Intravenous Administration of Diphenhydramine Reduces Histamine-Induced Vasodilator Effects in the Retina and Choroid

Gu¨nther Weigert,1 Claudia Zawinka,1 Hemma Resch,1 Leopold Schmetterer,1,2 and Gerhard Garho¨fer1,3

PURPOSE. Intravenous administration of histamine causes an and choroid, H1 receptors are involved in the histamine-medi- increase in choroidal blood flow (ChBF) and retinal vessel ated hemodynamic effects in vivo. (Invest Ophthalmol Vis Sci. diameters in healthy subjects. The receptor mediating this 2006;47:1096–1100) DOI:10.1167/iovs.05-1174 response has not yet been identified. The present study was undertaken to clarify whether H1 receptor blockade with di- hereas the role of histamine in the acute allergic re- phenhydramine affects the hemodynamic response of hista- Wsponse is well established, the potential physiological mine in the choroid and the retina. role of histamine in the control of vascular tone remains to be METHODS. A randomized, double-masked, placebo-controlled, clarified fully. Several lines of evidence indicate that histamine two-way crossover study was performed in 18 healthy, male, acts as a regulator of blood flow in the eye.1–3 In vitro exper- nonsmoking subjects. Histamine (0.32 ␮g/kg per minute over iments in isolated retinal arteries first demonstrated an endo- 30 minutes) was infused intravenously in the absence (NaCl as thelium-dependent relaxation of retinal vessels caused by his- 4 placebo) or presence of the H1 blocker diphenhydramine (1.0 tamine. This is in keeping with experiments in humans mg/min over 50 minutes). Ocular hemodynamic parameters, indicating a vasodilative role of histamine in the retina, paral- blood pressure, and intraocular pressure were measured be- leled by an increase in choroidal blood flow (ChBF).1–3 fore drug administration, after infusion of diphenhydramine or However, the exact mechanism underlying this histamine- placebo, and after co-infusion of histamine. Subfoveal ChBF induced effect is still a matter of investigation. Although there and fundus pulsation amplitude (FPA) were measured with is evidence that the vascular effects of histamine are dependent laser Doppler flowmetry and laser interferometry, respectively. on the presence of an intact endothelium,1 the receptors me- Retinal arterial and venous diameters were measured with a diating this effect have not yet been identified. Until now, three retinal vessel analyzer. Retinal blood velocity was assessed with different histamine receptor subtypes have been identified.5–7 bidirectional laser Doppler velocimetry. The H1 and H2 receptor types are present in the arteriolar smooth muscle, whereas the H type has been hypothesized to RESULTS. Administration of histamine caused a decrease in 2 be the dominant receptor participating in the vasodilator re- mean arterial pressure by Ϫ4% Ϯ 9% (ANOVA P ϭ 0.01). This sponse to histamine.8 Histamine H receptors are presynaptic effect was blunted by coadministration of diphenhydramine 3 receptors in the central nervous system and on peripheral (ANOVA, P ϭ 0.04). Histamine significantly increased FPA and neurons of the gastrointestinal and bronchial tracts, modulat- subfoveal ChBF. Coadministration of diphenhydramine signifi- ing the endogenous release of a variety of neurotransmitters.9 cantly reduced this effect (ANOVA; FPA P ϭ 0.001, ChBF P ϭ We showed recently that cimetidine, a H receptor antago- 0.049). Histamine significantly increased retinal arterial diame- 2 nist is not able to inhibit the blood flow response to histamine, ter by ϩ3.5% Ϯ 4.5% and retinal venous diameter by ϩ3.7% Ϯ strongly suggesting that H receptors are not responsible for 2.8%. Again, coadministration of diphenhydramine signifi- 2 the blood flow effect of histamine in the eye.3 In the present cantly reduced the vasodilative effect to ϩ0.3% Ϯ 5.5% in study we hypothesized that administration of diphenhydra- retinal arteries (ANOVA, P ϭ 0.00006) and to ϩ0.9% Ϯ 2.5% in mine, a histamine type-1 receptor antagonist, alters the vaso- retinal veins (ANOVA, P ϭ 0.004). dilative effect of histamine in the ocular circulation. CONCLUSIONS. The present data confirm that histamine increases ChBF and retinal vessel diameters in healthy subjects. Admin-

