- Email: [email protected]
Effects of tamsulosin and silodosin on isolated albino and pigmented rabbit iris dilators: Possible mechanism of intraoperative floppy-iris syndrome
LABORATORY SCIENCE
Effects of tamsulosin and silodosin on isolated albino and pigmented rabbit iris dilators: Possible mechanism of intraoperative floppy-iris syndrome Toshiaki Goseki, MD, PhD, Hitoshi Ishikawa, MD, PhD, Shiori Ogasawara, MS, Kimiyo Mashimo, BS, Noriko Nemoto, BS, Yuko Taguchi, MS, Kazuo Yago, PhD, Kimiya Shimizu, MD, PhD
PURPOSE: To determine the mechanism of intraoperative floppy-iris syndrome (IFIS) by examining the binding affinity of tamsulosin and silodosin to a-receptors and melanin pigment using control and a2-blocker chronically administered in rabbit models. SETTING: Department of Ophthalmology, Kitasato University School of Medicine, Kanagawa, Japan. DESIGN: Experimental study. METHODS: The study was performed in isolated albino and pigmented rabbit iris dilators using pharmacologic and morphologic examinations. RESULTS: For pharmacologic examinations, the mean pKB values (pKB Z log KB, where log KB is the equilibrium dissociation constant of the antagonist–receptor complex) of tamsulosin in albino and pigmented rabbits were 9.10 and 8.08 and those of silodosin, 10.3 and 8.11, respectively. The pKB values of tamsulosin and silodosin in albino rabbits were significantly higher than in pigmented rabbits. In the isolated rabbit iris dilator, the maximum contraction evoked by 10 3 mol/L phenylephrine gradually decreased by repetitive application in the chronic a-blocker–administered models. For morphologic examinations, the sizes of the pigment granules of pigment epitheliums for the a-blocker–administered models were irregular. The shape of shared nucleus of dilator muscles and pigment epitheliums changed to lobular, and the dilator muscle layer was thinner than in the control. CONCLUSIONS: The high affinity of a-blockers for a1-adrenoreceptors is important in the analysis of the mechanism of IFIS. However, IFIS should not be attributed to long-term binding with receptors alone; the drug–melanin interaction causing dilator muscle atrophy is probably the other important factor in the mechanism of IFIS. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2012; 38:1643–1649 Q 2012 ASCRS and ESCRS
Intraoperative floppy-iris syndrome (IFIS) was first described by Chang and Campbell in 2005.1 The syndrome is characterized by 3 intraoperative features: a flaccid iris stroma that undulates and billows in response to the intraocular fluid current, a propensity for the floppy iris stroma to prolapse toward the sites of phacoemulsification and side-port incisions despite proper wound construction, and progressive intraoperative pupil constriction despite standard preventive preoperative pharmacologic measures.1,2 Because such symptoms have often been seen in Q 2012 ASCRS and ESCRS Published by Elsevier Inc.
patients under treatment with a1-blockers to improve urination in prostatic hyperplasia, their cause has been found to be associated with a1-adrenergic antagonists.1–4 Tamsulosin has a long half-life, and a relatively constant receptor blockade could result in a form of disuse atrophy of the iris dilator smooth muscle. This might explain not only the poor pupil dilation in patients receiving tamsulosin but also the flaccid and floppy iris stroma observed even after the medication is stopped.1 In our earlier study of electron microscopic images of 0886-3350/$ - see front matter doi:10.1016/j.jcrs.2012.05.025
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dilators of IFIS patients,5 we reported the existence of pigment granules of different sizes around the iris dilator and showed that the shared nuclei of the dilator muscles and pigment epithelia became lobular in appearance. We also reported vacuolar degeneration of dilator muscles. The adherence of a-blockers to the iris pigment is important in the study of the side effects of medication on the iris. Thus, it would be valuable to evaluate the influences of iris pigment on drugs using albino rabbits without pigment and pigmented rabbits whose iris dilator receptors have similar pharmacologic characteristics. The effects of the slow onset (initial binding) and long duration (slow release) of many drugs are important to evaluate.6,7 Thus, the aim of the present study was to examine the binding affinity of tamsulosin and silodosin to a-receptors and melanin pigment, in vivo and in vitro, in a rabbit model in which an a-blocker was chronically administered. This study was performed on isolated albino and pigmented rabbit iris dilators using pharmacologic and morphologic examinations to determine the mechanism of IFIS. MATERIALS AND METHODS All experiments were performed according to guiding principles for animal experimentation of Kitasato University (approval from the Animal Experiments Ethics Committee,
Submitted: March 8, 2012. Final revision submitted: May 5, 2012. Accepted: May 8, 2012. From the Department of Ophthalmology (Goseki, Mashimo, Shimizu), the Research Center for Biological Imaging (Nemoto), Kitasato University School of Medicine, the Department of Orthoptics and Visual Science (Ishikawa), School of Allied Health Sciences, Kitasato University, Kanagawa, and the Graduate School of Pharmaceutical Sciences (Ogasawara, Taguchi, Yago), School of Pharmacy, Kitasato University, Tokyo, Japan. Supported by the Parents’ Association Grant of Kitasato University, School of Medicine, Caterpillar Japan research subsidy for young researchers, and Kanagawa Ophthalmologists Association (Ophthalmic Clinical Research Grant).
Kitasato University: 2011-005). Male Japanese white rabbits (albino rabbits) and Dutch rabbits (pigmented rabbits) were used. They were purchased at 8 weeks of age and were housed in a temperature-controlled and humiditycontrolled room (24 C to 25 C and 55% to 60%, respectively).
