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(Investigative Ophthalmology and Visual Science. 2003;44:3947-3951.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0855
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Effects of Adrenomedullin on Ocular Hemodynamic Parameters in the Choroid and the Ophthalmic Artery

Guido T. Dorner,1,2 Gerhard Garhöfer,1 Karl-Heinz Huemer,1,3 Elisabeth Golestani,1 Claudia Zawinka,1 Leopold Schmetterer,1,4 and Michael Wolzt1

1From the Departments of Clinical Pharmacology, 2Ophthalmology, 3Physiology, and 4Medical Physics, Allgemeines Krankenhaus Vienna, Vienna, Austria.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. Adrenomedullin acts as a vasodilator and may play a role in inflammatory processes in the eye. This study was designed to determine whether nitric oxide formation is involved in the response to adrenomedullin in the ocular vasculature in vivo.

METHODS. The effects of systemic intravenous adrenomedullin (3.2–16.0 pmol/[kg · min])) on choroidal blood flow were assessed by measurement of fundus pulsation amplitude and laser Doppler flow in the macula, and on blood flow in the ophthalmic artery by ultrasound Doppler flow in pilot studies (n = 7). Subsequently, in a double-blind randomized placebo-controlled crossover study in eight healthy male subjects the effects of 12.8 pmol/(kg · min) adrenomedullin on ocular and systemic hemodynamics were investigated. Adrenomedullin was co-infused with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (3 mg/kg bolus and 30 µg/[kg · min] continuous intravenous infusion) or vehicle control on separate study days.

RESULTS. Adrenomedullin dose dependently increased choroidal blood flow and flow velocity in the ophthalmic artery. NG-monomethyl-L-arginine reduced the effect of adrenomedullin on fundus pulsation amplitude, but did not alter the flow response in the ophthalmic artery. Systemic hemodynamics were unaffected by adrenomedullin infusion.

CONCLUSIONS. Ocular blood flow is sensitive to changes in adrenomedullin concentrations. The acute vasodilator effects of adrenomedullin are nitric oxide-dependent in the choroid, but not in the ophthalmic artery.

Adrenomedullin[1-52] (ADM) is a member of the calcitonin peptides family and is found in different human tissues.1 2 The peptide is synthesized and secreted by vascular endothelial cells into both the blood stream and the interstitium to exert its action on vascular smooth muscle cells.3 4 5 6 Elevated plasma levels of ADM have been demonstrated in cardiovascular, respiratory, hepatic, metabolic, and renal disorders.7 8 9 10 11 12 A regulatory role of ADM in the growth of human retinal pigment epithelial cells has been demonstrated by Udono et al.13 14 Peripherally administered ADM exerts vasodilation and triggers conjunctival inflammation in the rabbit eye.15 Elevated levels of ADM were found in the vitreous of patients with proliferative retinopathy.16 In addition, ADM has a relaxant effect on iris sphincter muscle17 and is expressed in the ciliary body.18

The exact mechanism underlying the vasodilation response to ADM in the eye has not been clarified. Homozygous deletion of ADM synthesis is lethal and heterozygous knockout animals have hypertension due to reduced nitric oxide (NO) production.19 This is compatible with in vitro experiments showing increased release of endogenous NO and activation of potassium channels by ADM.20 21 It has also been demonstrated, however, that ADM can induce vasorelaxation through direct receptor-mediated activation of adenylate cyclase,22 23 24 and inotropic effects through direct intracellular calcium increase.25

The purpose of the present study was to characterize the dose–response relationship of ADM in the eye and to investigate whether the hemodynamic effect is dependent on formation of constitutive NO. ADM was therefore infused in the absence or presence of a structural inhibitor of the NO-synthase, NG-monomethyl-L-arginine (L-NMMA).


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Subjects
The study protocol was approved by the Ethics Committee of the Vienna University School of Medicine and adhered to the guidelines of the Declaration of Helsinki. After written informed consent was obtained, 15 healthy, nonsmoking, drug-free male volunteers between 19 and 36 years of age (mean ± SD: 27 ± 4 years) were enrolled in the study. Each volunteer passed a screening examination that included a history and physical examination, 12-lead electrocardiogram, complete blood cell count with differential, clinical chemistry and coagulation tests, urine drug screening, and hepatitis B and C and human immunodeficiency virus antibody tests. Subjects were asked to refrain from alcohol and caffeine for at least 12 hours before study days. Studies were performed after a light breakfast in a quiet room with an ambient temperature of 22°C and complete resuscitation facilities.

