LABORATORY SCIENCES Effect of Latanoprost on Regional Blood Flow and Capillary Permeability in the Monkey Eye Johan Stjernschantz, MD, PhD; Go¨ran Sele´n, PhD; Maria Astin, PhD; Maritha Karlsson; Bahram Resul, PhD Objective: To evaluate the effects of latanoprost on ception of the anterior sclera, in which a moderate increase regional blood flow and capillary permeability in the in blood flow was detected. No effect on capillary perme- monkey eye. ability to albumin was detected when studied 30 minutes to 21⁄2 hours and 5 to 6 hours after dose administration. Methods: Anesthetized cynomolgus monkeys were unilaterally treated with a single dose containing 6 µg of Conclusion: Latanoprost, a selective prostaglandin F re- latanoprost; or 10 µg of PhXA34 (13,14-dihydro-15R, ceptor agonist, exerted no or only slight vascular effects S-17-phenyl-18,19,20-trinor-prostaglandin F2a [PGF2a]- for up to 6 hours after dose administration in the mon- isopropyl ester), which contains about 50% latano- key eye, with the exception of the anterior sclera, in which prost. Regional blood flow in the eye was measured with a moderate increase in blood flow was detected. radioactively labeled microspheres; capillary permeabil- ity was measured by determining the extravascular Clinical Relevance: Naturally occurring prostaglan- plasma-equivalent albumin space using 125I-albumin, 131I- dins may cause marked microcirculatory changes in the albumin, and 51Cr-labeled erythrocytes. eye that could be of clinical concern. Latanoprost, a selective prostaglandin F receptor agonist, seems to be Results: Latanoprost or PhXA34 had no or only a slight devoid of such effects. effect on the regional blood flow when measured 1, 21⁄2, 3, 41⁄2, and 6 hours after dose administration, with the ex- Arch Ophthalmol. 1999;117:1363-1367 ATANOPROST (13,14-dihydro- induce vasoconstriction in the eye, par- 17-phenyl-18,19,20-trinor- ticularly in the posterior pole, that could prostaglandin F2a [PGF2a]- be detrimental and aggravate the glauco- isopropyl ester), the active matous disease.13 Conversely, it may also principal in latanoprost eye- be of interest to know whether latano- Ldrops (Xalatan, Pharmacia & Upjohn), is prost induces increased blood flow in the a selective prostaglandin F receptor ago- eye, and particularly in the posterior pole, nist that is used for the reduction of the which could be advantageous in the treat- intraocular pressure in the treatment of ment of glaucoma. Finally, since natu- glaucoma. Latanoprost has been shown to rally occurring prostaglandins have been reduce the intraocular pressure effectively implicated to play a role in ocular inflam- during long-term treatment in patients with mation, it is of interest to investigate open-angle glaucoma and ocular hyperten- whether latanoprost has any effect on the 1-4 From the Department of sion. While PGF2a as well as PGF2a– capillary permeability. The present study Neuroscience, Unit of isopropyl ester have been shown to in- determined the vascular effects of latano- Pharmacology, Uppsala duce marked conjunctival hyperemia in prost in the primate eye to address the University (Drs Stjernschantz healthy volunteers and in patients with points raised. and Resul), and the Research glaucoma,5,6(pp447-458) latanoprost induces Laboratories of Pharmacia & significantly less hyperemia.7,8 Upjohn (Drs Sele´n and Astin RESULTS and Ms Karlsson), Uppsala, The regional blood flow in the eye 1 to 6 Sweden. All authors were See also page 1305 employees of Pharmacia & hours after topical application of PhXA34 Upjohn at the time of the study. Prostaglandin F2a is a known vaso- or latanoprost is provided in Table 1.Inthe None of the authors have any dilator but can also cause vasoconstric- eyelid,conjunctiva,andanteriorsclera,there proprietary interest in tion (eg, in the brain).9-12 The question has, was a tendency toward lower blood flow in latanoprost. therefore, arisen whether latanoprost could theexperimentaleyecomparedwiththecon- ARCH OPHTHALMOL / VOL 117, OCT 1999 WWW.ARCHOPHTHALMOL.COM 1363 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 MATERIALS AND METHODS cobalt 57, ruthenium 103, or niobium 95 (New England Nuclear Life Science Products, Boston, Mass) as described previously.14 A bolus of approximately 106 microspheres per Animals were treated according to the tenets of the Asso- injection was introduced into the left ventricle of the heart. ciation for Research in Vision and Ophthalmology State- A reference blood sample was collected from a femoral ar- ment on the Use of Animals in Ophthalmic and Vision Re- tery in test tubes under free flow conditions for 1 minute from search, and the experiments were approved by the local the start of the injection of the microspheres. By using mi- ethics committee for animal experimentation. Ten cyno- crospheres with different radioactive labels, it was possible molgus monkeys of either sex, weighing 2 to 4 kg, were to determine the blood flow at different occasions in each used for the experiments. Anesthesia was induced