Experiment 1 Albino and pigmented rabbits were humanely killed with an overdose of intravenous pentobarbital sodium. The eyes were immediately enucleated and placed in freshly prepared Krebs solution of the following composition (mmol/L): sodium chloride 94.8, potassium chloride 4.7, magnesium sulfate 1.2, calcium chloride 2.5, potassium dihydrogen phosphate 1.2, sodium bicarbonate 25.0, and glucose 11.7. The pH was routinely checked and adjusted to 7.4. A dilator muscle specimen (3.0 to 4.0 mm wide, 4.0 to 5.0 mm long) from a rabbit was prepared under a stereomicroscope according to the method of Kern.8 The specimen was mounted vertically in a 5 mL organ bath containing Krebs solution kept at 37 C; 95% oxygen and 5% carbon dioxide were passed through it. A dilator muscle specimen was connected to an isometric tension transducer (Grass FT-03C) with an initial load of 50 mg (Figure 1). The drug exposure was initiated after an equilibration period of at least 60 minutes. The responsiveness of each preparation was first tested with 100 mmol/L phenylephrine to ensure that the same amplitude of contraction would be obtained each time. Phenylephrine was added cumulatively to the organ bath.9 The reproducibility of the concentration-response curve was evaluated at 60-minute intervals. After the control concentration-response curves were determined, the preparations were equilibrated with a competitive antagonist for 10 minutes. The concentration-response curves were then determined in the presence of the antagonist in the same preparation.
Data Analysis The responses were expressed as a percentage of the maximum contraction, where the response to 100 mmol/L of phenylephrine on each tissue was defined as 100%. The results were expressed as the arithmetic mean with the standard error of the mean (SEM). The apparent dissociation constants (KB) of the antagonists were determined by the following equation: KB Z [B]/(dr 1), where [B] is the molar concentration of the antagonist and dr is the ratio between the agonist effective concentration 50 (EC50) values in the presence and absence of the antagonist. The apparent affinity of the antagonist pKB was then expressed as its negative log dissociation constant (ie, pKB Z log Kb, where log Kb is the equilibrium dissociation constant of the antagonist–receptor complex)
C.W.P. Reynolds, Department of International Medical Communications, Tokyo Medical University, and Yuko Tajima provided linguistic advice. Shigekazu Uga provided commentary on morphologic examinations. The Center for Genetic Studies of Integrated Biological Functions, Kitasato University School of Medicine, provided technical support. Presented at the 29th Pupil Colloquium, T€ubingen, Germany, September 2011. Corresponding author: Toshiaki Goseki, MD, PhD, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan. E-mail: [email protected].
Figure 1. Muscle preparation.
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(Prism, Graphpad Software, Inc.). Statistical differences between the mean pKB values were determined by the Student t test. A P value less than 0.05 was considered statistically significant.
Experiment 2 Pigmented rabbits were given gluteal muscle injections starting at 10 weeks of age according to the following conditions: For the a-blocker administration model, tamsulosin or silodosin 0.1 mL (0.2 mg/kg) was administered 5 days a week for 4 weeks (20 times in total). To avoid any effect of previously administered medication, a washout period of at least 1 month was allowed after the medication was given. In a control group comprising pigmented rabbits, sodium chloride solution was administered 5 days a week for 4 weeks (20 times in total). As in experiment 1, the rabbits were humanely killed with an overdose of intravenous pentobarbital sodium. The eyes used for pharmacologic examinations were immediately enucleated and placed in freshly prepared Krebs solution. The eyes used for morphologic examinations were fixed overnight with 4% glutaraldehyde buffered with 0.075 M phosphate solution.
Pharmacologic Examinations As in experiment 1, the iris dilator muscles of the rabbits were isolated and the changes in the maximum contraction examined. Phenylephrine was administered cumulatively 4 times at 60-minute intervals. Adequate washout periods were allowed after each administration. Morphologic Examinations For examinations with transmission electron microscopy, after being washed in buffer, the specimens were post-fixed overnight with 1% osmium tetroxide in the same buffer solution, dehydrated in an ethanol series, and embedded in Quetol 812. After polymerization, the specimens were cut with a Reichert-Nissei ultratome (Ultracut N, Reichert Optische Werke AG). These sections were stained with lead citrate and uranyl acetate and examined with an electron microscope (HU-12A, Hitachi High-Technologies Corp.). Data Analysis The maximum contraction response for the first phenylephrine cumulative administration was defined
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as 100%. Then, each of the second to the fourth cumulative administrations was expressed as a percentage based on the contraction of the first cumulative administration. The Mann-Whitney U test was used to test the significance between the control and tamsulosin and between the control and silodosin at each phenylephrine concentration. A P value less than 0.05 was considered statistically significant.
Chemicals
The sources of the chemicals used were as follows: phenylephrine hydrochloride, Wako Chemical, Inc.; tamsulosin, Astellas Pharma Inc.; and silodosin, Kissei Pharmaceutical Co., Ltd. All other chemicals were of reagent grade.
RESULTS The study used 20 male albino rabbits and 28 male pigmented rabbits. Experiment 1 General Observations This experiment used all 20 albino rabbits and 20 pigmented rabbits. The specimens of the rabbit iris dilator muscle mounted in an organ bath gradually relaxed until a steady tone was reached during a 60-minute equilibrium period. Spontaneous contractions did not occur at any time during these procedures. The mean maximum tension induced by 1 mmol/L phenylephrine was 143 mg G 6 (SD) (n Z 50) in albino rabbits and 154 G 5 mg (n Z 51) in pigmented rabbits. Figure 2 shows typical tracings of cumulative administration of phenylephrine with and without silodosin. Agonist–Antagonist Interactions
Figures 3 and 4 show the concentration-response curves for phenylephrine in the absence and presence of several different concentrations of tamsulosin and silodosin in the albino and pigmented rabbit iris dilator muscles. The doseresponse curves of phenylephrine with tamsulosin
Figure 2. Typical tracing showing effects of cumulative application of phenylephrine to the albino rabbit iris dilator in the absence and presence of silodosin 1 nmol/L (PE Z phenylephrine). J CATARACT REFRACT SURG - VOL 38, SEPTEMBER 2012
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Figure 3. Concentration-response curves in the albino (A) and pigmented (B) rabbit iris dilator to phenylephrine in the absence and presence of tamsulosin. The bars at each point indicate the SEM (PE Z phenylephrine).
