Ciliary Muscle Contractility Research Articles

Changes in Ocular Parameters and Intraocular Lens Powers in Aging Cycloplegic Eyes

Age-related changes in lens elasticity and ciliary muscle contractility can affect how ocular parameters respond to cycloplegia, and therefore intraocular lens (IOL) power measurements calculated by formulas using anterior chamber depth (ACD), lens thickness (LT), or white-to-white (WtW) for effective lens position prediction can vary. In response, using swept-source optical biometry in prepresbyopic and presbyopic eyes, we investigated changes in ocular parameters and IOL power calculations attributable to cycloplegia. Cross-sectional study. In 38 prepresbyopic and 42 presbyopic eyes, we measured pupil diameter, radius of corneal curvature values, central corneal thickness, WtW, ACD, LT, and axial length both before and after cycloplegia. We determined IOL power calculations with the Sanders-Retzlaff-Kraff/theoretical, Holladay 2, and Haigis formulas. To pinpoint the effect of cycloplegia, we recorded refractive predictions in pre- and postdilation conditions according to the same IOL power calculations, even if postdilation IOL power calculations had changed. With cycloplegia, pupil diameter changed significantly more in presbyopic eyes (P < .001). Central corneal thickness decreased in prepresbyopic eyes (P= .048), whereas WtW increased in presbyopic eyes (P= .02). In both groups, ACD and LT changed significantly (P < .001). IOL power calculations according to the Holladay 2 formula differed in prepresbyopic eyes (P= .042), and refractive predictions with the Holladay 2 and Haigis formulas differed significantly in prepresbyopic eyes (P= .043 and P= .022, respectively). Surgeons should consider the effect of cycloplegia on refractive prediction errors and IOL power calculations determined with Haigis and Holladay 2 formulas, especially in prepresbyopic ages.

Innovations in Glaucoma Surgery: Improving the Results.

Glaucoma still represents the most frequent cause of irreversible blindness worldwide. The technological advances lead to innovative surgeries, which are rapidly introduced in clinical practice. New devices to lower intraocular pressure without opening the eye wall, bypassing the trabecular meshwork, or shunting the aqueous humor to the suprachoroidal space have been approved undergoing clinical assessment within clinical trials. Currently, other devices under evaluation are showing promising results. Although these methods will increase the options available for glaucoma surgeons, it is unclear if they could replace the present standard surgeries, such as trabeculectomy, deep sclerectomy, and glaucoma drainage devices. Moreover, the standard procedures are continuously modified in different ways to become safer and more effective. In this issue L. Choritz et al. investigate whether increased concentrations of endothelin-1 in the aqueous humor samples of glaucoma patients influenced wound healing and bleb fibrosis after standard trabeculectomy with mitomycin C. Endothelin-1 is a potent vasoconstrictor produced in the eye by the ciliary epithelium and to be released into the aqueous humor. It has been implicated in the pathophysiology of glaucoma. Endothelin-1 is believed to be involved in the regulation of intraocular pressure (IOP) via effects on the contractility of ciliary muscle and trabecular meshwork. W. Niu et al. evaluated the efficacy and safety of three different biodegradable terpolymers after trabeculectomy in rabbit eyes compared with Ologen™. The use of these implants aims to reduce the use of mitomycin C as an antiscarring agent. The first implant used was a porous collagen-glycosaminoglycan matrix, which prevents the adhesion of the conjunctiva and sclera and the collapse of the subconjunctival space after trabeculectomy, leading to collagen deposition and microcyst formation after penetrating antiglaucomatous surgery. Despite the increasing use of antifibrotic agents to modulate the wound healing response, bleb failure remains a common complication of glaucoma filtration surgery. In the paper by W. Liu et al. the needle revision and subconjunctival mitomycin C injection were compared with needling and subconjunctival 5-Fluorouracil injection for early dysfunctional filtration blebs after trabeculectomies. Neovascular glaucoma is one of the most recalcitrant glaucoma types to treatment and has one of the worst outcomes compared to other types of glaucoma. Neovascular glaucoma often needs surgical treatment because medical treatment fails to adequately control intraocular pressure. In a retrospective study, H. Yan investigated the long term surgical outcomes, treating neovascular glaucoma complicated by vitreous haemorrhage with 23-gauge vitrectomy combined with phacoemulsification, panretinal laser photocoagulation, and trabeculectomy without using anti-VEGF agents. C. Cagini et al. explored the role of canaloplasty in the surgical management of glaucoma with an extensive review. Canaloplasty is a nonpenetrating blebless surgical technique for open-angle glaucoma, similar to viscocanalostomy, in which a flexible microcatheter is inserted within Schlemm's canal for the entire 360 degrees. The results of this ab externo technique are really encouraging. S. A. Gandolfi et al. compared canaloplasty with an ab interno minimally invasive glaucoma surgery, the Hydrus™ implant. Both techniques are innovative and aim to restore the natural pathway, dilating a large size of Schlemm's canal. The results of this retrospective, comparative case series were collected after 2-year follow-up. A. F. Resende et al. presented a review on the iStent. This trabecular bypass stent is another minimally invasive glaucoma surgery device that has quickly gained popularity in the last years. Randomized controlled trials are still needed to assess the role of these devices in glaucoma surgery. Finally, S. Jacob et al. presented a new surgical technique, the stab incision glaucoma surgery. Even though it looks similar to standard trabeculectomy the main advantages are the sliding of the superior conjunctiva without dissecting, the creation of a superficial corneoscleral tunnel in a single step, the punch of the internal lip of the tunnel, and finally the suture of the conjunctival incision alone. In summary, this issue includes different approaches presented by diverse authors covering several topics related to improving of standard filtering surgery and wound healing and to new surgical techniques. This publication will provide valuable information that should be helpful in clinical practice for the whole ophthalmology community, mainly for glaucoma surgeons. Michele Figus Shlomo Melamed Antonio Ferreras Giorgio Marchini Vital P. Costa

