E E 'iii 80 i P % E 8 120

ii Q 2 100

z 80

minutes 210 270

Fig. 3. Effect of oral placebo (open bars) or nifedipine (hatched bars) on fundus pulsation amplitude (FF’A), optic disc flow (flow), mean arterial pressure (MAP), and pulse rate after infusion of 2 ngkglmin ET-l. Horizontal arrow indicates the 30-minute ET-l infusion period. Vertical arrow indicates the time point of oral placebo or nifedipine administration. Data are presented as mean values 2 SD. Asterisks indicate time points at which significant differences between nifedipine and oral placebo, as calculated with Wilcoxon signed-rank test, were observed.

CLINICAL PHARMA COLOGY &THERAPEUTICS VOLUME 63, NUMBER 1 Strenn et al. 61

ET-1 4 ng/kg/min

2 100 IL

80

3 100 .g E 0

5 80 B

aI H 100

I 2 80

0 30 90 150 210 270

minutes

Fig. 4. Effect of oral placebo (open bars) or nifedipine (hatched bars) on fundus pulsation amplitude (FPA), optic disc flow (flow), mean arterial pressure (MAP), and pulse rate after infusion of 4 ng/kg/min ET-l. Horizontal arrow indicates the 30-minute ET-l infusion period. Vertical arrow indicates the time point of oral placebo or nifedipine administration. Data are presented as mean values + SD. Asterisks indicate time points at which significant differences between nifedipine and oral placebo, as calculated with Wilcoxon signed-rank test, were observed.

62 Strenn et al.

all patients with glaucoma benefit from calcium channel blockers.2,3,27 On the basis of the results of this study it can be hypothesized that calcium channel blockers are effective in patients with either increased local ocular ET-l levels or with abnor- mally increased ocular sensitivity to ET-l. More- over, our results show that even very low doses of nifedipine may be of therapeutic value in patients with normal tension glaucoma. This is of critical importance for acceptance of this therapeutic ap- proach by patients with glaucoma because there is a high discontinuation rate in patients with systemic hypertension who receive high doses of nifedipine.7 This discontinuation rate is the result of a negative effect on the quality of life, which is mainly caused by the well-known side effects of nifedipine such as headache, flush, sensation, nausea, and edema.3873g

It is worth noting that both methods used to estimate ocular hemodynamics provided comparable results in this study, despite the difference in parameters assessed. Local FPA is a measure of local pulsatile blood flow. Therefore it is mainly influenced by the pulsatile caliber changes of the larger ocular vessels underlying the measurement point. In contrast, laser Doppler flowmetry estimates microcirculation of the optic nerve. We found a significant effect of nifedipine after 2 nglkglmin on FPA but not on optic disk flow, which cannot be attributed to a different reactivity of microvasculature and macrovasculature. It is much more likely that the better signal-to-noise ratio of fundus pulsation measurements22 compared with laser Doppler measurements2’ is responsible for this difference in significance levels. It is noteworthy that FPA values were significantly higher at baseline in group A than in group B. However, the ET-l-induced effects on FPA were comparable in both groups, which shows that the reactivity of ocular vasculature was comparable between the two groups. Moreover, the antagonist effects of nifedipine, as shown by the FPA measurements, were confirmed by the results from laser Doppler flowmetry.

In conclusion, we have shown that low-dose nifedipine does not increase optic nerve head blood flow at baseline but reverses ET-l-induced constric- tions in ocular vasculature. This shows that the therapeutic effect of calcium channel blockers in patients with normal tension glaucoma is closely related to the endothelin system. Moreover, this study provides a strong rationale for a study of low-dose nifedipine as a supplementary medication in patients with glaucoma.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