Figure 4. Concentration-response curves in the albino (A) and pigmented (B) rabbit iris dilator to phenylephrine in the absence and presence of silodosin. The bars at each point indicate the SEM (PE Z phenylephrine).
and silodosin shifted to the right. Table 1 shows the mean pKB values of tamsulosin and silodosin.
The pigment granules were irregular in size and were clumped together in the a-blocker administration models. The appearance of the shared nuclei of the dilator muscles and pigment epithelia became lobular, and the dilator muscle layer was thinner than that in the control. There were no significant differences between the tamsulosin and silodosin administration models.
Experiment 2 Functional Examinations Figure 5, A, shows typical trac-
ings of the cumulative administration of phenylephrine. The maximum contractions of the control and the a-blocker administration model (tamsulosin and silodosin) did not differ significantly for the first and second phenylephrine cumulative administrations. However, the maximum contractions of the a-blocker administration model decreased significantly for the third and fourth administrations (Figure 5, B). Morphologic Examinations Figure 6 compares the
model administered the a-blocker and the control.
DISCUSSION In this study, we focused on iris pigment granules to find the causes of IFIS. We performed in vitro experiments in albino rabbits and pigmented rabbits and evaluated the variance in their responses. In the isolated albino rabbit and pigmented rabbit iris dilator, tamsulosin and silodosin inhibited the contraction of
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Table 1. The pKB values for tamsulosin and silodosin. Mean (pKB) G SD Drug Tamsulosin Silodosin
Albino Rabbit
Pigmented Rabbit
P Value
9.10 G 0.08 10.3 G 0.13
8.08 G 0.10 8.11 G 0.07
!.001 !.001
pKB Z log KB, where log KB is the equilibrium dissociation constant of the antagonist–receptor complex
phenylephrine in a dose-dependent manner. Compared with other nonselective a-blockers, the inhibitory effects of tamsulosin and silodosin were pKB 8.0 or more, indicating the high affinity for a1-receptor of the rabbit iris dilator. The current classification recognizes the existence of 3 a1-adrenoceptors (a1A, a1B, a1D). It is conceivable that a1A receptors are present in the pupil dilator muscles.10,11 Michel and Vrydag12 found that the same type of receptor was present in the urethral smooth muscle and prostate gland. A previous study13 showed that the pA2 values (pA2 Z log of the molar concentration of antagonist producing a 2-fold shift to the right of the agonist concentration-response curve) of tamsulosin in the albino rabbit iris dilator when the response of noradrenaline was inhibited equaled 9.45. In the pigmented rabbit iris dilator, the response of phenylephrine was inhibited to equal 7.96.14 In our experiment, the pKB values obtained in albino rabbits and pigmented rabbits were 9.10 and 8.08, respectively, similar to those in the previous reports.13,14 On the other hand, it has also been reported that the pA2 values of silodosin in the albino rabbit iris dilator during inhibition of the response of noradrenaline equaled 9.84.13 We
Figure 5. A: Typical tracing showing effects of cumulative application of phenylephrine to the rabbit iris dilator. Phenylephrine was cumulatively administered 4 times. B: Changes in the maximum contraction for the second to fourth phenylephrine cumulative administration when the maximum contraction of the first administration was 100% (PE Z phenylephrine).
found the pupil dilator muscle pKB value of albino rabbits to be 10.3 in our experiment, which was close to the value in the previous study.13 We were not able to find previous studies of the pA2 or pKB values of
Figure 6. Iris dilator muscles are myoepithelium differentiated from anterior pigment epithelium so the nucleus (A: solid square) is shared by iris dilator muscles and pigment epithelium. Control and a-blocker administration models were compared and the sizes of the pigment granules of pigment epithelia (dotted circle) were irregular. The shared nucleus of dilator muscles and pigment epithelia (B: solid circle) were denatured. The dilator muscle layer (arrow) was thinner than in the control.
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silodosin in the iris dilator muscles of pigmented rabbits. We believe that the pKB value of 8.11 of silodosin found in pigmented rabbits in our study is reliable because our tamsulosin and silodosin results in albino rabbits are similar to those in previous studies. One study15 found that the pA2 values of tamsulosin and silodosin used in the albino rabbit prostate to inhibit the response of phenylephrine were 9.99 and 10.05, respectively. Another study16 of the human prostate found that the response of noradrenaline was inhibited 9.68 and 9.45. This indicates that tamsulosin and silodosin also have a high affinity for the a-receptors of the prostate gland. The difference in pKB values between albino rabbits and pigmented rabbits was 1.02 (approximately 10 times) for tamsulosin and 2.19 (approximately 100 times) for silodosin. The receptors of pigmented rabbits and albino rabbits have similar pharmacologic characteristics; thus, the difference in the pKB values might be caused not only by affinity for receptors but also by other factors. This indicates that the deposition of drugs to pigments is likely. These results suggest that not only do these drugs have high affinity for the a1-receptors of the rabbit iris dilator, they also have a high affinity for melanin pigment granules. Liposoluble drugs and chemicals, such as tamsulosin and silodosin, in the iris can bind to pigment, including that in the spindle cells, and can also be readily available for reaction with smooth muscle membrane receptors.6,7 In the morphologic examinations (experiment 2), atrophy of the dilator muscles was obvious in the a-blocker administration model. In studies that used optical coherence tomography, patients using systemic a1-adrenergic receptor antagonists had significantly thinner dilator muscle regions.17 Thinner dilator muscle regions were also recognized in the isolated eyes of patients who were administered a-blockers over an extended period.18 We reported vacuolar degeneration and atrophy of dilator muscles in the tissues of the pupil dilator muscles of IFIS patients5 as well as a size difference in pigment granules around the dilator muscles. We also found that the shared nuclei of dilators and upper epithelia became lobular in appearance.5 The dilator is composed of the cells of the outer layer of the primitive optic cup that partially retain their epithelial character so they appear as myoepithelial cells.19 The epithelial cells, which contain melanin, share a nucleus with smooth muscle cells. This is a unique morphologic relationship between pigment epithelium and iridial smooth muscle cells that influences drug action.20 Thus, degeneration of shared nuclei may result in degeneration of pupil dilator muscle cells.