Pilot Study
In a dose-finding pilot study, four healthy male subjects received intravenous doses of ADM that were increased stepwise (0 [saline], 3.2, 6.4, 9.6, 12.8 and 16 pmol/[kg · min]) with an infusion period of 45 minutes per dose step. This study was not masked and was performed according to an open-label design. Systemic hemodynamics, blood flow in the ophthalmic artery, and fundus pulsation amplitude (FPA) were measured.

In a second unmasked study three healthy male subjects received intravenous doses of ADM that were also increased stepwise (0 [saline], 3.2, 9.6 and 16 pmol/[kg · min]) with an infusion period of 30 minutes per dose step. FPA and laser Doppler flow of the macula were measured.

Main Study
This study was designed to investigate the systemic and regional pharmacodynamic effects of ADM, without or with concomitant inhibition of constitutive NO synthesis. A sample size calculation for this study was performed based on the results of the first pilot study. For this sample size calculation, an {alpha} error of 0.05 and a power of 0.8 was chosen. Using the data for the standard deviation of FPA measurements in healthy volunteers,26 we sought to detect a 50% reduction of ADM-induced effects on FPA (i.e., a change in FPA by 12% over baseline), because an average increase in FPA of approximately 24% was observed with the selected ADM dose of 12.8 pmol/(kg · min) in the pilot study. Accordingly, a placebo controlled, double-masked, randomized, two-way crossover study was performed in eight healthy male subjects. After baseline conditions were established, which was ensured by a resting period with repeated measurement of systemic hemodynamic parameters, the NO synthase inhibitor L-NMMA (3 mg/kg intravenous bolus and a 30-µg/[kg ·min] continuous infusion over 75 minutes) or placebo was administered on different trial days. This dose regimen was based on the results of a previous study in our laboratory.27 Thirty minutes after the start of L-NMMA infusion, ADM (12.8 pmol/[kg · min]; infusion period 45 minutes) was co-infused on both study days. All treatments were administered into cubital veins with automated infusion pumps. The washout interval between trial days was at least 4 days.

Drugs Used
ADM was obtained from the American Peptide Company (Sunnyvale, CA). After fractionation and lyophilization, the peptide content was quantified by reverse amino acid analysis and screened for pyrogenicity. L-NMMA was purchased from Clinalfa (Läufelfingen, Switzerland). Physiologic saline solution was used as the placebo.

Noninvasive Measurement of Systemic Hemodynamics
Mean arterial blood pressure was measured noninvasively in 10-minute intervals on the upper arm by an automated oscillometric device (HP CMS patient monitor; Hewlett Packard, Palo Alto, CA). Pulse rate was monitored continuously by finger photoplethysmography with the same device (HP CMS patient monitor). The sensitivity of this equipment has been reported.28

Blood Flow in the Ophthalmic Artery
Mean blood flow velocity (MFV) in the right ophthalmic artery was assessed using Doppler ultrasound.29 Blood flow velocity in the ophthalmic artery was measured with a 7.5-MHz probe (CFM 750; Vingmed Sound, Horten, Norway) just before the crossing at the optic nerve. All parameters were determined as mean values over at least three cardiac cycles.

Fundus Pulsation Measurements
Pulse synchronous pulsations of the ocular fundus were assessed by laser interferometry on the subject’s right eye, using a method described in detail by Schmetterer et al.30 Briefly, the eye is illuminated by the beam of a single-mode laser diode ({lambda} = 783 nm) along the optical axis. A laser power of not more than 100 µW is much lower than the limit set by the American National Standards Institute. 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 and retina during a cardiac cycle can be calculated. Distance changes between cornea and retina lead to corresponding variation of the interference order, {Delta} N(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, {Delta} L(t), corresponding to the cornea-retina distance changes, can be calculated by {Delta} L(t) = {Delta} N(t) · {lambda}/2. The maximum distance change is the FPA and estimates the local pulsatile blood flow.26 FPA closely correlates with pneumotonometric pulsatile choroidal blood flow measurements.26 31 The short-term and day-to-day variability of the method is small, which allows the detection of even slight changes in local pulsatile blood flow after pharmacological stimulation.32 To obtain information on the choroidal blood flow, the macula, where the retina has no vasculature, was selected for measurements.

