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Effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure in glaucomatous monkey eyes
Experimental Eye Research 80 (2005) 629–632 www.elsevier.com/locate/yexer
Effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure in glaucomatous monkey eyes Rong-Fang Wanga,*,1, Steven M. Podosa,1,2, Thomas W. Mittaga,1, Tomihisa Yokoyomab,3 a
Department of Ophthalmology, Mount Sinai School of Medicine of New York University, Box 1183, One Gustave L. Levy Place, New York, NY, USA b Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan Received 21 July 2004; accepted in revised form 25 November 2004 Available online 4 January 2005
Abstract To evaluate the effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure (IOP) in monkey eyes with unilateral laser-induced glaucoma. A multiple-dose study was performed in 8 glaucomatous monkey eyes. One 50 ml drop of CS-088, 2% or 4%, was topically applied to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. IOP was measured hourly for 6 hours beginning at 9:30 a.m. for one baseline day, one vehicle-treated day, and daily for 5 days of treatment with CS-088. The washout period between the two drug concentrations was at least 2 weeks. Twice daily administration of 2 % CS-088 for 5 days did not reduce the IOP until the third dose on day 2 of the treatment regimen. A significant (p!0.02) reduction in IOP began 1 hour after the third dose, and lasted for 3 hours. The maximum reduction in IOP was 5.3G 0.8 (meanGSEM) mmHg (15%) (p!0.001), with the longest duration of IOP reduction of at least 6 hours after dosing on day 5. The 4% dose of CS-088 reduced (p!0.05) IOP from 1 to 5 hours after the first dose. The maximum reduction in IOP was 6.9G1.0 mmHg (20%), with the longest duration of IOP reduction of at least 18 hours after administration on day 5. Both 2% and 4% CS-088 showed enhancement of the ocular hypotensive effect with repeated dosing. 4% CS-088 produced greater (p!0.05) IOP reduction with longer duration of action than 2%. Topically applied CS-088, a new antagonist drug at the angiotensin AT1 receptor, reduced IOP in glaucomatous monkey eyes in a dose-dependent manner. q 2004 Elsevier Ltd. All rights reserved. Keywords: CS-088; angeotensin II receptor type 1 antagonist; angeotensin converting enzyme; renin-angiotensin system; intraocular pressure; glaucoma; monkey
Oral administration of an angiotensin II (Ang II) receptor type 1 (AT1) antagonist (Costagliola et al., 1999, 2000) or an angiotensin converting enzyme (ACE) inhibitor (Constad et al., 1988; Costagliola et al., 1995) has been shown to reduce intraocular pressure (IOP) in normotensive subjects and in patients with open angle glaucoma. Topical application of various ACE inhibitors significantly reduces IOP in ocular hypertensive rabbits (Shah et al., 2000). * Corresponding author. Dr Rong-Fang Wang, Department of Ophthalmology, Mount Sinai School of Medicine of New York University, Box 1183, One Gustave L. Levy Place, New York, NY, USA. E-mail address: [email protected] (R.-F. Wang). 1 Drs Wang, Podos, and Mittag have no commercial or financial interest in the drug evaluated in this article. 2 Dr Podos is a consultant to Alcon Laboratories, Inc. and Pfizer, Inc. 3 Dr Yokoyoma is an employee of Sankyo Co. Ltd. 0014-4835/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.exer.2004.11.012
The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, fluid volume homeostasis and electrolyte balance. Modifications in the activity of this system will induce changes in blood pressure and in IOP (Costagliola et al., 2000). The presence and the functional role of RAS, including ACE activities, the concentration of angiotensinogen and Ang II, and the density of Ang II AT1 receptor in the ocular tissues and fluids have been demonstrated in several species, including humans (Goel and Jabbour, 1991; Wallow et al., 1993; Danser et al., 1994; Meyer, 1995). These findings indicate that the eye contains a local RAS which may be involved in the regulation of IOP. CS-088, an angiotensin AT1 receptor antagonist, reduces IOP in rabbits. A small increase in uveoscleral outflow, with no changes in aqueous inflow or outflow facility, has been
630
R.-F. Wang et al. / Experimental Eye Research 80 (2005) 629–632