In experiment 2, we found that long-term binding to pigment caused the size of the pigment granules to become irregular and the appearance of the shared nuclei of the dilator muscles and pigment epithelia to become lobular. Finally, the dilator muscle layer was thinner than that in the control. We believe that long-term a1-receptor blocking and a high affinity for melanin finally cause dilator muscle atrophy. These are major reasons for the development of IFIS. During the functional examinations (experiment 2), we found a significant difference on the third and fourth phenylephrine cumulative administrations in the a-blocker administration model (tamsulosin and silodosin). We assume this was caused by disuse atrophy of the dilator muscles. Administration of epinephrine or phenylephrine into the anterior chamber before cataract surgery has been recommended to prevent IFIS21–23; however, the results in our functional examination (experiment 2) also show that it is possible to encourage tachyphylaxis in cases in which disuse atrophy of dilator muscles is prominent. In conclusion, the affinity for a1-adrenoreceptors is important in the analysis of the mechanism of IFIS. However, IFIS should not be attributed to binding with receptors alone; a drug–melanin interaction causing dilator muscle atrophy is probably the other important factor. Tamsulosin and silodosin were found to have a high affinity for melanin, which is important in the mechanism of IFIS. Clinically, patients who have dark iris pigments require attention before surgery because there is a possibility they will develop IFIS. WHAT WAS KNOWN Intraoperative floppy-iris syndrome is often seen in patients under treatment with a1-blockers to improve urination in prostatic hyperplasia; the cause has been associated with a1-adrenergic antagonists. WHAT THIS PAPER ADDS The high affinity of a-blockers for a1-adrenoreceptors is an important factor in the mechanism of IFIS. The drug– melanin interaction causing dilator muscle atrophy is probably the other important mechanism of IFIS.
REFERENCES 1. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg 2005; 31:664–673 2. Cheung CMG, Awan MAR, Sandramouli S. Prevalence and clinical findings of tamsulosin-associated intraoperative floppy-iris syndrome. J Cataract Refract Surg 2006; 32:1336–1339
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3. Oshika T, Ohashi Y, Inamura M, Ohki K, Okamoto S, Koyama T, Sakabe I, Takahashi K, Fujita Y, Miyoshi T, Yasuma T. Incidence of intraoperative floppy iris syndrome in patients on either systemic or topical a1-adrenoceptor antagonist. Am J Ophthalmol 2007; 143:150–151 4. Chadha V, Borooah S, Tey A, Styles C, Singh J. Floppy iris behavior during cataract surgery: associations and variations. Br J Ophthalmol 2007; 91:40–42. Available at: http://www.ncbi.nlm. nih.gov/pmc/articles/PMC1857591/pdf/40.pdf. Accessed May 18, 2012 5. Goseki T, Shimizu K, Ishikawa H, Nishimoto H, Uga S, Nemoto N, Patil PN. Possible mechanism of intraoperative floppy iris syndrome: a clinicopathological study. Br J Ophthalmol 2008; 92:1156–1158 6. Salazar-Bookaman MM, Wainer I, Patil PN. Relevance of drugmelanin interactions to ocular pharmacology and toxicology. J Ocul Pharmacol 1994; 10:217–239 7. Patil PN. Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles. J Pharm Pharmacol 2004; 56:1045–1053 €ren 8. Kern R. Die adrenergischen Receptoren der intraokula Muskeln des Menschen; eine in vitro-Studie [The adrenergic receptors of the intraocular muscles of man; an in vitro-Study]. Albrecht von Graefes Arch Klin Exp Ophthalmol 1970; 180:231–248 9. van Rossum J, van den Brink F. Cumulative dose-response curves. I. Introduction to the technique. Arch Int Pharmacodyn Ther 1963; 143:240–246 10. Grayson TH, Ellis JM, Chen S, Graham RM, Brown RD, Hill CE. Immunohistochemical localization of a1B-adrenergic receptors in the rat iris. Cell Tissue Res 1998; 293:435–444 11. Ishikawa H, Miller DD, Patil PN. Comparison of post-junctional a-adrenoceptors in iris dilator muscle on humans, and albino and pigmented rabbits. Naunyn Schmiedebergs Arch Pharmacol 1996; 354:765–772 12. Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006; 147(suppl 2):S88–S119. Available at: http://www.ncbi. nlm.nih.gov/pmc/articles/PMC1751487/pdf/147-0706619a.pdf. Accessed May 18, 2012 13. Nakamura S, Taniguchi T, Suzuki F, Akagi Y, Muramatsu I. Evaluation of a1-adrenoceptors in the rabbit iris: pharmacological characterization and expression of mRNA. Br J Pharmacol 1999; 127:1367–1374. Available at: http://www.pubmedcentral. nih.gov/picrender.fcgi?artidZ1760646&blobtypeZpdf. Accessed May 18, 2012 14. Palea S, Chang DF, Rekik M, Regnier A, Lluel P. Comparative effect of alfuzosin and tamsulosin on the