istration of the H1 receptor blocker diphenhydramine signiﬁ- MATERIALS AND METHODS cantly reduced histamine-induced changes in ocular perfusion parameters. These results strongly indicate that in the retina Subjects Eighteen healthy, male, nonsmoking volunteers were included (age range: 22–32 years, mean: 26.4 Ϯ 2.8 years [SD]). The nature of the From the Departments of 1Clinical Pharmacology, 2Biomedical study was explained, and all subjects signed a written, informed con- Engineering and Physics, and 3Ophthalmology, Medical University of sent to participate. The study protocol was approved by the Ethics Vienna, Vienna, Austria. Committee of Vienna University School of Medicine and adhered to the Supported by the Austrian Science Fonds Fonds zur Fo¨rderung der guidelines of Good Clinical Practice and the Declaration of Helsinki. wissenschaftlichen Forschung Grant FWF-P16514. Each subject passed a screening examination, including medical his- Submitted for publication September 2, 2005; revised October 20 tory and physical examination; 12-lead electrocardiogram; complete and November 16, 2005; accepted January 13, 2006. blood count; activated partial thromboplastin time; thrombin time; Disclosure: G. Weigert, None; C. Zawinka, None; H. Resch, ﬁbrinogen; clinical chemistry (sodium, potassium, creatinine, uric acid, None; L. Schmetterer, None; G. Garho¨fer, None glucose, cholesterol, triglycerides, alanine aminotransferase, aspartate The publication costs of this article were defrayed in part by page ␥ charge payment. This article must therefore be marked “advertise- transcarbamoylase, -glutamyl-transferase, alkaline phosphatase, total ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. bilirubin, total protein), total IgE antibodies; hepatitis A, B, and C and Corresponding author: Gerhard Garho¨fer, Department of Clinical HIV serology; urinalysis; and a urine drug screening. Only subjects with Pharmacology, Wa¨hringer Gu¨rtel 18–20, A-1090 Vienna, Austria; IgE plasma levels of less than 100 kU/L were included. Subjects were [email protected]. excluded if any abnormality was found as part of the pretreatment

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tion of 25 readings/s. The fundus was illuminated with light in the range of wavelengths between 567 and 587 nm. In this spectral range, the contrast between retinal vessels and the surrounding tissue is optimal. Retinal irradiance was approximately 220 ␮W/cm2, which is approximately 50 times lower than the maximum level allowed for constant illumination of the retina at the wavelengths mentioned earlier. The system provides excellent reproducibility and sensitiv- ity.10,11 In the present study, major temporal arteries and veins were studied. Measurements of retinal venous diameters were taken between 1 and 2 disc diameters from the margin of the optic disc. Red blood cell (RBC) velocity was measured at the same locations as retinal vessel diameters by using bidirectional laser Doppler velocimetry. FIGURE 1. Time schedule. Laser Doppler Velocimetry screening, unless the investigators considered the abnormality to be In the present study, we used a fundus camera–based system with a clinically irrelevant. Further exclusion criteria were a history of mi- single mode laser diode at a centerline wavelength of 670 nm (model graine or other types of headaches. Moreover, an ophthalmic exami- 4000; Oculix Sarl, Arbaz, Switzerland). The principle of blood flow nation, including slit lamp biomicroscopy and indirect funduscopy, velocity measurement by laser Doppler velocimetry is based on the was performed. Inclusion criteria were normal ophthalmic findings, optical Doppler effect. Laser light, which is scattered by moving ametropia of less than 3 D, and anisometropia of less than 1 D. particles (e.g., erythrocytes) shifts in frequency. This frequency shift is proportional to the blood flow velocity in the retinal vessel. The Study Design maximum Doppler shift corresponds to the centerline erythrocyte frequency. Measurements were performed in main inferior temporal Subjects were studied in a randomized, balanced, double-masked, 12 two-way crossover design infusing histamine in combination with the retinal veins.