observed when CS-088 was topically applied to the rabbits (Inoue et al., 2001a,b). We have investigated the effect of CS-088 on IOP following multiple-dose applications in monkey eyes with laser-induced unilateral glaucoma. Eight adult female cynomolgus monkeys, each weighing 3–6 kg, in which glaucoma had been induced in one eye by repeated argon or diode laser photocoagulation of the midtrabecular meshwork, were used in this study (Wang et al., 1998) IOP was measured hourly for 6 hr beginning at 9:30 a.m. for one baseline day, one vehicle-treated day (during the week preceding the treatment), and 5 days of treatment with CS-088, using a pneumatonometer (Model 30 classic, Mentor Inc, Norwell, Mass). The animals were sedated with intramuscular ketamine hydrochloride (1–5 mg/kg, depending on the individual), and one drop of 0.5% proparacaine hydrochloride was administered topically 5 min before IOP measurements. CS-088 and vehicle solution were prepared and provided by the Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd (Tokyo, Japan). A two-level dose study was performed using concentrations of 2 and 4% in the same group of 8 glaucomatous monkey eyes. Following one baseline day and one vehicle-treated day (one 50 ml drop of vehicle to the glaucomatous eye at 9:30 a.m. and 3:30 p.m.), one 50 ml drop of CS-088, 2 or 4%, was applied topically to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. The washout period between the two drug concentrations was at least 2 weeks. The two-tailed paired t-test and the Bonferroni t-test were used for statistical analysis. A value of p!0.05 was considered statistically significant. Data were calculated as the meanGSEM. All experiments complied with the Association for Research in Vision and Ophthalmology Resolution on the Use of Animals in Research and were approved by the Institutional Animal Care and Utilization Committee of Mount Sinai School of Medicine, New York, NY. We found that twice daily administration of 2% CS-088 did not reduce (pO0.20) the IOP until the third dose on day 2 of the treatment regimen. A significant (p!0.02) reduction in IOP was observed 1 hr after the third dose, and lasted for 3 hr. The maximum reduction (p!0.01) in IOP occurred 2 or 3 hr after each morning dosing and was 2.9G0.8 (meanGSEM) mmHg (9%) on day 2, 4.3G 0.6 mmHg (13%) on day 3, and 5.3G0.8 mmHg (15%) on day 5. The longest duration of IOP reduction was for at least 6 hr after the fifth dose (Fig. 1). The 4% dose of CS-088 reduced (p!0.05) IOP from 1 to 5 hr after the first dose. The maximum reduction (p!0.005) in IOP was 3.3G 0.7 mmHg (10%) on day 1, 5.5G0.8 mmHg (16%) on day 3, and 6.9G1.0 mmHg (20%) on day 5. IOP was still reduced (p!0.05) at 0 hr prior to the morning dosing on day 3 through day 5, suggesting the longest duration of IOP reduction was at least 18 hr after the fifth dose (Fig. 1). The magnitude and duration of the ocular hypotensive effect were increased with repeated dosing for both 2 and 4% concentrations. A significant (p!0.05) difference in IOP
Fig. 1. Effects of twice-daily administration of CS-088 2 and 4%, for 5 days on intraocular pressure (IOP) in 8 glaucomatous monkeys. Points represent meanGSEM mmHg of IOP on the vehicle-treated day and days 1,3 and 5 of treatment. Asterisks indicate a significant reduction in IOP (*p!0.05, **p!0.005) of treated eyes with glaucoma compared with values in the same eyes treated with vehicle (2-tailed Bonferroni t-test).
reduction between day 3 and day 5 could be observed at 2 hr with 2% CS-088, and at 2 hr and 4 hr with 4% CS-088. Compared with the 2% concentration, 4% CS-088 produced a longer duration of action (18 vs. 6 hr) and greater (p!0.05) IOP reduction from 3 to 6 hr after the first dose on day 1, and at 0 hr prior to the fifth dose on day 3 (Fig. 2). Significant differences in IOP were not observed comparing the baseline and vehicle- treated days. Mild mucous discharge of the conjunctiva was observed in one of 8 monkey eyes with the 4% concentration on treatment days 3–5. No other inflammation of the anterior segment of the eye was apparent during the 5 days of treatment. Topical administration of CS-088, an angiotensin antagonist at the AT1 receptor, reduces IOP in ocular
R.-F. Wang et al. / Experimental Eye Research 80 (2005) 629–632
Fig. 2. Comparison of reduction in intraocular pressure (IOP) comparing CS-088 2 and 4% in 8 glaucomatous monkeys. Points represent mean changeGSEM mmHg of IOP from vehicle-treated values. Asterisks indicate significant difference of IOP reduction (*p!0.05, **p!0.005) comparing CS-088 2 and 4% (2-tailed paired t-test).