Morphological study of the accommodative apparatus in the monkey eye.

For more than a century there has been debate concerning the mechanism of accommodation—whether the lens capsule or lens material itself determines the functional relationship between ciliary muscle contractility and lens deformation during refractive adaptation. This morphological study in monkey eyes investigates the composition and distribution of several connective tissue components in the accommodative apparatus relaying muscle force to lens organization. Elastin distributes on the marginal surface of the ciliary process. A zonule is composed of fibrillin produced by epithelial cells of the process. In the progress of extension over the posterior chamber, fibrils unite into strands and possess longitudinal plasticity. By induction of the elastin network, strands extend in a concentric direction covering the equatorial region of the capsule. Upon tethering to the lens, the strand ramifies into fibrils, penetrating deeply close to the epithelial layer of the lens and binding with the collagen of the intercellular spaces. Tight linkage of the zonule with the capsule transmits precise contractility. Inside the lens, the cortical layer's elastic connective tissue network forms widely spaced lamellae of crystalline fibers. In contrast, the central nuclear lamellae are tightly opposed. The accumulation of lamellae is greater in the anterior cortex than in the posterior, yielding a more variable anterior chamber depth in the visual axis. The plasticity of the zonule and connective tissue distribution inside the lens produces an adjustable configuration. Thus, tight linkage between the dynamism of the capsule with interaction of the lenticular flexibility provides a novel understanding of accommodation. Anat Rec, 298:630–636, 2015.

Signaling cross-talk between cannabinoid and muscarinic systems actives Rho-kinase and increases the contractile responses of the bovine ciliary muscle

The aim of the present study was to evaluate the role of a possible interaction between cannabinoid and muscarinic systems, both widely expressed in the ocular structure and involved in the control of bovine ciliary muscle contractility and intraocular pressure modulation. The ciliary muscle strips isolated by bovine eyes were exposed cumulatively to anandamide in the presence and in the absence of carbachol (5nM), in a miograph system for isometric recording. The experiments were also conducted in the presence of AM251 (100nM), 4-DAMP (100nM), Pertussis toxin (500ng/ml), U73122 (0.1 and 1μM), chelerythrine (1 and 10μM) and Y27632 (1 and 10μM). Contractile responses were expressed as the percentage of 10μM carbachol-induced contraction. The anandamide-induced contraction on bovine ciliary muscle strips was enhanced by the previous stimulation of Gq-protein-coupled muscarinic M3 receptors with carbachol. The contractile response to anandamide plus carbachol was affected by different inhibitors such as Pertussis toxin, phospholipase C, protein kinase C and Rho-kinase. The key results of the present study show that sequential activation of muscarinic M3 receptors and cannabinoid CB1 receptors produce synergistic contractile effects of the bovine ciliary muscle by involving the activation of Rho-kinase and protein kinase C.