CLINICAL PHARMACOLOGY &THERAPEUTICS JANUARY 1998

Kitazawa Y, Shirai H, Go FJ. The effect of Ca2+ antagonist on visual field in low-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 1989;227:408-12. Netland PA, Chaturvedi N, Dreyer EB. Calcium channel blockers in the management of low-tension and open-angle glaucoma. Am J Ophthalmol 1993; 115:608-13. Pillunat LE, Lang GK, Harris A. Ocular carbon diox- ide reactivity and calcium channel blockers in normal pressure glaucoma. In: Drance SM, editor. Update of glaucoma, ocular blood flow and drug treatment. Am- sterdam: Kugler Publications; 1995. p. 67-71. Harino S, Riva CE, Petrig BL. Intravenous nicardipine in cats increases optic nerve head but not retinal blood flow. Invest Ophthalmol Vis Sci 1992;33:2885- 90. Rankin SJA, Walman BE, Buckley AR, Drance SM. Color Doppler imaging and spectral analysis of the optic nerve vasculature in glaucoma. Am J Ophthal- mol 1995;119:685-93. Harris A, Sergott RC, Spaeth GL, Katz JL, Shoe- maker JA, Martin BJ. Color Doppler analysis of ocular vessel blood velocity in normal-tension glaucoma. Am J Ophthalmol 1994;118:642-9. Hamard P, Hamard H, Dufaux J, Quesnot S. Optic nerve head blood flow using a laser Doppler velocim- eter and hemorheology in primary open angle glaucoma and normal pressure glaucoma. Br J Ophthal- mol 1994;78:449-53. Sugiyama T, Moriya S, Oku H, Azuma H. Association of endothelin-1 with normal tension glaucoma: clinical and fundamental studies. Surv Ophthalmol 1995; 39:S49-56. Yoo K, Tschudi M, Liischer TF. Endothelium- dependent regulation of vascular tone on the porcine ophthalmic artery. Invest Ophthalmol Vis Sci 1991; 32:1791-8. Haefliger IO, Flammer J, Ltischer TF. Nitric oxide and endothelin-1 are important regulators of human ophthalmic artery. Invest Ophthalmol Vis Sci 1992; 3312340-3. Meyer P, Lang MG, Flammer J, Liischer TF. Effects of calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in porcine ciliary arteries. Exp Eye Res 1995;60:505-10. Chakravarthy U, Gardiner TA, Anderson P, Archer DB, Trimble ER. The effect of endothelin 1 on the retinal microvascular pericyte. Microvasc Res 1992; 43:241-54. Brown SM, Jampol LM. New concepts of regulation of retinal vascular tone. Arch Ophthalmol 1996;114: 199-204. Cioffi GA, Orgiil S, Onda E, Bacon DR, Van Buskirk EM. An in vivo model of chronic optic nerve ischemia: the dose-dependent effects of endothelin-1 on

the optic nerve microvasculature. Curr Eye Res 1995; 14:1147-53. Orgiil S, Cioffi GA, Bacon DR, Van Buskirk EM. An endothelin-l-induced model of chronic optic nerve &hernia in rhesus monkeys. J Glaucoma 1996;5: 135-8.

CLINICAL PHARMA COLOGY &THERAPEUTICS VOLUME 63, NUMBER 1

1.5.

16.

17.

18.

19.

Schmetterer L, Find1 0, Strenn K, Jilma B, Graselli U, Eichler HG, et al. Effects of endothelin-1 (ET-l) on ocular hemodynamics. Curr Eye Res 1997;16:687-92. Nyborg NCB, Prieto D, Benedito S, Nielsen PJ. Endothelin-1 induced contraction of bovine retinal small arteries is reversible and abolished by nitrendip- ine. Invest Ophthalmol Vis Sci 1991;32:27-31. Schmetterer L, Lexer F, Unfried C, Sattmann H, Fercher A. Topical measurement of fundus pulsations. Opt Eng 1995;34:711-6. Schmetterer L, Wolzt M, Salomon A, Rheinberger A, Unfried C, Zanaschka G, et al. The effect of isopro- terenol, phenylephrine and sodium nitroprusside on fundus pulsations in healthy volunteers. Br J Ophthal- mol 1996;80:217-23.

20.

21.

22.

23.

24.

25.

26.