hypertensive rabbits. The reduction in IOP is comparable to that of timolol (Inoue et al., 2001a,b). Oral administration of Losartan potassium, an active AT1 Ang II receptor antagonist, reduces IOP 14.8–20% in normotensive subjects with or without essential arterial hypertension, and in patients with open angle glaucoma with or without arterial
631
hypertension (Costagliola et al., 2000). The results of the current study show that a multiple dose regimen of topically applied CS-088 significantly reduces IOP in glaucomatous monkey eyes. Both the 2 and 4% concentrations produce an increase in ocular hypotensive effect with repeated dosing, without tachyphylaxis or anterior segment inflammation during the 5 days of treatment. The reduction in IOP appears to be dose-dependent. The 4% CS-088 produces greater IOP reduction (20 vs. 15%) and longer duration of action (18 vs. 6 hr) than the 2% CS-088. The IOP reduction with 4% CS088 applied topically is equivalent to that with systemically administered Losartan potassium. The mechanism by which Ang II AT 1 receptor antagonists reduce IOP is not fully clarified. It appears to be complex and not a sole mechanism of action. An increase in total outflow facility is observed in normal subjects and in patients with glaucoma following oral administration of Losartan potassium, but the lack of correlation between blood pressure and IOP makes it unlikely that there is a reduction in episcleral venous pressure with a consequent increase in trabecular outflow. The block of the AT1 receptor by Losartan potassium reduces the rates of aqueous humor flow with a subsequent reduction in IOP (Costagliola et al., 2000). Topical administration of various ACE inhibitors, enalaprilat, ramiprilat, and fosinopril, reduces IOP in rabbits. These compounds reduce IOP by inhibition of ACE in aqueous humor and in ocular tissue, resulting in decrease of Ang II formation within the eye. Indomethacin blocks the IOP-lowering effect of enalaprilat, indicating that prostaglandins may mediate, at least in part, the ocular hypotensive effect of enalaprilat (Shah et al., 2000). In addition to ACE, chymase, an alternative Ang II- generating enzyme, has been found to be present in the cardiovascular and ocular tissue of humans, monkeys and dogs. Chymaselike activity has been detected in the anterior uveal tract, choroid and sclera. In monkey eyes, the activity is higher in the uveal tract than in the heart. Chymase may be involved in the local Ang II generation in the eye, indicating that this enzyme might play a role in the physiological regulation of IOP or be involved in the pathogenesis of ocular disease by producing Ang II (Shiota et al., 1997). In rabbits CS-088, an angiotensin AT1 receptor antagonist, reduces IOP with a 17% increase in uveoscleral outflow, but without changes in outflow facility and in rates of aqueous humor flow (Inoue et al., 2001a,b). Although there is a small increase in uveoscleral outflow, the mechanism for the significant IOP lowering by CS-088 is not understood in the rabbit and is unknown in the monkey eye. It has been demonstrated that Ang II via the AT2 receptor is involved in programmed cell death i.e. apoptosis (Tanaka et al., 1995). Glaucomatous optic nerve neuropathy is a chronic process where apoptosis plays an important role in the retinal ganglion cell death. Angiotensin-induced vasoconstriction of the ocular vasculature has also been considered as a pathogenic mechanism for glaucomatous
632
R.-F. Wang et al. / Experimental Eye Research 80 (2005) 629–632
optic nerve damage (Anderson, 1983). All these experimental results strongly indicate that blockade of the systemic or ocular RAS activities may not only reduce IOP, but may also play a neuroprotective role in glaucoma. CS-088, a new antagonist drug at the angiotensin AT1 receptor, may have a potential for the treatment of glaucoma. Further mechanism studies with this compound are warranted.
Acknowledgements Grant support: EY01867 from the National Institutes of Health, Bethesda, MD, and unrestricted grant (S. Podos) from Research to Prevent Blindness, Inc., New York, NY and Sankyo Co. Ltd, Tokyo, Japan.