The Effect of Phenylephrine on the Ciliary Muscle and Accommodation

To objectively measure changes in the human ciliary muscle dimensions in vivo after instillation of topical phenylephrine, a mydriatic and vasodilating agent. A cross-sectional study of 25 healthy young adults was conducted. Measurements of pupil size, accommodation, and ciliary muscle thickness were made both before and 30 min after instillation of 1% proparacaine and 2.5% phenylephrine. Accommodation was measured in three ways: subjectively using a push-up technique and Royal Air Force (RAF) rule, and objectively using both the Grand Seiko autorefractor and PowerRefractor. Images of the temporal ciliary muscle were acquired using the Visante Anterior Segment Optical Coherence Tomographer (OCT). Ciliary muscle images were objectively analyzed using a computer-based segmentation technique. Amplitude of accommodation using the push-up test was reduced by about 1 D with phenylephrine (p < 0.001). Phenylephrine did not change the accommodative response to a 4 D Badal target as measured by either autorefraction or photorefraction (p > 0.30). There was statistically significant thickening of the anterior region and thinning of the posterior region of the ciliary muscle with accommodation (p < 0.001, all locations). Phenylephrine did not affect either baseline ciliary muscle thickness or the accommodative contraction of the muscle (p > 0.09). Low-dose phenylephrine does not affect ciliary muscle dimensions, ciliary muscle contractility, or accommodative response to a 4 D near target.

The Effect of Cataract Extraction on the Contractility of Ciliary Muscle

To evaluate the changes in the pilocarpine-induced contractility of the ciliary muscle in eyes with presbyopia before and after cataract extraction using ultrasound biomicroscopy (UBM). Prospective interventional case series. A clear corneal phacoemulsification and posterior chamber intraocular lens (AcrySof SA60AT; Alcon Laboratories, Fort Worth, Texas, USA) was implanted in 23 eyes in 15 subjects. UBM was performed with and without instilling 2% pilocarpine, as well as before and two months after cataract extraction. The mean (+/- standard deviation) age was 65.33 +/- 6.09 years (range, 56 to 75 years). The increase in the axial length of the ciliary body (CBAXL) was used as a surrogate indicator of the centripetal ciliary muscle contraction during accommodation. Images of the ciliary body were compared visually using Adobe Photoshop 7.0 (Adobe Systems Inc., San Jose, California, USA). The CBAXL value with and without pilocarpine before cataract extraction was 1.708 +/- 0.165 mm and 1.689 +/- 0.187 mm, respectively, which was not significantly different (P = .261). The CBAXL value with and without pilocarpine after cataract extraction was 1.998 +/- 0.375 mm and 1.675 +/- 0.279 mm, respectively, which was significantly different (P < .001). The visually compared configurations of the changes in the ciliary body were compatible with the analysis of the measured parameters. Pilocarpine induced only subtle movement of the ciliary body before cataract surgery. However, after cataract extraction, it induced significant centripetal movement of the ciliary body compared with that without pilocarpine. This shows that a lenticular sclerotic component may influence both lens movement and the contractility of the ciliary muscle, and is believed to be related to the presbyopia.

Effect of Latanoprost, Prostaglandin F 2α and Nipradilol on Isolated Bovine Ciliary Muscle

Purpose: Ciliary muscle tone is considered to be an important factor for control of uveoscleral outflow. In an attempt to clarify the functional roles of the ciliary muscle in uveoscleral outflow, the effects of latanoprost, prostaglandin (PG)F 2α or nipradilol, all of which are known to increase uveoscleral outflow, were investigated, using the bovine ciliary muscle. Methods: We isolated longitudinal ciliary muscle from bovine eyes and investigated the effects of these three agents on the mechanical properties of this muscle using isometric tension recording methods. Results: Latanoprost and PGF 2α evoked small but discrete contractions at a concentration of 0.1 μM even during the sustained contraction evoked by 10 mM acetylcholine (ACh). However, nipradilol did not evoke any response at concentrations up to 0.1 mM. None of these agents had an effect on the amplitude of the ciliary muscle twitch contraction evoked by electrical field stimulation. Conclusions: Our findings indicate that these three agents have no relaxant effect on isolated bovine ciliary muscle even during the sustained contraction evoked by ACh. Further, these agents had no effect on the contraction evoked by field stimulation, which indicates that the drugs have no presynaptic effects. These results are inconsistent with the hypothesis that drugs that increase uveoscleral outflow relax the ciliary muscle with a consequent increase in uveoscleral outflow. Further investigation of the role of ciliary muscle contractility on uveoscleral outflow is warranted.

Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase

Purpose. Rho-associated coiled coil-forming protein kinase (ROCK) is a downstream target of a small GTPase, Rho. The kinase has been reported to regulate actomyosin-based contractility of smooth muscles by modulation of myosin phosphatase activity. Contractility of ciliary muscle could be implicated in regulation of intraocular pressure while that of ocular vessels could affect blood flow to retina. The present study has been performed to investigate the effect of a ROCK inhibitor on intraocular pressure in rabbits. Methods. An inhibitor of ROCK, Y-27632, was dissolved in an ophthalmic solution and topically administered to the eye of a Japanese white rabbit. Intraocular pressure was measured by pneumatonography (n = 12, 24 eyes). Constriction of ciliary muscle was measured by the Magnus method using 12 eyes. Results. Topical application of 0.1 and 0.03% Y-27632 significantly decreased the intraocular pressure, with maximum decreases of 5.3 and 4.3 mm Hg after 90 minutes compared with the control eye. Y-27632 inhibited the carbachol-induced constriction of rabbit ciliary muscle. Conclusions. The ROCK inhibitor reduced intraocular pressure in rabbits by topical instillation. The inhibitor relaxed the excised ciliary muscle which was previously constricted by carbachol suggesting that the inhibitor acts to increase the uveoscleral outflow. Our results suggest that the ROCK inhibitor is a promising treatment for glaucoma therapy in the next generation.

The regulation of trabecular meshwork and ciliary muscle contractility.

Current models of aqueous humor outflow no longer treat trabecular meshwork (TM) as an inert tissue passively distended by the ciliary muscle (CM). Instead, ample evidence supports the theory that trabecular meshwork possess smooth muscle-like properties and is actively involved in the regulation of aqueous humor outflow and intraocular pressure. In this model, trabecular meshwork and ciliary muscle appear as functional antagonists, with ciliary muscle contraction leading to a distension of trabecular meshwork with subsequent reduction in outflow. and with trabecular meshwork contraction leading to the opposite effect. Smooth-muscle relaxing substances would therefore appear to be ideal candidates for glaucoma therapy with the dual goal of reducing intraocular pressure via the trabecular meshwork and of improving vascular perfusion of the optic nerve head. However, for such substances to effectively lower intraocular pressure, the effect on the ciliary muscle would have to he minimal. For this reason, more information is needed on the signalling processes involved in regulating trabecular meshwork and ciliary muscle contractility. This review attempts to outline current knowledge of signal transduction pathways leading to relaxation and contraction of ciliary muscle and trabecular meshwork. Pathways can be classified as involving or not involving changes of membrane voltage and of requiring or not requiring external calcium: possibly, other pathways exist. These different pathways involve different ion channels and isoforms of PKC and are expressed to a differing degree in ciliary muscle and trabecular meshwork, leading to differential responses when exposed to relaxing or contracting pharmacological agents. Some of these agents. like tyrosine kinase inhibitors and inhibitors of PKC. have been shown to relax trabecular meshwork while leaving ciliary muscle comparatively unaffected. This profile makes these substances appear as ideal drugs for simultaneously improving ocular outflow and retinal circulation, parameters that determine the time course of visual deterioration in glaucoma.

Ocular hypotensive, vasorelaxant and cyclic AMP intermediation activities of clozapine displaying antiglaucoma properties

Clozapine, an atypical antipsychotic agent with multiple receptor antagonist activities, was investigated in vivo and in vitro to discover its effects on intraocular pressure and blood flow, on the contractility of ciliary muscle and nonophthalmologic blood vessels, on calcium concentration in A7r5 smooth muscle cells, and on cyclic AMP intermediation. The adrenergic and muscarinic mechanisms involved in the above effects were also examined. In rabbits, clozapine (0.1, 0.25, and 0.5%) prolonged (IOP) recovery time and inhibited IOP response. Clozapine (0.1 and 0.25%) also produced a significant increase in ocular blood flow in this iris, ciliary, retina, and choroid at 30 to 180 min after drug administration. In isolated guinea pig thoracic aorta, clozapine relaxed phenylephrine (10 μM)- and KCl (75 mM)-induced contractions, the estimated IC50 values being 20.4 ± 3.1 nM and 10.6 ± 1.8 μM, respectively. Clozapine (0.1–100 μM) inhibited phenylephrine (10 μM)-induced influx of Ca2+, the estimated IC50 value being 0.4 ± 0.1 nM. In isolated pig eye ciliary muscles, clozapine (1.0–100 μM) inhibited carbachol (10 μM)-induced contractions, the estimated IC50 value being 5.8 ± 1.2 μM. Clozapine (0.1–100 μM) increased cyclic AMP accumulation in pig's ciliary bodies, including ciliary process, ciliary muscle, and trabecular meshwork. Pretreatment with carbachol (100 μM) first decreased, then increased, clozapine-induced cyclic AMP accumulation. Studies of pretreatments with various muscarinic receptor antagonists at 100 μM revealed that pirenzepine significantly enhanced clozapine (100 μM)-induced cyclic AMP accumulations in trabecular meshwork, while 4-DAMP methiodide inhibited it in ciliary bodies, and methoctramine decreased it in ciliary process. The ocular hypotensive effects of clozapine may be mostly related to its muscarinic agonist/antagonist activities and associated cyclic AMP increasing activities, which lead to ciliary muscle relaxation and a possibly associated increase in uveoscleral outflow. Clozapine's ability to increase blood flow and relax vessels may be attributed to its ability to block α-adrenergic and decrease intracellular calcium. IOP is considered the major cause of glaucoma, and compounds which are capable of reducing IOP are considered useful for glaucoma treatment. Based on the results above, clozapine may potentially be important in the development of new antiglaucoma agents. Drug Dev. Res. 44:163–173, 1998. © 1998 Wiley-Liss, Inc.