H1 receptor antagonist diphenhydramine or a placebo. Two study days were scheduled for each subject with washout periods of at least 5 Calculation of Retinal Blood Flow days between study days. On both study days histamine was adminis- Blood ﬂow in retinal veins was calculated based on maximum eryth-

tered intravenously in a dose of 0.32 ␮g/kg per minute, with a coad- rocyte velocity (Vmax) measured by laser Doppler velocimetry and ministration of diphenhydramine in a dose of 1.0 mg/min, or placebo retinal vessel diameter measured by the RVA, both assessed in retinal

on the other study day. Both substances were administered with an veins. Mean blood flow velocity was calculated as (Vmax/2). Blood flow ϭ ⅐ infusion pump (Braun, Melsungen, Germany). The total volume load through a specific retinal vein was then calculated as Q (Vmax/2) for each volunteer was 88 mL. A time schedule is shown in Figure 1. (␲ ⅐ d2/4), where d is the diameter of the vein. On the trial days, subjects arrived after a light breakfast. Baseline hemodynamic parameters were recorded with the subject in a sitting Laser Doppler Flowmetry position after the values had stabilized. All subjects were studied with Measurements of subfoveal ChBF were performed by laser Doppler dilated pupils after instillation with tropicamide (Mydriaticum Agepha; flowmetry (model 4000; Oculix Sari), as described by Riva et al.13 For Agepha, Vienna, Austria). One drop was applied to the study eye at the this purpose, the vascularized tissue was illuminated by coherent laser beginning of the resting period. Diphenhydramine (Dibondrin, 30 mg light. Scattering on moving RBCs leads to a frequency shift in the ampule; Montavit GmbH, Absam, Austria) or a placebo was given scattered light. In contrast, static scatterers in tissue do not change intravenously over a period of 50 minutes. Five minutes after the start light frequency, but lead to randomization of light direction impinging of the infusion, ocular hemodynamic parameters were assessed again on RBCs. This light diffusion in vascularized tissue leads to a broaden- in a predetermined order (fundus pulsation amplitude [FPA], laser ing of the spectrum of scattered light, from which mean RBC velocity Doppler velocimetry, laser Doppler flowmetry, retinal vessel analyzer). (vel), the blood volume (vol), and the blood flow (flow) can be Twenty minutes after the start of the diphenhydramine or placebo calculated in relative units. In the present study, laser Doppler flow- infusion, histamine (Mayrhofer Pharmazeutika, Linz, Austria) was ad- metry was performed in the fovea to assess ChBF. ministered for 30 minutes. Fifteen minutes after the start of the infusion of histamine, the measurement procedures were repeated. Pulse Laser Interferometry rate and blood pressure were measured in 5-minute intervals and a real-time electrocardiogram was monitored continuously throughout Pulse synchronous pulsations of the eye fundus were assessed by laser the study period. interferometry. The method is described in detail by Schmetterer et al.14 Briefly, the eye is illuminated along the optical axis by the beam Methods of a single-mode laser diode (␭ ϭ 783 nm). The laser power of not more than 100 ␮W is much lower than the limit set by the American Noninvasive Measurement of National Standards Institute. The light is reflected at both the front side Systemic Hemodynamics of the cornea and the retina. The two re-emitted waves produce interference fringes from which the distance changes between cornea Systolic, diastolic, and mean arterial (MAP) blood pressure were mea- and retina during a cardiac cycle can be calculated. The FPA has been sured every 5 minutes on the upper arm with an automated oscillom- shown to estimate the pulsatile blood flow component in the cho- eter. Pulse rate was automatically recorded from a finger pulse oxime- roid.15,16 ter. An electrocardiogram was recorded continuously with a standard four-lead device (HP-CMS monitor; Hewlett Packard, Palo Alto, CA). Measurement of IOP Retinal Vessel Analyzer The IOP was measured with a Goldmann applanation tonometer (Haag The retinal vessel analyzer (RVA; Imedos, Jena, Germany) is a commer- Streit, Vienna, Austria). cially available system that comprises a fundus camera, a video camera, a high-resolution video recorder, a real-time monitor, and a personal Statistical Analysis computer with vessel diameter–analyzing software. The RVA allows for For data analysis, hemodynamic parameters are expressed as percent- a precise determination of retinal vessel diameter with a time resolu- age change from baseline (⌬%). Effects of histamine and diphenhydra-