References Anderson, D.R., 1983. The mechanism of damage to the optic nerve, in: Krieglstein, G.K., Leydhecker, W. (Eds.), Glaucoma update II. Springer, Berlin, pp. 89–94. Constad, W.H., Fiore, P., Samson, C., Cinotti, A.A., 1988. Use of an angiotensin converting enzyme inhibitor in ocular hypertension and primary open angle glaucoma. Am. J. Ophthalmol. 105, 674–677. Costagliola, C., Di Bernadette, R., De Caprio, L., Verde, R., Mastropasqua, L., 1995. Effect of oral captopril (SQ 14225) on intraocular pressure in man. Eur. J. Ophthalmol. 5, 19–25. Costagliola, C., Verolino, M., Iaccarino, G., de Rosa, M.L., Ciancaglini, M., Mastropasqua, L., 1999. Effect of Losartan potassium oral administration on intraocular pressure in humans. Clin. Drug. Invest. 29, 329–332.
Costagliola, C., Verolino, M., de Rosa, M.L., Iaccarino, G., Ciancaglini, M., Mastropasqua, L., 2000. Effect of oral Losartan potassium administration on intraocular pressure in normotensive and glaucomatous human subjects. Exp. Eye Res. 71, 167–171. Danser, A.H.J., Derkx, F.H.M., Admiraal, P.J.J., Deinum, J., de Jong, P.T.V.M., Schalekamp, M.A.D.H., 1994. Angiotensin levels in the eye. Invest. Ophthalmol. Vis. Sci. 35, 1008–1018. Goel, A.K., Jabbour, N.M., 1991. Vitreous level of angiotensin-II in patients with diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 32, 1027. Inoue, T., Yokoyoma, T., Mori, Y., Sasaki, Y., Hosokawa, T., Yanagisawa, H., Koike, H., 2001a. The effect of topical CS-088, an angiotensin AT1 receptor antagonist on intraocular pressure and aqueous humor dynamics in rabbits. Curr. Eye Res. 23, 133– 138. Inoue, T., Yokoyoma, T., Koike, H., 2001b. The effect of angiotensin II on uveoscleral outflow in rabbits. Curr. Eye Res. 23, 139–143. Meyer, P., Flammer, J., Luscher, T.F., 1995. Local action of the rennin angiotensin system in the porcine ophthalmic circulation: effects of ACE-inhibitors and angiotensin receptors antagonists. Invest. Ophthalmol. Vis. Sci. 36, 555–562. Shah, G.B., Sharma, S., Mehta, A.A., Goyal, R.K., 2000. Oculohypotensive effect of angiotensin-converting enzyme inhibitors in acute and chronic models of glaucoma. J. Cardoovasc. Pharmacol. 36, 169–175. Shiota, N., Saegusa, Y., Nishimura, K., Miyazaki, M., 1997. Angiotensin IIgenerating system in dog and monkey ocular tissues. Clin. Exp. Pharmacol. Physiol. 24, 243–248. Tanaka, M., Ohnishi, J., Ozawa, Y., Sugimoto, M., Usuki, S., Naruse, M., Murakami, K., Miyazaki, H., 1995. Characterization of angiotensin II receptor type 2 during differentiation and apoptosis of rat ovarian cultured grannulosa cells. Biochem. Biophys. Res. Commun. 207, 503–598. Wallow, I.H.L., Sramek, S.J., Bindley, C.D., Darjatmoko, S.R., Gange, S.J., 1993. Ocular rennin angiotensin: immunocytochemical localization of prorenin. Curr. Eye Res. 12, 945–950. Wang, R-F., Schumer, R.A., Serle, J.B., Podos, S.M., 1998. A comparison of argon laser and diode laser photocoagulation of the trabecular meshwork to produce the glaucoma monkey model. J. Glaucoma 7, 45–49.
Effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure in glaucomatous monkey eyes Rong-Fang Wanga,*,1, Steven M. Podosa,1,2, Thomas W. Mittaga,1, Tomihisa Yokoyomab,3 a
Department of Ophthalmology, Mount Sinai School of Medicine of New York University, Box 1183, One Gustave L. Levy Place, New York, NY, USA b Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan Received 21 July 2004; accepted in revised form 25 November 2004 Available online 4 January 2005
Abstract To evaluate the effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure (IOP) in monkey eyes with unilateral laser-induced glaucoma. A multiple-dose study was performed in 8 glaucomatous monkey eyes. One 50 ml drop of CS-088, 2% or 4%, was topically applied to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. IOP was measured hourly for 6 hours beginning at 9:30 a.m. for one baseline day, one vehicle-treated day, and daily for 5 days of treatment with CS-088. The washout period between the two drug concentrations was at least 2 weeks. Twice daily administration of 2 % CS-088 for 5 days did not reduce the IOP until the third dose on day 2 of the treatment regimen. A significant (p!0.02) reduction in IOP began 1 hour after the third dose, and lasted for 3 hours. The maximum reduction in IOP was 5.3G 0.8 (meanGSEM) mmHg (15%) (p!0.001), with the longest duration of IOP reduction of at least 6 hours after dosing on day 5. The 4% dose of CS-088 reduced (p!0.05) IOP from 1 to 5 hours after the first dose. The maximum reduction in IOP was 6.9G1.0 mmHg (20%), with the longest duration of IOP reduction of at least 18 hours after administration on day 5. Both 2% and 4% CS-088 showed enhancement of the ocular hypotensive effect with repeated dosing. 4% CS-088 produced greater (p!0.05) IOP reduction with longer duration of action than 2%. Topically applied CS-088, a new antagonist drug at the angiotensin AT1 receptor, reduced IOP in glaucomatous monkey eyes in a dose-dependent manner. q 2004 Elsevier Ltd. All rights reserved. Keywords: CS-088; angeotensin II receptor type 1 antagonist; angeotensin converting enzyme; renin-angiotensin system; intraocular pressure; glaucoma; monkey
Oral administration of an angiotensin II (Ang II) receptor type 1 (AT1) antagonist (Costagliola et al., 1999, 2000) or an angiotensin converting enzyme (ACE) inhibitor (Constad et al., 1988; Costagliola et al., 1995) has been shown to reduce intraocular pressure (IOP) in normotensive subjects and in patients with open angle glaucoma. Topical application of various ACE inhibitors significantly reduces IOP in ocular hypertensive rabbits (Shah et al., 2000). * Corresponding author. Dr Rong-Fang Wang, Department of Ophthalmology, Mount Sinai School of Medicine of New York University, Box 1183, One Gustave L. Levy Place, New York, NY, USA. E-mail address: [email protected] (R.-F. Wang). 1 Drs Wang, Podos, and Mittag have no commercial or financial interest in the drug evaluated in this article. 2 Dr Podos is a consultant to Alcon Laboratories, Inc. and Pfizer, Inc. 3 Dr Yokoyoma is an employee of Sankyo Co. Ltd. 0014-4835/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.exer.2004.11.012
The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, fluid volume homeostasis and electrolyte balance. Modifications in the activity of this system will induce changes in blood pressure and in IOP (Costagliola et al., 2000). The presence and the functional role of RAS, including ACE activities, the concentration of angiotensinogen and Ang II, and the density of Ang II AT1 receptor in the ocular tissues and fluids have been demonstrated in several species, including humans (Goel and Jabbour, 1991; Wallow et al., 1993; Danser et al., 1994; Meyer, 1995). These findings indicate that the eye contains a local RAS which may be involved in the regulation of IOP. CS-088, an angiotensin AT1 receptor antagonist, reduces IOP in rabbits. A small increase in uveoscleral outflow, with no changes in aqueous inflow or outflow facility, has been
630
R.-F. Wang et al. / Experimental Eye Research 80 (2005) 629–632