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contractile response of isolated rabbit prostatic and dilator smooth muscles; possible model for intraoperative floppy-iris syndrome. J Cataract Refract Surg 2008; 34: 489–496 Yamagishi R, Akiyama K, Nakamura S, Hora M, Masuda N, Matsuzawa A, Murata S, Ujiie A, Kurashina Y, Iizuka K, Kitazawa M. Effect of KMD-3213, an ala-adrenoceptor-selective antagonist, on the contractions of rabbit prostate and rabbit and rat aorta. Eur J Pharmacol 1996; 315:73–79 Moriyama N, Akiyama K, Murata S, Taniguchi J, Ishida N, Yamazaki S, Kawabe K. KMD-3213, a novel a1A-adrenoceptor antagonist, potently inhibits the functional a1-adrenoceptor in human prostate. Eur J Pharmacol 1997; 331:39–42 Prata TS, Palmiero P-M, Angelilli A, Sbeity Z, De Moraes CGV, Liebmann JM, Ritch R. Iris morphologic changes related to a1-adrenergic receptor antagonists; implications for intraoperative floppy iris syndrome. Ophthalmology 2009; 116: 877–881 Santaella RM, Destafeno JJ, Stinnett SS, Proia AD, Chang DF, Kim T. The effect of a1-adrenergic receptor antagonist tamsulosin (Flomax) on iris dilator smooth muscle anatomy. Ophthalmology 2010; 117:1743–1749 Duke-Elder S, Wybar K. System of ophthalmology. Volume 2: The Anatomy of the Visual System. London, UK, Henry Kimpton, 1961; 181–185 Walls GL. The Vertebrate Eye and its Adaptive Radiation. New York, NY, Hafner, 1967; 14 15 Chang DF, Braga-Mele R, Mamalis N, Masket S, Miller KM, Nichamin LD, Packard RB, Packer M, for the ASCRS Cataract Clinical Committee. Clinical experience with intraoperative floppy-iris syndrome; results of the 2008 ASCRS member survey. J Cataract Refract Surg 2008; 34:1201–1209 Shugar JK. Use of epinephrine for IFIS prophylaxis [letter]. J Cataract Refract Surg 2006; 32:1074–1075 Shugar JK. Prophylaxis for IFIS [letter]. J Cataract Refract Surg 2007; 33:942–943
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First author: Toshiaki Goseki, MD, PhD Department of Ophthalmology, Kitasato University School of Medicine, Kanagawa, Japan
Effects of tamsulosin and silodosin on isolated albino and pigmented rabbit iris dilators: Possible mechanism of intraoperative floppy-iris syndrome Toshiaki Goseki, MD, PhD, Hitoshi Ishikawa, MD, PhD, Shiori Ogasawara, MS, Kimiyo Mashimo, BS, Noriko Nemoto, BS, Yuko Taguchi, MS, Kazuo Yago, PhD, Kimiya Shimizu, MD, PhD
PURPOSE: To determine the mechanism of intraoperative floppy-iris syndrome (IFIS) by examining the binding affinity of tamsulosin and silodosin to a-receptors and melanin pigment using control and a2-blocker chronically administered in rabbit models. SETTING: Department of Ophthalmology, Kitasato University School of Medicine, Kanagawa, Japan. DESIGN: Experimental study. METHODS: The study was performed in isolated albino and pigmented rabbit iris dilators using pharmacologic and morphologic examinations. RESULTS: For pharmacologic examinations, the mean pKB values (pKB Z log KB, where log KB is the equilibrium dissociation constant of the antagonist–receptor complex) of tamsulosin in albino and pigmented rabbits were 9.10 and 8.08 and those of silodosin, 10.3 and 8.11, respectively. The pKB values of tamsulosin and silodosin in albino rabbits were significantly higher than in pigmented rabbits. In the isolated rabbit iris dilator, the maximum contraction evoked by 10 3 mol/L phenylephrine gradually decreased by repetitive application in the chronic a-blocker–administered models. For morphologic examinations, the sizes of the pigment granules of pigment epitheliums for the a-blocker–administered models were irregular. The shape of shared nucleus of dilator muscles and pigment epitheliums changed to lobular, and the dilator muscle layer was thinner than in the control. CONCLUSIONS: The high affinity of a-blockers for a1-adrenoreceptors is important in the analysis of the mechanism of IFIS. However, IFIS should not be attributed to long-term binding with receptors alone; the drug–melanin interaction causing dilator muscle atrophy is probably the other important factor in the mechanism of IFIS. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2012; 38:1643–1649 Q 2012 ASCRS and ESCRS
Intraoperative floppy-iris syndrome (IFIS) was first described by Chang and Campbell in 2005.1 The syndrome is characterized by 3 intraoperative features: a flaccid iris stroma that undulates and billows in response to the intraocular fluid current, a propensity for the floppy iris stroma to prolapse toward the sites of phacoemulsification and side-port incisions despite proper wound construction, and progressive intraoperative pupil constriction despite standard preventive preoperative pharmacologic measures.1,2 Because such symptoms have often been seen in Q 2012 ASCRS and ESCRS Published by Elsevier Inc.