Michelson G, Groh M, Langhans M, Schmauss B. Zweidimensionale Kartierung der retinalen und pap- illaren Mikrozirkulation mittels Scanning-Laser- Doppler-Flowmetrie. Klin Monatsbl Augenheilkd 1995;207:180-90. Michelson G, Langhans MJ, Groh MJM. Clinical in- vestigation of the combination of a scanning laser ophthalmoscope and laser Doppler flowmeter. Ger J Ophthalmol 1995;4:342-9. Schmetterer L, Strenn K, Find1 0, Breiteneder H, Graselli U, Agneter E, et al. The effect of antiglau- coma drugs on ocular hemodynamics in healthy volunteers. Clin Pharmacol Ther 1997;61:583-95. Langham ME, Tomey K. A clinical procedure for the measurement of the ocular pulse-pressure relation- ship and the ophthalmic arterial pressure. Exp Eye Res 1978;27:17-25. Langham ME, Farrell RA, O’Brien V, Silver DM, Schilder P. Blood flow in the human eye. Acta Oph- thalmol 1989;67(suppl 191):9-13. Flammer J, Guthauser U. Behandlung choroidaler Vasospasmen mit Kalziumantagonisten. Klin Mo- natsbl Augenheilkd 1987;190:199-200. Harris A, Cantor B, Edwards JD. Long term hemodynamic and visual function changes in normal tension glaucoma treated with oral nifedipine. Ophthal- mology 1995;102(suppl):90.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

Strenn et al. 63

Schmidt KG, Mittag TW, Pavlovic S, Hessemer V. Influence of physical exercise and nifedipine on ocular pulse amplitude. Graefes Arch Clin Exp Ophthal- mol 1996;234:527-32. Drance SM. Some factors in the production of low tension glaucoma. Br J Ophthalmol 1972;56:229-42. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM. Nocturnal arterial hypotension and its role in optic nerve head ischaemic disorders. Am J Ophthal- mol 1994;117:603-24. Netland PA, Grosskreutz CL, Feke GT, Hart LT. Color Doppler analysis of ocular circulation alter topical calcium channel blocker. Am J Ophthalmol 1995; 119:694-700. Netland PA, Feke GT, Konno S, Goger DG, Fuji0 N. Optic nerve head circulation after topical calcium channel blocker. J Glaucoma 1996;5:200-6. Vierhapper H, Wagner 0, Nowotny P, Waldhlusl W. Effect of endothelin-1 in man. Circulation 1990;81: 1415-8. Kaiser IH, Flammer J, Wenk M, Ltischer T. Endothelin-1 plasma levels in normal-tension glaucoma: abnormal responses to postural changes. Graefes Arch Clin Exp Ophthalmol 1995;233:481-8. Andrawis NS, Gilligan J, Abernethy DR. Endothelin-I mediated vasoconstriction: specific blockade by verapamil. Clin Pharmacol Ther 1992;52: 583-9. Bauer LA, Murray K, Horn JR, Opheim K, Olesen J. Influence of nifedipine therapy on indocyanine green and oral propanolol pharmacokinetics. Eur J Clin Pharmacol 1989;37:257-60. Reiss WG, Bauer LA, Horn JR, Zierler BK, Easter- ling TR, Strandness DE. The effects of oral nifedipine on hepatic blood flow in humans. Clin Pharmacol Ther 1991;50:379-84. Fletcher AE, Bulpitt CJ, Chase DM, Collins WC, Furberg CD, Goggin TK et al. Quality of life with three antihypertensive treatments: cilazapril, atenolol, nifedipine. Hypertension 1992;19:499-507. Bayley S, Dobbs RJ, Robinson BF. Nifedipine in the treatment of hypertension: report of a double blind uncontrolled trial. Br J Clin Pharmacol 1982;14:509- 12. Palmer A, Fletcher A, Hamilton G, Muriss S, Bulgitt C. A comparison of verapamil and nifedipine on quality of life. Br J Clin Pharmacol 1990;30:365-70.

Documents

Reversal of endothelin-1—induced ocular hemodynamic effects by low-dose nifedipine in humans