Accommodation and presbyopia

The mechanism of accommodation has been studied for at least four hundred years. The most interesting aspect of accommodation is that its time course is well in advance of other physiological functions —it begins to decline by adolescence and is lost about two-thirds of the way through the normal life span. The state of presbyopia is reached when accommodation has declined sufficiently to interfere with close tasks requiring acute vision. Presbyopia is generally considered to originate with the ‘plant’ of the accommodative system, either within the lens and its capsule or within their support structures. One of the lenticular theories, the Hess-Gullstrand theory, is distinguished from other theories by its claim that as age increases there is an increasing excess amount of ciliary muscle contraction beyond the ability of the lens and capsule to respond to it. For all other theories, the maximum possible amount of ciliary muscle contraction is always necessary to produce maximum accommodation, at least beyond the age at which it reaches its peak. From my review of the present understanding of the mechanisms of accommodation and the theories of the development of presbyopia, I conclude that there is overwhelming evidence against the Hess-Gullstrand theory and that it is unlikely that changes in the ciliary muscle contractility contribute significantly to the development of presbyopia.

Accommodation and presbyopia

SummaryThe mechanism of accommodation has been studied for at least four hundred years. The most interesting aspect of accommodation is that its time course is well in advance of other physiological functions – it begins to decline by adolescence and is lost about two‐thirds of the way through the normal line span. The state of presbyopia is reached when accommodation has declined sufficiently to interfere with close tasks requiring acute vision. Presbyopia is generally considered to originate with the ‘plant’ of the accommodative system, either within the lens and its capsule or within their support structures. One of the lenticular theories, the Hess–Gullstrand theory, is distinguished from other theories by its claim that as age increases there is an increasing excess amount of ciliary muscle contraction beyond the ability of the lens and capsule to respond to it. For all other theories, the maximum possible amount of ciliary muscle contraction is always necessary to produce maximum accommodation, at least beyond the age at which it reaches its peak. From my review of the present understanding of the mechanisms of accommodation and the theories of the development of presbyopia, I conclude that there is overwhelming evidence against the Hess–Gullstrand theory and that it is unlikely that changes in the ciliary muscle contractility contribute significantly to the development of presbyopia.

L-Type Voltage-Dependent Ca2+ and ATP-Sensitive K+ Channels Are Not Involved in the Regulation of Bovine Ciliary Muscle Contractility

We compared the effects of L-type voltage-dependent Ca2+ and ATP-sensitive K+ channels modulators on contractility in isolated bovine ciliary muscle with those in rabbit aortae. Nifedipine (0.1 and 1 microM), a dihydropyridine Ca2+ channel blocker, did not relax bovine ciliary muscle precontracted with 100 mM KCl. Nondihydropyridine Ca2+ channel blockers, semotiadil fumarate (SD-3211, 1 microM) diltiazem (10 microM) and verapamil (1 microM), did not affect contractility, but at higher concentrations, they all had a relaxant effect. Bay K 8644, a L-type voltage-dependent Ca2+ channel activator, even at 1 microM, did not contract ciliary muscle partially depolarized with 10 mM KCl, whereas at 0.01 and 0.1 microM it contracted partially depolarized rabbit aortae. Furthermore, diazoxide (100 microM), an ATP-sensitive K+ channel opener, had a relaxant effect on aortae precontracted with 25 mM KCl, but not on ciliary muscle. This relaxation was inhibited by glibenclamide (10 microM), an ATP-sensitive K+ channel blocker, indicating that diazoxide relaxes rabbit aortae by activating ATP-sensitive K+ channels. These results suggest that L-type voltage-dependent Ca2+ and ATP-sensitive K+ channels play a minor role in the regulation of bovine ciliary muscle contractility.

O-203 - L-type voltage-dependent Ca2+ channel modulators do not affect bovine ciliary muscle contractility.

O-203 - L-type voltage-dependent Ca2+ channel modulators do not affect bovine ciliary muscle contractility.