with ket- experiment. At the end of the experiment, the animal was amine hydrochloride, 25 mg/kg body weight intramuscu- euthanized and the eyes were dissected as described. larly. Polyethylene tubings were inserted into both fem- The capillary permeability in the different tissues of oral arteries for registration of arterial blood pressure and the eye was determined by measuring the extravascular collection of blood samples, and into both femoral veins plasma-equivalent albumin space.15,16 Human serum albu- for intravenous (IV) injections. A Ringer-acetate solution min labeled with iodine 125 (125I) or iodine 131 (131I) (In- was infused IV at a rate of 10 mL/h. A catheter for injec- stitutt for Energiteknikk, Kjeller, Norway) was used as a tion of the microspheres was inserted into the left heart ven- tracer, and free iodine was separated from labeled albu- tricle through the right brachial artery. Anesthesia was main- min immediately before the experiment using gel filtra- tained by IV injections of a diluted pentobarbital sodium tion (Sephadex G-25M, PD-10; Amersham Pharmacia Bio- solution, 15 mg/mL. The animals underwent a trache- tech AB, Uppsala, Sweden). The amount of free iodine in otomy and were connected to a ventilator for artificial ven- the infusion solution was less than 1%. Heparinized blood tilation. The PO2,PCO2, and pH of the arterial blood were was collected from the animal and incubated for 1 hour at regularly checked and adjusted when necessary, by chang- 37°C with a chromium 51 (51Cr)–labeled sodium cromate ing the ventilation, by administering a sodium bicarbon- solution (New England Nuclear Life Science Products). The ate solution IV, or both. A heating pad was used to main- blood was centrifuged, and the supernatant discarded. The tain normal body temperature. erythrocytes were washed with isotonic saline solution and Two series of experiments were performed. In the first, 5 centrifuged 6 times to remove unbound 51Cr. The final sus- animals were treated with PhXA34 (13,14-dihydro-15R, S-17- pension of erythrocytes contained less than 1% free 51Cr. phenyl-18,19,20-trinor-PGF2a-isopropyl ester), which con- In the first series of experiments, an IV bolus injection tains about 50% latanoprost, and the blood flow was mea- of 125I-albumin was given 30 minutes after topical instilla- sured 1 and 21⁄2 hours after dose administration. The capillary tion of PhXA34, followed by an IV infusion to maintain a stable permeability was determined during 2 postdosing periods: plasma level until the end of the experiment. Similarly, but 131 30 minutes to 21⁄2 hours and 11⁄2 to 21⁄2 hours. In the second 11⁄2 hours after instillation of PhXA34, I-albumin was in- series of experiments, 5 animals were treated with latano- jected IV and then infused to maintain a stable plasma level prost and the blood flow was determined 3, 41⁄2, and 6 hours until the end of the experiment; finally, the labeled eryth- after dose administration. The capillary permeability was de- rocytes were injected IV at 2 hours, ie, 30 minutes before termined between 5 and 6 hours after dose administration. the end of the experiment. Thus, it was possible to deter- Regional blood flow was measured using micro- mine the extravascular plasma-equivalent albumin space spheres (mean ± SEM size, 15.5 ± 0.1 µm) labeled with during 2 periods, 30 minutes to 21⁄2 hours and 11⁄2 to 21⁄2 trol eye at 1 hr after dose administration, although the dif- The values of the extravascular plasma-equivalent ferencewasnotstatisticallysignificant(P = .11,P = .40,P = .18, albumin space measured 30 minutes to 21⁄2 hours, 11⁄2 respectively). With time, the blood flow of these tissues to 21⁄2 hours, and 5 to 6 hours after topical application tended to become higher in the experimental eyes than in of PhXA34 or latanoprost are provided in Table 2. There the control eyes, and the difference reached statistical sig- was no difference between the experimental and con- nificance in the anterior sclera (Table 1). In the posterior trol eyes in the extravascular plasma-equivalent albu- sclera, the blood flow was low in the experimental and min space of any of the tissues studied. Thus, the capil- control eyes throughout the experiment, with a tendency lary permeability to albumin was not increased by the toward higher blood flow in the experimental eye through- administration of latanoprost or PhXA34 to the eye. The out the postdosing period. The blood flow of the intraocu- largest extravascular plasma-equivalent albumin space in lar tissues, the iris, the ciliary body, the choroid, and the the control and experimental eyes generally was found retina did not change 1 to 6 hours after instillation of the at the end of the 30 minutes to 21⁄2-hour period after dos- test drugs, with the exception of the ciliary body, in which ing, which is logical since the labeled albumin had time a small but statistically significant increase was found at 21⁄2 to circulate 1 hour longer than during the other periods hours after application of PhXA34 (Table 1).