Macular Blood Flow: Laser Doppler Flowmetry
Measurement of choroidal blood flow was performed by laser Doppler flowmetry (LDF) according to the method of Riva et al.33 The vascularized tissue is illuminated by coherent laser light and scattering by moving red blood cells (RBCs) leads to a frequency shift in the scattered light. In contrast, static scatters in tissue do not change the light frequency, but lead to randomization of light direction impinging on RBCs. This diffusion of light in vascularized tissue causes a broadening of the spectrum of scattered light, from which the choroidal blood flow can be calculated in relative units. In the present study LDF was performed in the fovea to assess macular blood flow.

Data Analysis
All statistical analyses were performed on computer (Statistica software ver. 4.5; StatSoft Inc., Tulsa, OK). In the dose-determination pilot study, the effects of ADM on hemodynamic parameters are descriptively presented. In the pharmacodynamic study differences between groups at baseline were assessed by the Mann-Whitney test. The effects of ADM and L-NMMA on outcome variables were assessed by repeated-measure ANOVA versus baseline and versus placebo treatment, respectively. P < 0.05 was considered the level of significance. For data description, values are given as the mean ± SEM.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The drugs under study were well tolerated without adverse events.

Pilot Study
The hemodynamic effects of ADM are presented in Tables 1 and 2 . MFV in the ophthalmic artery increased dose dependently and was paralleled by an increase in FPA. ADM, at doses of 12.8-pmol/(kg · min) or more, decreased mean blood pressure and increased pulse rate.


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  		TABLE 1. Effect of Increasing Doses of ADM on Hemodynamic Parameters with a 45-Minute Infusion Period

 

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  		TABLE 2. Effect of Increasing Doses of ADM on Hemodynamic Parameters with a 30-Minute Infusion Period

 
Figure 1 shows the dose-dependent increase of FPA and blood flow in the macula by ADM.



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  		FIGURE 1. Effect of 3.2, 9.6, and 16 pmol/(kg · min) ADM on choroidal blood flow, as assessed by FPA and LDF in the macula. Data are presented as percentage change over baseline (mean ± SEM, n = 3).

 
Main Study
Baseline parameters are given in Table 3 and were comparable between trial days. Results are illustrated in Figures 2 and 3 .


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  		TABLE 3. Baseline Parameters of Study Days

 


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  		FIGURE 2. Effect of L-NMMA ({blacksquare}) or placebo ({circ}) with co-infusion of ADM on FPA and MFV in the ophthalmic artery (MFV ophthal). Boxes: periods of drug infusion. Results are presented as the percentage change over baseline (mean ± SEM, n = 8).

 


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  		FIGURE 3. Effect of L-NMMA ({blacksquare}) or placebo ({circ}) with co-infusion of ADM on MAP and pulse rate. Boxes: periods of drug infusion. Results are presented as the percentage change over baseline (mean ± SEM, n = 8).

 
Effect of NO Synthase Inhibition
L-NMMA significantly reduced FPA (Fig. 2 ; maximum change: -13.5% ± 3.5%; mean ± SEM; P < 0.034), but had no effect on MFV (P = 0.15) in the ophthalmic artery. A small increase in mean arterial pressure (MAP) and a reduction in pulse rate were noted (Fig. 3) , but these changes did not reach the level of significance.

Effect of ADM
ADM at 12.8 pmol/(kg · min) significantly increased FPA (Fig. 2 ; +23.2% ± 9.1%) and MFV (+37.5% ± 15.2%) in the ophthalmic artery (P < 0.001, ANOVA). However, there was no consistent effect on MAP (Fig. 3 ; -8.1% ± 2.0%, P = NS) or pulse rate (+10.7% ± 6.4%, P = NS), and there were only small changes over baseline.

Co-infusion of L-NMMA with ADM
L-NMMA blunted the effect of ADM on FPA. The ADM-induced increase in FPA was significantly reduced when L-NMMA was coadministered (+9.1% ± 4.4%; P < 0.01). By contrast, no effect on the ADM-induced blood flow increase in the ophthalmic artery (Fig. 2) or on systemic hemodynamics was observed.


   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
In the present study, we investigated whether ADM increases ocular hemodynamic parameters in the choroid and the ophthalmic artery in healthy volunteers. Our results demonstrate that ADM induced vasodilation in these vascular beds. In addition, we investigated whether inhibition of NO synthase alters the hemodynamic effects of ADM in these vascular beds in healthy humans. Whereas this was the case in the choroid, ADM-induced effects on MFV in the ophthalmic artery were not modified by L-NMMA.

