Glaucoma is the second leading cause of blindness affecting over 60 million people worldwide. The objectives of this study were to expand the existing methods of trend analysis in visual field time series data testing to aid in the early and accurate detection of glaucoma progression. Visual field data including 54 locations for each of 140 eyes (one per participant among 96 cases and 44 controls) were evaluated using the Humphrey Field Analyzer II program 24-2 Swedish interactive thresholding algorithm (SITA) standard test strategy and Goldmann size III stimuli. One eye was randomly selected for the study and data were collected between 2003 and 2009. Two visual field examinations were conducted at baseline and at eight additional time points of visual field exams taken every six months for four years. Demographic, clinical, structural and other health data in the VIP study were collected from the electronic medical record and health questionnaires. A variety of pointwise linear regression (PLR) criteria have been proposed for determining glaucomatous visual field progression. However, alternative PLR criteria have only been assessed on a limited basis. The first aim of this glaucoma progression detection study thoroughly examined PLR cut-point criteria to maximize the sensitivity and specificity of this standard tool in visual field analysis. The pointwise linear regression A2 (PLRA2) method was used to analyze the data, and Ocular Hypertension Treatment Study (OHTS) data were used to validate the decision rule. Results showed that visual field trend analysis using PLR can be refined by adjusting the standard slope-based and significance level-based criteria. By considering more restrictive declines in visual field data (e.g., < -1.2dB/y, which is approximately 12 times the normal rate of age-related decay) and relaxing the significance level criterion of the PLR slope to p < 0.04 a high specificity can be maintained, while increasing the hit rate, i.e., the proportion of glaucoma cases in which progression was detected by PLR. This work serves to improve a familiar and commonly used method of time series visual field trend analysis that can be implemented quickly to improve early detection of glaucoma progression. The second aim of this project was to investigate the performance of the nonlinear exponential and tobit regression models relative to the normal regression model in the analysis of visual field decay. The goodness-of-fit, as measured by Akaike Information Criteria (AIC), and rates of progression obtained by fitting three alternative regression models to longitudinal visual field data were compared at the location level. The results showed that visual field trend analysis using the tobit regression model results in a better model fit to visual field data, increased precision in the estimation of the rate of progression, and provides a specific advantage in modeling data from cases with advanced glaucoma. The third, and final, aim of this glaucoma progression research project sought to determine if demographic, clinical and health factors, including intraocular pressure, retinal nerve fiber layer thickness, hypertension and diabetes, differ in participants whose visual field data are best fit overall by one statistical model compared to another. This was the first study to examine person-level factors that may affect the fit of proposed analysis models for visual field data, and to utilize bivariable and multivariable methods to understand patient-level predictors of visual field model fit. In the majority of eyes, the tobit model provided either a significantly better fit or there was no difference among models. Significant differences in patient characteristics included baseline MD and previous ocular surgery. This indicates that the tobit model may fit visual field time series data at least as well as the normal and nonlinear exponential models in all cases and controls; and in some advanced cases, it may provide a significantly improved fit. This research overcame critical barriers in visual field trend analysis by increasing the sensitivity of PLR methods and further developing methods using alternative distributions to determine significant loss of function within each visual field test location. Furthermore, results of this study will contribute to the ongoing improvement of visual field trend analysis and the early detection and treatment of glaucoma progression.