observed when CS-088 was topically applied to the rabbits (Inoue et al., 2001a,b). We have investigated the effect of CS-088 on IOP following multiple-dose applications in monkey eyes with laser-induced unilateral glaucoma. Eight adult female cynomolgus monkeys, each weighing 3–6 kg, in which glaucoma had been induced in one eye by repeated argon or diode laser photocoagulation of the midtrabecular meshwork, were used in this study (Wang et al., 1998) IOP was measured hourly for 6 hr beginning at 9:30 a.m. for one baseline day, one vehicle-treated day (during the week preceding the treatment), and 5 days of treatment with CS-088, using a pneumatonometer (Model 30 classic, Mentor Inc, Norwell, Mass). The animals were sedated with intramuscular ketamine hydrochloride (1–5 mg/kg, depending on the individual), and one drop of 0.5% proparacaine hydrochloride was administered topically 5 min before IOP measurements. CS-088 and vehicle solution were prepared and provided by the Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd (Tokyo, Japan). A two-level dose study was performed using concentrations of 2 and 4% in the same group of 8 glaucomatous monkey eyes. Following one baseline day and one vehicle-treated day (one 50 ml drop of vehicle to the glaucomatous eye at 9:30 a.m. and 3:30 p.m.), one 50 ml drop of CS-088, 2 or 4%, was applied topically to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. The washout period between the two drug concentrations was at least 2 weeks. The two-tailed paired t-test and the Bonferroni t-test were used for statistical analysis. A value of p!0.05 was considered statistically significant. Data were calculated as the meanGSEM. All experiments complied with the Association for Research in Vision and Ophthalmology Resolution on the Use of Animals in Research and were approved by the Institutional Animal Care and Utilization Committee of Mount Sinai School of Medicine, New York, NY. We found that twice daily administration of 2% CS-088 did not reduce (pO0.20) the IOP until the third dose on day 2 of the treatment regimen. A significant (p!0.02) reduction in IOP was observed 1 hr after the third dose, and lasted for 3 hr. The maximum reduction (p!0.01) in IOP occurred 2 or 3 hr after each morning dosing and was 2.9G0.8 (meanGSEM) mmHg (9%) on day 2, 4.3G 0.6 mmHg (13%) on day 3, and 5.3G0.8 mmHg (15%) on day 5. The longest duration of IOP reduction was for at least 6 hr after the fifth dose (Fig. 1). The 4% dose of CS-088 reduced (p!0.05) IOP from 1 to 5 hr after the first dose. The maximum reduction (p!0.005) in IOP was 3.3G 0.7 mmHg (10%) on day 1, 5.5G0.8 mmHg (16%) on day 3, and 6.9G1.0 mmHg (20%) on day 5. IOP was still reduced (p!0.05) at 0 hr prior to the morning dosing on day 3 through day 5, suggesting the longest duration of IOP reduction was at least 18 hr after the fifth dose (Fig. 1). The magnitude and duration of the ocular hypotensive effect were increased with repeated dosing for both 2 and 4% concentrations. A significant (p!0.05) difference in IOP
Fig. 1. Effects of twice-daily administration of CS-088 2 and 4%, for 5 days on intraocular pressure (IOP) in 8 glaucomatous monkeys. Points represent meanGSEM mmHg of IOP on the vehicle-treated day and days 1,3 and 5 of treatment. Asterisks indicate a significant reduction in IOP (*p!0.05, **p!0.005) of treated eyes with glaucoma compared with values in the same eyes treated with vehicle (2-tailed Bonferroni t-test).
reduction between day 3 and day 5 could be observed at 2 hr with 2% CS-088, and at 2 hr and 4 hr with 4% CS-088. Compared with the 2% concentration, 4% CS-088 produced a longer duration of action (18 vs. 6 hr) and greater (p!0.05) IOP reduction from 3 to 6 hr after the first dose on day 1, and at 0 hr prior to the fifth dose on day 3 (Fig. 2). Significant differences in IOP were not observed comparing the baseline and vehicle- treated days. Mild mucous discharge of the conjunctiva was observed in one of 8 monkey eyes with the 4% concentration on treatment days 3–5. No other inflammation of the anterior segment of the eye was apparent during the 5 days of treatment. Topical administration of CS-088, an angiotensin antagonist at the AT1 receptor, reduces IOP in ocular
R.-F. Wang et al. / Experimental Eye Research 80 (2005) 629–632
Fig. 2. Comparison of reduction in intraocular pressure (IOP) comparing CS-088 2 and 4% in 8 glaucomatous monkeys. Points represent mean changeGSEM mmHg of IOP from vehicle-treated values. Asterisks indicate significant difference of IOP reduction (*p!0.05, **p!0.005) comparing CS-088 2 and 4% (2-tailed paired t-test).