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TABLE 1. Baseline Parameters of Ocular and Systemic Hemodynamic by ϩ3.5% Ϯ 4.5% (ANOVA, time effect P ϭ 0.0001). Coadmin- Measurements on the Two Study Days istration of diphenhydramine significantly reduced this increase to ϩ0.3% Ϯ 5.5% (ANOVA, interaction: P ϭ 0.004, Placebo/ placebo versus diphenhydramine: P ϭ 0.00006). Administra- Histamine Diphenhydramine/ ϩ Parameter Day Histamine Day tion of histamine increased retinal venous diameter by 3.7% Ϯ 2.8% (ANOVA, time effect: P ϭ 0.000016). Coadministration MAP (mm Hg) 83 Ϯ 881Ϯ 9 of diphenhydramine also reduced this vasodilative effect of PR (bpm) 70 Ϯ 770Ϯ 7 histamine to ϩ0.9% Ϯ 2.5% (ANOVA, interaction: P ϭ 0.00006, IOP (mm Hg) 13 Ϯ 113Ϯ 2 placebo versus diphenhydramine: P ϭ 0.004). ChBF (arbitrary units) 8.8 Ϯ 2.0 8.6 Ϯ 1.3 Histamine did not change RBC velocity (Fig. 2). Neither Arterial vessel diameter (␮m) 121 Ϯ 11 123 Ϯ 16 placebo nor diphenhydramine affected RBC velocity (ANOVA, Venous vessel diameter (␮m) 152 Ϯ 12 154 Ϯ 13 interaction: P ϭ 0.6). Calculated retinal blood flow in retinal FPA (␮m) 4.0 Ϯ 1.2 3.9 Ϯ 1.3 Ϯ Ϯ veins also remained unchanged after administration of hista- RBV (cm/s) 2.0 0.7 2.1 0.4 mine and was not altered by coadministration of diphenhydra- RBF (␮l/min) 22 Ϯ 624Ϯ 5 mine. (ANOVA, interaction: P ϭ 0.3). Baseline parameters were obtained during the 10 minutes before infusion. Results are presented as the mean Ϯ SD. Parameters included Mean arterial pressure (MAP), pulse rate (PR), intraocular pressure DISCUSSION (IOP), subfoveal choroidal blood flow assessed with laser Doppler flowmetry (ChBF), retinal arterial and venous diameters, fundus pulsa- The vasomotor effects of histamine have been studied in sev- tion amplitude (FPA) as assessed with laser interferometry, red blood eral vascular beds in human and animal experiments. In gen- cell velocity (RBV) assessed with bidirectional laser Doppler velocim- eral, intravenous administration of histamine causes a decline etry and calculated retinal blood flow (RBF) in one single vein. in peripheral vascular resistance, indicated by a decrease in systemic blood pressure.2 This indicates net vasodilatation, although both contractile and relaxing effects, as mediated by mine on hemodynamic parameters were assessed by two-way ANOVA the activation of both H and H receptors, may occur. In for repeated measurements, using the absolute values. The interaction 1 2 contrast to this systemic effect, the effects of histamine on a between time and treatment was used to assess statistical differences. specific vascular bed are quite variable and hard to predict, Planned comparisons were used to calculate differences between di- because marked species and regional differences have been phenhydramine and placebo (treatment effect) and time effects. Re- reported regarding the receptor density and distribution.17,18 sults are given as the mean Ϯ SD. Shapiro-Wilks’ W test was used to test In the ocular vasculature, several lines of evidence, mainly for normal data distribution. Calculations were performed on com- based on experiments in isolated vessels, demonstrate the puter (Statistica software package; Statsoft, Tulsa, OK). vasodilative role of histamine.4,8,19 These results have been confirmed by in vivo animal experiments, where an increase in RESULTS retinal blood flow in the rat eye has been observed after intravitreal administration of histamine.20 The few experimen- Systemic Hemodynamics and IOP tal data available from in vivo human experiments, also confirm Baseline pulse rate and IOP were comparable on both study this vasodilative role of histamine in the eye. Intravenously days (Table 1). Neither administration of diphenhydramine nor administered histamine caused an increase in mean flow velocity in the ophthalmic artery as well as an increase in pulsatile placebo affected MAP, whereas administration of histamine 1 decreased MAP by Ϫ4% Ϯ 9% (ANOVA, time effect: P ϭ 0.01). ChBF. In addition, it has recently been shown that histamine increases ChBF and retinal vessel diameter in young, healthy Coadministration of diphenhydramine reduced the MAP-low- 2 ering effect of histamine (ANOVA, interaction: P ϭ 0.04; pla- volunteers. cebo versus diphenhydramine: P ϭ 0.04). Infusion of diphen- However, interpretation of these results is hampered by the hydramine tended to decrease pulse rate, but this effect did not fact that the receptor mediating this vasodilative potential has reach significance (Fig. 2; ANOVA, interaction: P ϭ 0.1). None not yet been identified. It has been recognized that both H1 of the study drugs altered IOP. and H2 receptors are localized uniformly within the inner layers of cerebral arteriolar smooth muscle.21 Experiments in ChBF Parameters isolated human subcutaneous resistance arteries indicated that both H and H receptors are responsible for the histamine As shown in Figure 2, neither placebo nor diphenhydramine 1 2 effects, but the H2 type seemed to be the dominant receptor affected subfoveal ChBF, as assessed with laser Doppler flow- participating in the vasodilator responses to histamine in the metry. Histamine, however, increased subfoveal ChBF by skin.8 ϩ Ϯ ϭ 12% 16% (ANOVA time effect: P 0.01). Coadministration In the retina and the choroid, direct evidence of the recep- of diphenhydramine reduced this histamine-induced increase tors mediating the vascular effects of histamine is sparse. Stud- ϩ Ϯ ϭ to 5% 13% (ANOVA, interaction: P 0.04, placebo versus ies in isolated bovine retinal arteries showed a concentration- ϭ diphenhydramine: P 0.049). FPA, as measured by the means dependent vasodilator effect of histamine.4 In contrast to the of laser interferometry was not affected by administration of skin, the vasodilative effect in ocular vessels was clearly inhib- placebo or diphenhydramine (Fig. 2). Histamine, however, ited by coadministration of the H receptor antagonist mepyra- ϩ Ϯ 1 significantly increased FPA by 15% 9% (ANOVA, time mine.4 This indicates that in the eye, the hemodynamic effect ϭ effect: P 0.001). Again, this effect was significantly reduced was mainly caused by the activation of H receptors, although ϩ Ϯ 1 by coadministration of diphenhydramine to 1% 5% activation of H receptors seemed to contribute to the hista- ϭ 2 (ANOVA, interaction: P 0.001, placebo versus diphenhydramine response.4 As stated earlier this contradictory result may ϭ mine: P 0.001). be explained by the fact that the action of histamine on vascular smooth muscle depends on the tissue and species. Fur- Retinal Blood Flow thermore, histamine responses are known to be location and Diphenhydramine alone had no effect on retinal arterial or concentration dependent. Even a heterogeneity in the re- venous diameters. Histamine increased retinal arterial diameter sponse of segmental vessel to histamine is described.17,18