<p> In the work of this doctoral dissertation a new resonator sensor technique, first presented in 1989, has been further developed and evaluated with focus on technical characteristics and applications within the medical field.</p><p> In a first part a catheter-type tactile sensor using the resonator sensor technique was evaluated in a silicone model and applied to human prostate in vitro. The main finding was that different histological compositions of prostate tissue correlated with the frequency shift, .fS, of the resonator sensor and that the common property was the hardness of the tissue. The results indicated that hardness of the prostate tissue, and maybe hardness of human tissue in general, can be expressed according to a cone penetration standard (DIN ISO 2137) and that the hardness can be measured with this tactile sensor system. The tissue hardness application for the resonator sensor technique has to be further developed and evaluated in a larger study. The study also produced results that has led to the basic understanding of the resonator sensor system. One important result was that .fS of the sensor system was related to the contact area between sensor and sample. This indicated that the resonance sensor could be used for contact area measurement.</p><p> In a second part, containing three studies, the area-sensing capability from the first study was utilised in the development and evaluation of the applanation resonator sensor (ARS) for measurement of intraocular pressure (IOP). For the purpose of evaluating IOP-tonometers, an in vitro pig-eye model was developed, and it was shown that a saline column connected to the vitreous chamber could be used successfully to induce variations in IOP.</p><p> A ARS sensor with a flat contact surface was applied onto the cornea with constant force and .fS was measured. A mathematical model based on the Imbert-Fick law and the assumption that .fS was linearly related to contact area was proposed and verified with a convincing result. IOP measured with the ARS correlated well (r=0.92, n=360) with the IOP elicited by a saline column.</p><p> The ARS in a constant-force arrangement was evaluated on healthy human subjects in vivo. The results verified the sensor principle but revealed a nonnegligible source of error in off-centre positioning between the sensor and cornea. The sensor probe was redesigned and evaluated in the in vitro model. The new probe, with a spherical contact surface against the eye reduced the sensitivity to off-centre positioning. It was also shown that a .fS normalisation procedure could reduce the between-eye differences.</p><p> The ARS method for IOP measurement was further developed using combined continuous force and area measurement during the dynamic phase when the sensor initially contacts the cornea. A force sensor was included with the resonator sensor in one probe. Evaluation was performed with the in vitro pig-eye model. The hypothesis was that the IOP could be deduced from the differential change of force and area during that phase. The study showed good accuracy and good reproducibility with a correlation of r=0.994 (n=414) between measured pressure in the vitreous chamber and IOP according to the ARS. Measurement time was short, 77 ms after initial contact. Problems with inter-eye differences and low resolution at high pressures were reduced. The ARS method is the first to combine simultaneous, continuous sampling of both parameters included in the applanation principle. Consequently, there is a potential for reducing errors in the clinical IOP tonometry. </p>

In the work of this doctoral dissertation a new resonator sensor technique, first presented in 1989, has been further developed and evaluated with focus on technical characteristics and applications within the medical field. In a first part a catheter-type tactile sensor using the resonator sensor technique was evaluated in a silicone model and applied to human prostate in vitro. The main finding was that different histological compositions of prostate tissue correlated with the frequency shift, .fS, of the resonator sensor and that the common property was the hardness of the tissue. The results indicated that hardness of the prostate tissue, and maybe hardness of human tissue in general, can be expressed according to a cone penetration standard (DIN ISO 2137) and that the hardness can be measured with this tactile sensor system. The tissue hardness application for the resonator sensor technique has to be further developed and evaluated in a larger study. The study also produced results that has led to the basic understanding of the resonator sensor system. One important result was that .fS of the sensor system was related to the contact area between sensor and sample. This indicated that the resonance sensor could be used for contact area measurement. In a second part, containing three studies, the area-sensing capability from the first study was utilised in the development and evaluation of the applanation resonator sensor (ARS) for measurement of intraocular pressure (IOP). For the purpose of evaluating IOP-tonometers, an in vitro pig-eye model was developed, and it was shown that a saline column connected to the vitreous chamber could be used successfully to induce variations in IOP. A ARS sensor with a flat contact surface was applied onto the cornea with constant force and .fS was measured. A mathematical model based on the Imbert-Fick law and the assumption that .fS was linearly related to contact area was proposed and verified with a convincing result. IOP measured with the ARS correlated well (r=0.92, n=360) with the IOP elicited by a saline column. The ARS in a constant-force arrangement was evaluated on healthy human subjects in vivo. The results verified the sensor principle but revealed a nonnegligible source of error in off-centre positioning between the sensor and cornea. The sensor probe was redesigned and evaluated in the in vitro model. The new probe, with a spherical contact surface against the eye reduced the sensitivity to off-centre positioning. It was also shown that a .fS normalisation procedure could reduce the between-eye differences. The ARS method for IOP measurement was further developed using combined continuous force and area measurement during the dynamic phase when the sensor initially contacts the cornea. A force sensor was included with the resonator sensor in one probe. Evaluation was performed with the in vitro pig-eye model. The hypothesis was that the IOP could be deduced from the differential change of force and area during that phase. The study showed good accuracy and good reproducibility with a correlation of r=0.994 (n=414) between measured pressure in the vitreous chamber and IOP according to the ARS. Measurement time was short, 77 ms after initial contact. Problems with inter-eye differences and low resolution at high pressures were reduced. The ARS method is the first to combine simultaneous, continuous sampling of both parameters included in the applanation principle. Consequently, there is a potential for reducing errors in the clinical IOP tonometry.

Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma. Since glaucoma is a leading cause of blindness, reliable methods for measuring the IOP are important. This doctoral dissertation presents a new method, applanation resonance tonometry (ART), for measurement of IOP. The method is based on resonance sensor technology combined with the novel multipoint analysis of continuously sampled data of both contact force and contact area. The ART was evaluated in in vitro porcine-eye studies as well as in clinic on both healthy volunteers and patients. A new symmetric probe with a larger sensor tip and improved aligning light was developed and evaluated in vitro. It showed that the error from off-centring was highly reduced. The new ART probe, used as a biomicroscope device (ARTBiom) and as a handheld device (ARTHand), was further evaluated in a clinical study designed in accordance with the International Standard Organisation’s (ISO) requirement. Both the ARTBiom and the ARTHand met the precision set by the requirements. Laser surgery is a common way to correct vision. The biomechanical effect of photorefractive keratectomy (PRK) on IOP measurements was evaluated using Goldmann applanation tonometry (GAT) and ART in an in vitro study. Both methods were affected, but to a different extent. The flat contact probe of GAT, as compared with the convex tip of ART, and single point vs. multipoint approach, provide explanation to the ART advantage regarding measurement error of IOP after PRK. In conclusion, resonance sensor technology has made it possible to introduce a new multipoint method for measuring IOP, and the method is relevant for measuring IOP in humans. It may be possible to reduce errors in the clinical measurement of IOP with this new method, especially after corneal surgery. The ART has the potential to become a useful clinical instrument for IOP measurement.

Intraocular pressure (IOP) measurement is a routine procedure and a fundament in glaucoma care. Elevated IOP is the main risk factor for glaucoma, and to date, reduction of IOP is the only possible treatment. In a retrospective clinical material, the prevalence of open angle glaucoma was estimated on the west coast of Iceland. IOP measurement and optic nerve head examination were used to capture glaucoma suspects, within the compulsory ophthalmological examination for the prescription of eye glasses. The results were mainly in agreement with a recent prospective study in the same region. This indicated that retrospective data, under certain conditions, may contribute with useful information on the prevalence of glaucoma. However, normal tension glaucoma is underestimated if perimetry and/or fundus photography are not included in the examination. Three studies focused on the measurement of IOP. Goldmann applanation tonometry (GAT) is the standard method. GAT is affected by corneal properties, e.g. central corneal thickness (CCT) and corneal curvature (CC). Refractive surgery changes these properties. This has put focus on how corneal biomechanics translate into tonometric errors and stimulated the development of new methods. As a result, Pascal ® Dynamic Contour Tonometry (PDCT) and Icare® rebound tonometry have been introduced. A method under development by our research group is Applanation Resonance Tonometry (ART). It is based on resonance technology and estimates IOP from continuous measurement of force and contact area. Comparison of PDCT, Icare and GAT in a prospective study showed that the concordance to GAT was close to the limits set by the International Standard Organization (ISO) for PDCT, while Icare was outside the limits. To investigate if laser-assisted subepithelial keratectomy (LASEK) affects tonometry, a study was performed where measurements with GAT, PDCT and ART were obtained before, three and six months after LASEK. The hypothesis was that PDCT and ART would be less affected by LASEK than GAT. The results showed a statistically significant reduction of measured IOP three and six months after LASEK for all tonometry methods. Change in visual acuity and IOP between three and six months suggested a prolonged postoperative process. A servo-controlled prototype (ART servo) was developed. A study was undertaken to assess the agreement of ARTservo and a further developed v manual prototype (ART manual) with GAT. The study design was in accordance with the requirements of the ISO standard for tonometers. ARTmanual fulfilled the precision requirements of the ISO standard. ARTservo did not meet all the requirements of the standard at the highest pressure levels. Four tonometry methods, GAT, PDCT, Icare and ART, were investigated. None of them was independent of both CCT and CC. The inconsistencies in the results emphasize the importance of study design. A meta-analysis comprising healthy eyes (IOP ≤ 21 mmHg) in the three papers, revealed age as an important confounder. In summary, glaucoma prevalence in Iceland was investigated and the results indicated that a retrospective approach can contribute with meaningful information. ART and PDCT had a similar agreement to GAT. ART manual fulfilled the precision requirements set by the ISO-standard, ARTservo and PDCT were close, while Icare was distinctly outside the limits. All tonometry methods were affected by LASEK and no method was completely independent of corneal properties.

