SEP 2012

EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.

Issue link: https://digital.eyeworld.org/i/82503

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Page 88 of 103

September 2012 Possible mechanism of intraoperative floppy-iris syndrome" took tamsulosin compared with age- matched controls, suggesting that chronic tamsulosin use may lead to atrophic anatomical changes in the iris.3,4 Prior studies in patients with IFIS by the authors of the current paper have demonstrated histologi- cal changes in iris pigment granules and the iris pigmented epithelium.5 As such, the authors explored the hypothesis that the interactions between α1 antagonists and iris melanin granules may play a crucial role in mediating IFIS. To study this question, the authors used explanted rabbit iris dilator muscles and measured iris tension in response to phenyle- phrine without and with an α1 agonist. They first looked at the concentration response curve to phenylephrine in Dutch pigmented rabbits and albino Japanese rabbits. Interestingly, they demonstrated that the concentration response curve for phenylephrine was less right-shifted with higher concentra- tions of tamsulosin in pigmented rabbit irides as compared to albino irides, and that pigmented rabbit iri- des had a higher pKb, a measure of affinity for a given receptor, com- pared to albinos. This illustrates that phenylephrine has a higher binding affinity to the α1 receptor for pig- mented as compared to albino iri- des, suggesting that the presence of melanin pigment may allow in- creased binding of the α1 receptor. One major assumption not verified in these experiments is that the pig- mented and albino rabbit irides are identical except for their melanin content. It is well known that differ- ent strains of animals can differ significantly in their physiological function and how they react to drugs from a pharmacokinetic and pharmacodynamic perspective. Ad- ditional control experiments exam- ining the distribution and quantity of α1A receptors between pigmented and albino irides would have sup- ported the authors' assumption. In a second set of experiments, the authors looked at the effect of α1A blockade on iris contraction in an in vivo model by administering daily intramuscular injections of tamsulosin or silodosin over 4 weeks. Of note, there were no albino rabbits utilized in these experiments. The authors noted a statistically significant reduction in maximum dilator contraction after repeated phenylephrine exposure (third and fourth exposure) in dilators receiv- ing α1A antagonists compared to controls. This suggests that there may be some increased fatigability of the iris dilator muscle in tamsu- losin-treated animals versus controls. While this decrement in dilator contraction may be attributa- ble to disuse atrophy from α1A blockade as the authors propose, it does not delineate the particular role of the iris pigment granules, as no comparison was done between pig- mented and albino rabbits. A more direct experiment to evaluate their hypothesis would be to study differ- ences in response to phenylephrine between pigmented and albino rab- bits that have received chronic α1A receptor blockade. The authors also conducted structural analyses using electron microscopy (EM) on rabbit irides that received chronic tamsulosin versus controls. The authors noted irregularities in the size and clump- ing of pigment granules, thinning of the dilator muscle, and a more lobular, irregular appearance of the shared nuclei of the dilator muscle and pigment epithelium, similar to what had been observed in the human specimens. However, no quantitative data comparing irregu- larities of pigment clumping and thickness of the dilator muscle was presented to interpret the variability of these morphological features. The authors postulate that α1A antago- nist affinity for melanin found in the epithelial cells contributes to dilator muscle atrophy. To provide stronger evidence for their hypothe- sis, one could perform EM analyses of pigmented and albino rabbit eyes that have been exposed to α1A an- tagonists. If iris dilator muscles are less susceptible to α1A antagonist- induced atrophy in albino as com- pared to pigmented rabbits, this would support the authors' hypothe- sis. Another potential experiment would be to study the dose response relationship of iris dilator muscle at- rophy based on increasing exposure to α1 antagonists in heavily versus lightly pigmented irides, using anterior segment OCT to quantitate levels of atrophy over time. continued on page 91

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