patients under treatment with a1-blockers to improve urination in prostatic hyperplasia, their cause has been found to be associated with a1-adrenergic antagonists.1–4 Tamsulosin has a long half-life, and a relatively constant receptor blockade could result in a form of disuse atrophy of the iris dilator smooth muscle. This might explain not only the poor pupil dilation in patients receiving tamsulosin but also the flaccid and floppy iris stroma observed even after the medication is stopped.1 In our earlier study of electron microscopic images of 0886-3350/$ - see front matter doi:10.1016/j.jcrs.2012.05.025
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dilators of IFIS patients,5 we reported the existence of pigment granules of different sizes around the iris dilator and showed that the shared nuclei of the dilator muscles and pigment epithelia became lobular in appearance. We also reported vacuolar degeneration of dilator muscles. The adherence of a-blockers to the iris pigment is important in the study of the side effects of medication on the iris. Thus, it would be valuable to evaluate the influences of iris pigment on drugs using albino rabbits without pigment and pigmented rabbits whose iris dilator receptors have similar pharmacologic characteristics. The effects of the slow onset (initial binding) and long duration (slow release) of many drugs are important to evaluate.6,7 Thus, the aim of the present study was to examine the binding affinity of tamsulosin and silodosin to a-receptors and melanin pigment, in vivo and in vitro, in a rabbit model in which an a-blocker was chronically administered. This study was performed on isolated albino and pigmented rabbit iris dilators using pharmacologic and morphologic examinations to determine the mechanism of IFIS. MATERIALS AND METHODS All experiments were performed according to guiding principles for animal experimentation of Kitasato University (approval from the Animal Experiments Ethics Committee,
Submitted: March 8, 2012. Final revision submitted: May 5, 2012. Accepted: May 8, 2012. From the Department of Ophthalmology (Goseki, Mashimo, Shimizu), the Research Center for Biological Imaging (Nemoto), Kitasato University School of Medicine, the Department of Orthoptics and Visual Science (Ishikawa), School of Allied Health Sciences, Kitasato University, Kanagawa, and the Graduate School of Pharmaceutical Sciences (Ogasawara, Taguchi, Yago), School of Pharmacy, Kitasato University, Tokyo, Japan. Supported by the Parents’ Association Grant of Kitasato University, School of Medicine, Caterpillar Japan research subsidy for young researchers, and Kanagawa Ophthalmologists Association (Ophthalmic Clinical Research Grant).
Kitasato University: 2011-005). Male Japanese white rabbits (albino rabbits) and Dutch rabbits (pigmented rabbits) were used. They were purchased at 8 weeks of age and were housed in a temperature-controlled and humiditycontrolled room (24 C to 25 C and 55% to 60%, respectively).
Experiment 1 Albino and pigmented rabbits were humanely killed with an overdose of intravenous pentobarbital sodium. The eyes were immediately enucleated and placed in freshly prepared Krebs solution of the following composition (mmol/L): sodium chloride 94.8, potassium chloride 4.7, magnesium sulfate 1.2, calcium chloride 2.5, potassium dihydrogen phosphate 1.2, sodium bicarbonate 25.0, and glucose 11.7. The pH was routinely checked and adjusted to 7.4. A dilator muscle specimen (3.0 to 4.0 mm wide, 4.0 to 5.0 mm long) from a rabbit was prepared under a stereomicroscope according to the method of Kern.8 The specimen was mounted vertically in a 5 mL organ bath containing Krebs solution kept at 37 C; 95% oxygen and 5% carbon dioxide were passed through it. A dilator muscle specimen was connected to an isometric tension transducer (Grass FT-03C) with an initial load of 50 mg (Figure 1). The drug exposure was initiated after an equilibration period of at least 60 minutes. The responsiveness of each preparation was first tested with 100 mmol/L phenylephrine to ensure that the same amplitude of contraction would be obtained each time. Phenylephrine was added cumulatively to the organ bath.9 The reproducibility of the concentration-response curve was evaluated at 60-minute intervals. After the control concentration-response curves were determined, the preparations were equilibrated with a competitive antagonist for 10 minutes. The concentration-response curves were then determined in the presence of the antagonist in the same preparation.
Data Analysis The responses were expressed as a percentage of the maximum contraction, where the response to 100 mmol/L of phenylephrine on each tissue was defined as 100%. The results were expressed as the arithmetic mean with the standard error of the mean (SEM). The apparent dissociation constants (KB) of the antagonists were determined by the following equation: KB Z [B]/(dr 1), where [B] is the molar concentration of the antagonist and dr is the ratio between the agonist effective concentration 50 (EC50) values in the presence and absence of the antagonist. The apparent affinity of the antagonist pKB was then expressed as its negative log dissociation constant (ie, pKB Z log Kb, where log Kb is the equilibrium dissociation constant of the antagonist–receptor complex)
C.W.P. Reynolds, Department of International Medical Communications, Tokyo Medical University, and Yuko Tajima provided linguistic advice. Shigekazu Uga provided commentary on morphologic examinations. The Center for Genetic Studies of Integrated Biological Functions, Kitasato University School of Medicine, provided technical support. Presented at the 29th Pupil Colloquium, T€ubingen, Germany, September 2011. Corresponding author: Toshiaki Goseki, MD, PhD, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan. E-mail: [email protected].
Figure 1. Muscle preparation.
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(Prism, Graphpad Software, Inc.). Statistical differences between the mean pKB values were determined by the Student t test. A P value less than 0.05 was considered statistically significant.