Intraocular pressure (IOP) is the most important risk factor for glaucoma development and progression. Most anti-glaucoma treatments aim to lower IOP by enhancing aqueous humor drainage from the eye. Aqueous humor drainage occurs via well-characterized trabecular meshwork (TM) and uveoscleral (UVS) pathways, and the recently described ciliary lymphatics. The relative contribution of the lymphatic pathway to aqueous drainage is not known. We developed a sheep model to quantitatively assess lymphatic drainage along with TM and UVS outflows. Following intracameral injection of 125I-bovine serum albumin (BSA), lymph and blood samples were continuously collected. Lymphatic and TM drainage were quantitatively assessed by measuring 125I-BSA recovery. This quantitative sheep model enables assessment of relative contributions of lymphatic drainage (1.64% ± 0.89%), TM (68.86% ± 9.27%) and UVS outflows (19.87% ± 5.59%), and may help to better understand the effects of glaucoma agents on outflow pathways.

Intraocular pressure (IOP) is the most important risk factor for glaucoma development and progression. Most anti-glaucoma treatments aim to lower IOP by enhancing aqueous humor drainage from the eye. Aqueous humor drainage occurs via well-characterized trabecular meshwork (TM) and uveoscleral (UVS) pathways, and the recently described ciliary lymphatics. The relative contribution of the lymphatic pathway to aqueous drainage is not known. We developed a sheep model to quantitatively assess lymphatic drainage along with TM and UVS outflows. Following intracameral injection of 125I-bovine serum albumin (BSA), lymph and blood samples were continuously collected. Lymphatic and TM drainage were quantitatively assessed by measuring 125I-BSA recovery. This quantitative sheep model enables assessment of relative contributions of lymphatic drainage (1.64% ± 0.89%), TM (68.86% ± 9.27%) and UVS outflows (19.87% ± 5.59%), and may help to better understand the effects of glaucoma agents on outflow pathways.

Les malalties que causen ceguesa total o parcial afecten a milions de persones arreu del món. Una de les principals causas de ceguesa és el glaucoma, malaltia caracteritzada per un augment de la pressió intraocular (IOP) i una pèrdua de visió perifèrica. La fisiopatologia del glaucoma està estretament relacionada amb la fisiologia de l'humor aquós, fluid contingut a les cambres oculars (anterior i posterior). Des de la cambra anterior, l'humor aquós s'eliminarà a través de: 1) la via uveoescleral, que és minoritària, i 2) la via convencional o trabecular, on la major part de l'humor aquós (aprox. 80%) s'elimina travessant la xarxa trabecular cap el canal d'Schlemm i les venes aquoses. L'humor aquós té dues funcions: 1) nodrir les estructures avasculars (còrnia i cristal·lí) i 2) mantenir la IOP dins dels marges fisiològics (15-16 mmHg). Quan s'altera l'equilibri entre la producció i l'evacuació de l'humor aquós, l'humor aquós s'acumula i la IOP augmenta. La xarxa trabecular és un teixit d'estructura similar a una esponja organitzat en diferents regions i en contacte directe amb el canal d'Schlemm. La part més propera al canal d'Schlemm és la que presenta major resistència al pas de l'humor aquós. Alteracions en aquesta via suposaran un augment de la resistència i, en conseqüència, un augment de la IOP. La contractilitat cel·lular i la regulació del volum de la cèl·lula trabecular, són dos mecanismes claus en la regulació de la permeabilitat de la xarxa trabecular. Aquests dos mecanismes induirien deformacions a la membrana que activarien canals mecanosensibles.Un d'aquests canals mecanosensibles és el canal de K+ d'alta conductància dependent de Ca2+ (BKCa), que es caracteritza per la seva activació per voltatges despolaritzants i està modulat pel calci intracel·lula i del qual s'ha demostrat la seva mecanosensibilitat en diferents teixits.Per aquesta raó, s'ha caracteritzat electrofisiològicament el canal BKCa a la cèl·lula trabecular i s'ha estudiat la seva modulació per diferents factors, entre ells l'stretch mecànic. El canal BKCa ha demostrat ésser mecanosensible augmentant la seva probabilitat d'obertura tant per canvis en la tensió de la membrana cel·lular com per increments del volum cel·lular (swelling). En altres sistemes el canal està modulat per la pressió parcial d'oxigen (PO2), de manera que estímuls hipòxics disminueixen l'activitat del canal produïnt despolaritzacions com en les cèl·lules del cos carotidi. A l'ull, l'humor aquós aporta oxigen a les estructures avasculars i a la xarxa trabecular. Els valors de PO2 de l'humor aquós són més baixos (aprox. 