Vasodilatory effects of systemic doses of ADM have been reported in several animal studies in the kidney,34 the lung,35 and the brain36 37 in various species. In humans, an intra-arterial infusion of ADM enhances total blood flow in the forearm.38 39 40 In the present study, ADM markedly increased FPA and LDF in the macula, indicating enhanced choroidal blood flow, and MFV in the ophthalmic artery. Doses, however, were slightly higher than in previous human studies, where ADM at a dose of 5.8 pmol/(kg · min) increased cardiac output and heart rate and decreased diastolic blood pressure when infused over 2 hours.41 In our cohort, doses up to 16 pmol/(kg · min) were also well tolerated, but had only a trivial effect on systemic hemodynamics at low doses. This may be due to subject-specific differences, but could also be attributable to prolonged administration and drug accumulation in the previous studies.

The exact mechanism by which ADM exerts its strong vasodilating effect is still a matter of discussion. We set out to study whether NO formation contributes as an intermediary in this action, but did not find a uniform response pattern. Although the NO synthase inhibitor L-NMMA reduced the action of ADM in the choroidal circulation, it failed to mitigate its effect in the ophthalmic artery. It is well known that the choroidal vasculature is particularly sensitive to the formation of NO.42 43 44 Impaired NO bioactivity could therefore affect ocular responses of hormones acting through the L-arginine/NO pathway. Our results indicate that there is a wide variability in the mechanisms underlying ADM-induced vasodilation in different vascular beds. One possibility may be that the increase in blood flow in the choroid is related to shear-stress–induced formation of NO in the vascular endothelium. Further studies are needed to test this hypothesis. In previous studies, comparable doses of L-NMMA were sufficient to blunt the hemodynamic effects of hypercapnia,45 insulin,46 and histamine47 in the choroid and the ophthalmic artery. The lack of effect of inhibition of constitutive NO synthase on MFV in the ophthalmic artery as opposed to the choroid has also been observed in a previous trial.48

The methods under study provide only indirect evidence that the observed hemodynamic effects of ADM in the choroid and the ophthalmic artery indeed result from local vasodilation. In the choroid, FPA has been shown to represent an adequate measure of pulsatile blood flow.26 31 We have shown that L-NMMA–induced reductions in FPA and choroidal blood flow, as measured with LDF, are comparable.27 In this series, changes in response to ADM were consistently detectable by laser interferometry and LDF, which argues against false-positive results. Because only minor changes in systemic blood pressure were observed with ADM, our data in the choroid are indicative of local vasodilation.

In the ophthalmic artery, an increase in MFV may be induced by changes in systemic hemodynamics, by local vasoconstriction within the measured vessel segment, or by a decrease in distal vascular resistance. Most likely, a decrease in distal vascular resistance accounts for the increase in MFV in the ophthalmic artery, compatible with the observed increase in FPA considering that approximately 25% of the blood flowing in the ophthalmic artery supplies the choroid.49 The slight decrease in MFV in the ophthalmic artery and in FPA during placebo did not reach the level of significance and is most likely attributable to the duration of the experiments, the variability of the methods, and the small sample size.

In conclusion, data in the present study indicate that ADM induces local vasodilating effects in the human eye. The ocular vasculature appears to be sensitive to changes in systemic ADM concentrations. Although inhibition of constitutive NO formation reduces ADM-induced vasodilation in the choroid, hemodynamic effects in the ophthalmic artery are not mitigated by L-NMMA.


   Footnotes
 
Supported by Grant 7553 from the Jubiläumsfonds der Oesterreichischen Nationalbank.

Submitted for publication August 21, 2002; revised December 2, 2002 and April 4 and April 16, 2003; accepted April 21, 2003.

Disclosure: G.T. Dorner, None; G. Garhöfer, None; K.-H. Huemer, None; E. Golestani, None; C. Zawinka, None; L. Schmetterer, None; M. Wolzt, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Michael Wolzt, Department of Clinical Pharmacology, University of Vienna, Medical School, Vienna, Austria; michael.wolzt{at}univie.ac.at.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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S. C. Lim, N. G. Morgenthaler, T. Subramaniam, Y. S. Wu, S. K. Goh, and C. F. Sum
The Relationship Between Adrenomedullin, Metabolic Factors, and Vascular Function in Individuals With Type 2 Diabetes
Diabetes Care, June 1, 2007; 30(6): 1513 - 1519.
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