Experiment 2 Pigmented rabbits were given gluteal muscle injections starting at 10 weeks of age according to the following conditions: For the a-blocker administration model, tamsulosin or silodosin 0.1 mL (0.2 mg/kg) was administered 5 days a week for 4 weeks (20 times in total). To avoid any effect of previously administered medication, a washout period of at least 1 month was allowed after the medication was given. In a control group comprising pigmented rabbits, sodium chloride solution was administered 5 days a week for 4 weeks (20 times in total). As in experiment 1, the rabbits were humanely killed with an overdose of intravenous pentobarbital sodium. The eyes used for pharmacologic examinations were immediately enucleated and placed in freshly prepared Krebs solution. The eyes used for morphologic examinations were fixed overnight with 4% glutaraldehyde buffered with 0.075 M phosphate solution.
Pharmacologic Examinations As in experiment 1, the iris dilator muscles of the rabbits were isolated and the changes in the maximum contraction examined. Phenylephrine was administered cumulatively 4 times at 60-minute intervals. Adequate washout periods were allowed after each administration. Morphologic Examinations For examinations with transmission electron microscopy, after being washed in buffer, the specimens were post-fixed overnight with 1% osmium tetroxide in the same buffer solution, dehydrated in an ethanol series, and embedded in Quetol 812. After polymerization, the specimens were cut with a Reichert-Nissei ultratome (Ultracut N, Reichert Optische Werke AG). These sections were stained with lead citrate and uranyl acetate and examined with an electron microscope (HU-12A, Hitachi High-Technologies Corp.). Data Analysis The maximum contraction response for the first phenylephrine cumulative administration was defined
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as 100%. Then, each of the second to the fourth cumulative administrations was expressed as a percentage based on the contraction of the first cumulative administration. The Mann-Whitney U test was used to test the significance between the control and tamsulosin and between the control and silodosin at each phenylephrine concentration. A P value less than 0.05 was considered statistically significant.
Chemicals
The sources of the chemicals used were as follows: phenylephrine hydrochloride, Wako Chemical, Inc.; tamsulosin, Astellas Pharma Inc.; and silodosin, Kissei Pharmaceutical Co., Ltd. All other chemicals were of reagent grade.
RESULTS The study used 20 male albino rabbits and 28 male pigmented rabbits. Experiment 1 General Observations This experiment used all 20 albino rabbits and 20 pigmented rabbits. The specimens of the rabbit iris dilator muscle mounted in an organ bath gradually relaxed until a steady tone was reached during a 60-minute equilibrium period. Spontaneous contractions did not occur at any time during these procedures. The mean maximum tension induced by 1 mmol/L phenylephrine was 143 mg G 6 (SD) (n Z 50) in albino rabbits and 154 G 5 mg (n Z 51) in pigmented rabbits. Figure 2 shows typical tracings of cumulative administration of phenylephrine with and without silodosin. Agonist–Antagonist Interactions
Figures 3 and 4 show the concentration-response curves for phenylephrine in the absence and presence of several different concentrations of tamsulosin and silodosin in the albino and pigmented rabbit iris dilator muscles. The doseresponse curves of phenylephrine with tamsulosin
Figure 2. Typical tracing showing effects of cumulative application of phenylephrine to the albino rabbit iris dilator in the absence and presence of silodosin 1 nmol/L (PE Z phenylephrine). J CATARACT REFRACT SURG - VOL 38, SEPTEMBER 2012
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Figure 3. Concentration-response curves in the albino (A) and pigmented (B) rabbit iris dilator to phenylephrine in the absence and presence of tamsulosin. The bars at each point indicate the SEM (PE Z phenylephrine).
Figure 4. Concentration-response curves in the albino (A) and pigmented (B) rabbit iris dilator to phenylephrine in the absence and presence of silodosin. The bars at each point indicate the SEM (PE Z phenylephrine).
and silodosin shifted to the right. Table 1 shows the mean pKB values of tamsulosin and silodosin.
The pigment granules were irregular in size and were clumped together in the a-blocker administration models. The appearance of the shared nuclei of the dilator muscles and pigment epithelia became lobular, and the dilator muscle layer was thinner than that in the control. There were no significant differences between the tamsulosin and silodosin administration models.
Experiment 2 Functional Examinations Figure 5, A, shows typical trac-
ings of the cumulative administration of phenylephrine. The maximum contractions of the control and the a-blocker administration model (tamsulosin and silodosin) did not differ significantly for the first and second phenylephrine cumulative administrations. However, the maximum contractions of the a-blocker administration model decreased significantly for the third and fourth administrations (Figure 5, B). Morphologic Examinations Figure 6 compares the
model administered the a-blocker and the control.
DISCUSSION In this study, we focused on iris pigment granules to find the causes of IFIS. We performed in vitro experiments in albino rabbits and pigmented rabbits and evaluated the variance in their responses. In the isolated albino rabbit and pigmented rabbit iris dilator, tamsulosin and silodosin inhibited the contraction of
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Table 1. The pKB values for tamsulosin and silodosin. Mean (pKB) G SD Drug Tamsulosin Silodosin
Albino Rabbit
Pigmented Rabbit
P Value
9.10 G 0.08 10.3 G 0.13
8.08 G 0.10 8.11 G 0.07
!.001 !.001
pKB Z log KB, where log KB is the equilibrium dissociation constant of the antagonist–receptor complex
phenylephrine in a dose-dependent manner. Compared with other nonselective a-blockers, the inhibitory effects of tamsulosin and silodosin were pKB 8.0 or more, indicating the high affinity for a1-receptor of the rabbit iris dilator. The current classification recognizes the existence of 3 a1-adrenoceptors (a1A, a1B, a1D). It is conceivable that a1A receptors are present in the pupil dilator muscles.10,11 Michel and Vrydag12 found that the same type of receptor was present in the urethral smooth muscle and prostate gland. A previous study13 showed that the pA2 values (pA2 Z log of the molar concentration of antagonist producing a 2-fold shift to the right of the agonist concentration-response curve) of tamsulosin in the albino rabbit iris dilator when the response of noradrenaline was inhibited equaled 9.45. In the pigmented rabbit iris dilator, the response of phenylephrine was inhibited to equal 7.96.14 In our experiment, the pKB values obtained in albino rabbits and pigmented rabbits were 9.10 and 8.08, respectively, similar to those in the previous reports.13,14 On the other hand, it has also been reported that the pA2 values of silodosin in the albino rabbit iris dilator during inhibition of the response of noradrenaline equaled 9.84.13 We
Figure 5. A: Typical tracing showing effects of cumulative application of phenylephrine to the rabbit iris dilator. Phenylephrine was cumulatively administered 4 times. B: Changes in the maximum contraction for the second to fourth phenylephrine cumulative administration when the maximum contraction of the first administration was 100% (PE Z phenylephrine).