55 mmHg) que en altres teixits més oxigenats (aprox. 95 mmHg). Per aquesta raó qualsevol procés que produeixi hipòxia a la cambra anterior tindrà un efecte més acusat. Per aquests motius s'ha estudiat quins mecanismes poden existir a les cèl·lules trabeculars per respondre a estats hipòxics. Els resultats obtinguts mostren com els corrents mitjançats pel canal BKCa disminueixen quan les cèl·lules trabeculars es tracten amb una solució hipòxica. Aquesta disminució dels corrents totals també s'observa en cèl·lules incubades en condicions d'hipòxia (5% O2).La hipòxia produeix alteracions a la mobilització del calci intracel·lular ([Ca2+]i) en diferents tipus cel·lulars. A les cèl·lules trabeculars s'ha estudiat l'efecte de la hipòxia sobre la [Ca2+]i i s'ha observat com la hipòxia modifica la resposta en relació al [Ca2+]i quan s'apliquen diferents substàncies vasoactives (bradikinina, endotel·lina-1) que influeixen sobre l'evacuació de l'humor aquós i que augmenten la [Ca2+]i a la cèl·lula trabecular. La hipòxia produeix entre d'altres efectes, un augment de la [Ca2+]i basal respecte les cèl·lules control (normòxiques) i disminueix l'increment de la [Ca2+]i produït per les substàncies agonistes. / SUBJECT: Electrophysiological characterization of a large conductance Ca2+-activated K+ channel (BKCa) in trabecular meshwork cells: modulation by membrane stretch and hypoxiaTEXT: The understanding of the physiology of the trabecular meshwork has advanced in the last few years, however few ionic channels have been characterized in this tissue. The large conductance Ca2+-activated K+ channel (BKCa) has been identified in the trabecular meshwork cells but its function is still unknown. BKCa channel is voltage dependent and its activity is modulated by intracellular calcium concentration ([Ca2+]i), with different functions depending on the cell type. In excitable cells it controls neuronal excitability, participates in neurotransmitter release and modulates contractile tone in vascular smooth muscle. In non-excitable cells it has been described its participation in cell volume regulation and its modulatory effect on different substances that mobilize [Ca2+]i.Besides [Ca2+]I, other substances such as cGMP or nitric oxide modulate the activity of BKCa channel in the trabecular meshwork. In other tissues, BKCa channel has shown mechanosensitive properties and it has also been described how its activity is modified by low PO2 values (hypoxia). Since trabecular meshwork cells are subjected to intraocular pressure and that aqueous humor contained in the anterior chamber presents PO2 values lower than other tissues, it is important to study the effects of these modulators on BKCa channel activity which will have a direct effect on the physiology of the trabecular meshwork.

La red trabecular es una estructura situada en la cámara anterior del ojo cuya función es drenar el humor acuoso. Alteraciones en ella pueden producir aumentos de la presión intraocular (IOP) los cuales pueden provocar pérdidas en el campo visual y por lo tanto cegueras parciales o totales (glaucoma).El objetivo de esta tesis doctoral se basa en el estudio de la fisiología de la red trabecular con el fin de tener un mayor conocimiento de sus funciones y así poder entender mejor su papel regulador dentro de la evacuación del humor acuoso. Dado que el ATP y otros derivados purinérgicos se encuentran presentes en el humor acuoso, en la realización de este proyecto se han estudiado los receptores purinérgicos en la red trabecular y el papel del ATP y derivados dinucleósidos polifosfato en la modulación de la evacuación del humor acuoso.Se ha evaluado el efecto del ATP mediante el estudio de los incrementos de Ca2+ con el fluoróforo fura-2. Este nucleótido provoca incrementos rápidos del Ca2+ intracelular que disminuyen lentamente hasta los valores basales. El porcentaje de respuesta frente a éste y otros agonistas muestra un perfil de respuesta (ATP = UTP > ATP-&#61543;-S >> ADP = UDP) corresponde al receptor purinérgico P2Y2, el cual es sensible al antagonista suramina.El Ca2+ movilizado tras la estimulación de los receptores P2Y procede de los depósitos citoplasmáticos y las vías de señalización intracelular involucran una proteína Gq/11 que estimula la fosfolipasa C-&#61538; y produce IP3 con la subsiguiente estimulación de receptores de IP3.Experimentos de inmunocitoquímica y western-blot confirman la existencia de un receptor P2Y2 además de la coexistencia con los subtipos P2Y1 y P2Y4.Se ha estudiado como el ATP extracelular modula corrientes de K+ mediadas por el canal de alta conductancia dependiente de calcio BKCa. La estimulación con ATP