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FIGURE 2. Effect of histamine in the absence (placebo, f) or presence (E) of diphenhydramine on the out- come parameters (n ϭ 18, means Ϯ SD) *Signiﬁcance between groups; #signiﬁcance of the effect of histamine after pretreatment with either diphenhydramine or placebo.

We recently showed that intravenous administration of ci- receptors do not play a major role in the regulation of ocular

metidine, an H2 receptor antagonist, has no inhibitory inﬂu- blood ﬂow. The results of the present study demonstrate that ence on histamine-induced changes in retinal and choroidal the histamine-induced increase in retinal vessel diameters and 3 circulation. From this experiment, it was concluded that H2 ChBF can be reduced by coadministration of an H1 receptor

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antagonist. These results strongly indicate that in the ocular 6. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Def- circulation, histamine’s effects are at least partially mediated by inition and antagonism of histamine H 2 -receptors. Nature. 1972; 236:385–390. H1 receptors. Although diphenhydramine is a potent and 7. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain hista- highly selective H1 receptor antagonist, we cannot entirely exclude that diphenhydramine also exerts, to a small extent, mine release mediated by a novel class (H3) of histamine receptor. Nature. 1983;302:832–837. antagonizing effects on H2 receptors. To exclude this con- 8. Van de Voorde J, Leusen I. Role of the endothelium in the vasodi- founding possibility with certainty, a specific H1 receptor agonist would be necessary, but such a receptor agonist is not lator response of rat thoracic aorta to histamine. Eur J Pharmacol. available for human experiments to date. 1983;87:113–120. 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