found the pupil dilator muscle pKB value of albino rabbits to be 10.3 in our experiment, which was close to the value in the previous study.13 We were not able to find previous studies of the pA2 or pKB values of
Figure 6. Iris dilator muscles are myoepithelium differentiated from anterior pigment epithelium so the nucleus (A: solid square) is shared by iris dilator muscles and pigment epithelium. Control and a-blocker administration models were compared and the sizes of the pigment granules of pigment epithelia (dotted circle) were irregular. The shared nucleus of dilator muscles and pigment epithelia (B: solid circle) were denatured. The dilator muscle layer (arrow) was thinner than in the control.
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silodosin in the iris dilator muscles of pigmented rabbits. We believe that the pKB value of 8.11 of silodosin found in pigmented rabbits in our study is reliable because our tamsulosin and silodosin results in albino rabbits are similar to those in previous studies. One study15 found that the pA2 values of tamsulosin and silodosin used in the albino rabbit prostate to inhibit the response of phenylephrine were 9.99 and 10.05, respectively. Another study16 of the human prostate found that the response of noradrenaline was inhibited 9.68 and 9.45. This indicates that tamsulosin and silodosin also have a high affinity for the a-receptors of the prostate gland. The difference in pKB values between albino rabbits and pigmented rabbits was 1.02 (approximately 10 times) for tamsulosin and 2.19 (approximately 100 times) for silodosin. The receptors of pigmented rabbits and albino rabbits have similar pharmacologic characteristics; thus, the difference in the pKB values might be caused not only by affinity for receptors but also by other factors. This indicates that the deposition of drugs to pigments is likely. These results suggest that not only do these drugs have high affinity for the a1-receptors of the rabbit iris dilator, they also have a high affinity for melanin pigment granules. Liposoluble drugs and chemicals, such as tamsulosin and silodosin, in the iris can bind to pigment, including that in the spindle cells, and can also be readily available for reaction with smooth muscle membrane receptors.6,7 In the morphologic examinations (experiment 2), atrophy of the dilator muscles was obvious in the a-blocker administration model. In studies that used optical coherence tomography, patients using systemic a1-adrenergic receptor antagonists had significantly thinner dilator muscle regions.17 Thinner dilator muscle regions were also recognized in the isolated eyes of patients who were administered a-blockers over an extended period.18 We reported vacuolar degeneration and atrophy of dilator muscles in the tissues of the pupil dilator muscles of IFIS patients5 as well as a size difference in pigment granules around the dilator muscles. We also found that the shared nuclei of dilators and upper epithelia became lobular in appearance.5 The dilator is composed of the cells of the outer layer of the primitive optic cup that partially retain their epithelial character so they appear as myoepithelial cells.19 The epithelial cells, which contain melanin, share a nucleus with smooth muscle cells. This is a unique morphologic relationship between pigment epithelium and iridial smooth muscle cells that influences drug action.20 Thus, degeneration of shared nuclei may result in degeneration of pupil dilator muscle cells.
In experiment 2, we found that long-term binding to pigment caused the size of the pigment granules to become irregular and the appearance of the shared nuclei of the dilator muscles and pigment epithelia to become lobular. Finally, the dilator muscle layer was thinner than that in the control. We believe that long-term a1-receptor blocking and a high affinity for melanin finally cause dilator muscle atrophy. These are major reasons for the development of IFIS. During the functional examinations (experiment 2), we found a significant difference on the third and fourth phenylephrine cumulative administrations in the a-blocker administration model (tamsulosin and silodosin). We assume this was caused by disuse atrophy of the dilator muscles. Administration of epinephrine or phenylephrine into the anterior chamber before cataract surgery has been recommended to prevent IFIS21–23; however, the results in our functional examination (experiment 2) also show that it is possible to encourage tachyphylaxis in cases in which disuse atrophy of dilator muscles is prominent. In conclusion, the affinity for a1-adrenoreceptors is important in the analysis of the mechanism of IFIS. However, IFIS should not be attributed to binding with receptors alone; a drug–melanin interaction causing dilator muscle atrophy is probably the other important factor. Tamsulosin and silodosin were found to have a high affinity for melanin, which is important in the mechanism of IFIS. Clinically, patients who have dark iris pigments require attention before surgery because there is a possibility they will develop IFIS. WHAT WAS KNOWN Intraoperative floppy-iris syndrome is often seen in patients under treatment with a1-blockers to improve urination in prostatic hyperplasia; the cause has been associated with a1-adrenergic antagonists. WHAT THIS PAPER ADDS The high affinity of a-blockers for a1-adrenoreceptors is an important factor in the mechanism of IFIS. The drug– melanin interaction causing dilator muscle atrophy is probably the other important mechanism of IFIS.
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First author: Toshiaki Goseki, MD, PhD Department of Ophthalmology, Kitasato University School of Medicine, Kanagawa, Japan