extracelular provoca un aumento significativo de la corriente de salida de K+ mediante la participación del receptor P2Y2 en la corriente y los aumentos de corriente dependen del Ca2+ intracelular para activarse.Por otro lado, Las células trabeculares poseen la capacidad de liberar ATP frente a estímulos hipotónicos y la cantidad de ATP liberado es proporcional a la hipotonicidad utilizada.Finalmente, se ha estudiado el ATP en la regulación de la facilidad de evacuación de humor acuoso(C). Para ello se utilizó la técnica de perfusión de segmentos anteriores oculares en condiciones de cultivo de órgano obteniéndose valores de C (&#61549;l/min/mmHg). El ATP no muestra ningún efecto sobre la C. El análogo no hidrolizable del ATP, el ATP-&#61543;-S, el cual es resistente a la acción de las ectonucleotidasas tampoco varia la C, indicando que quizá la el ATP estimula diferentes tipos de receptor.En el segundo objetivo del trabajo de tesis se han estudiado los análogos estructurales del ATP dinucleósidos polifosfato ya que estos activan receptores purinérgicos y además se ha demostrado que varían la IOP.Los efectos de los dinucleótidos polifosfato son similares a los mostrados por el ADP. El dinucleótido Up4U muestra una dinámica semejante a la observada por el ATP con incrementos más sostenidos en el [Ca2+]i. Las concentraciones a las que se producen estos incrementos de Ca2+ son grandes y a concentraciones fisiológicas sus efectos son muy bajos. Los dinucleótidos Ap3A y Ap4A producen un aumento en la C y su efecto está mediado por la activación del receptor P2Y1. El aumento provocado por el Ap4A se previene al prefundir juntamente con el antagonista del receptor P2Y1. El agonista selectivo del P2Y1 aumenta la C y su efecto no se produce en presencia del antagonista del P2Y1. / SUBJECT: Functional involvement of purinergic activation in trabecular meshwork.TEXT: The understanding of the physiology of the trabecular meshwork has advanced in the last few years, however purinergic receptors have not been characterized in this tissue and their role have not been determined.In this work it is shown that trabecular meshwork express three diferent subtypes of purinergic receptors: P2Y1, P2Y2 and P2Y4. They are activated by different purinergic agonists and depending on the subtype their response on the intracellular calcium levels are diferent.The activation of P2Y2 and P2Y4 leads Ca2+ mobilisations greater than the P2Y1 activation and their stimulation does not produce changes in outflow facility.On the other hand, the stimulation of P2Y1 receptor by compounds selective for the receptor or some dinucleosides polyphosphate lead an increase in the outflow facility. The increments do not seem to involve calcium signalling and perhaps the intracellular mechanisms could involve second messengers like cAMP.

DE LA TESIUno de los fármacos que se sigue utilizando en el tratamiento del glaucoma es la EPI, debido a su acción hipotensora (I lOP). Los efectos de la EPI han sido estudiados en diferentes preparaciones tanto in vitro como in vivo y se ha descrito en detalle su mecanismo de acción a nivel de la formación del humor acuoso. Sin embargo, se desconoce su mecanismo de acción sobre la evacuación del humor acuoso. Es necesario, por tanto, estudiar los efectos de la EPI sobre la evacuación del humor acuoso y caracterizar los mecanismos celulares específicos activados por la EPI. A pesar de que se han identificado diferentes tipos de receptores adrenérgicos en las células trabeculares no se conocen los subtipos farmacológicos implicados. Cabe suponer que cada subtipo de receptor adrenérgico (ai, ai, ßi, ß2, ßa, ß4) puede tener funciones diferentes en la regulación del la evacuación del humor acuoso. Por ello, deben establecerse los subtipos de receptores adrenérgicos presentes en las células trabeculares y cuáles de éstos están implicados en la evacuación del humor acuoso. La activación de los receptores adrenérgicos de las células trabeculares debe, al igual que en otros tipos celulares, iniciar diferentes vias de señalización intracelular. Queda por estudiar en estas células, que vías intracelulares se activan por los adrenérgicos, que modificaciones producen sobre la facilidad de evacuación del humor acuoso, y cuáles son los segundos mensajeros implicados. Se ha establecido que la estimulación adrenérgica modula, en las células trabeculares y en otros tipos celulares, los niveles de AMPc, aunque se desconocen los efectos de este segundo mensajero sobre evacuación del humor acuoso. En consecuencia, deben caracterizarse los efectos del AMPc sobre la facilidad de evacuación del humor acuoso.