hypertensive rabbits. The reduction in IOP is comparable to that of timolol (Inoue et al., 2001a,b). Oral administration of Losartan potassium, an active AT1 Ang II receptor antagonist, reduces IOP 14.8–20% in normotensive subjects with or without essential arterial hypertension, and in patients with open angle glaucoma with or without arterial
631
hypertension (Costagliola et al., 2000). The results of the current study show that a multiple dose regimen of topically applied CS-088 significantly reduces IOP in glaucomatous monkey eyes. Both the 2 and 4% concentrations produce an increase in ocular hypotensive effect with repeated dosing, without tachyphylaxis or anterior segment inflammation during the 5 days of treatment. The reduction in IOP appears to be dose-dependent. The 4% CS-088 produces greater IOP reduction (20 vs. 15%) and longer duration of action (18 vs. 6 hr) than the 2% CS-088. The IOP reduction with 4% CS088 applied topically is equivalent to that with systemically administered Losartan potassium. The mechanism by which Ang II AT 1 receptor antagonists reduce IOP is not fully clarified. It appears to be complex and not a sole mechanism of action. An increase in total outflow facility is observed in normal subjects and in patients with glaucoma following oral administration of Losartan potassium, but the lack of correlation between blood pressure and IOP makes it unlikely that there is a reduction in episcleral venous pressure with a consequent increase in trabecular outflow. The block of the AT1 receptor by Losartan potassium reduces the rates of aqueous humor flow with a subsequent reduction in IOP (Costagliola et al., 2000). Topical administration of various ACE inhibitors, enalaprilat, ramiprilat, and fosinopril, reduces IOP in rabbits. These compounds reduce IOP by inhibition of ACE in aqueous humor and in ocular tissue, resulting in decrease of Ang II formation within the eye. Indomethacin blocks the IOP-lowering effect of enalaprilat, indicating that prostaglandins may mediate, at least in part, the ocular hypotensive effect of enalaprilat (Shah et al., 2000). In addition to ACE, chymase, an alternative Ang II- generating enzyme, has been found to be present in the cardiovascular and ocular tissue of humans, monkeys and dogs. Chymaselike activity has been detected in the anterior uveal tract, choroid and sclera. In monkey eyes, the activity is higher in the uveal tract than in the heart. Chymase may be involved in the local Ang II generation in the eye, indicating that this enzyme might play a role in the physiological regulation of IOP or be involved in the pathogenesis of ocular disease by producing Ang II (Shiota et al., 1997). In rabbits CS-088, an angiotensin AT1 receptor antagonist, reduces IOP with a 17% increase in uveoscleral outflow, but without changes in outflow facility and in rates of aqueous humor flow (Inoue et al., 2001a,b). Although there is a small increase in uveoscleral outflow, the mechanism for the significant IOP lowering by CS-088 is not understood in the rabbit and is unknown in the monkey eye. It has been demonstrated that Ang II via the AT2 receptor is involved in programmed cell death i.e. apoptosis (Tanaka et al., 1995). Glaucomatous optic nerve neuropathy is a chronic process where apoptosis plays an important role in the retinal ganglion cell death. Angiotensin-induced vasoconstriction of the ocular vasculature has also been considered as a pathogenic mechanism for glaucomatous
632
R.-F. Wang et al. / Experimental Eye Research 80 (2005) 629–632
optic nerve damage (Anderson, 1983). All these experimental results strongly indicate that blockade of the systemic or ocular RAS activities may not only reduce IOP, but may also play a neuroprotective role in glaucoma. CS-088, a new antagonist drug at the angiotensin AT1 receptor, may have a potential for the treatment of glaucoma. Further mechanism studies with this compound are warranted.
Acknowledgements Grant support: EY01867 from the National Institutes of Health, Bethesda, MD, and unrestricted grant (S. Podos) from Research to Prevent Blindness, Inc., New York, NY and Sankyo Co. Ltd, Tokyo, Japan.
References Anderson, D.R., 1983. The mechanism of damage to the optic nerve, in: Krieglstein, G.K., Leydhecker, W. (Eds.), Glaucoma update II. Springer, Berlin, pp. 89–94. Constad, W.H., Fiore, P., Samson, C., Cinotti, A.A., 1988. Use of an angiotensin converting enzyme inhibitor in ocular hypertension and primary open angle glaucoma. Am. J. Ophthalmol. 105, 674–677. Costagliola, C., Di Bernadette, R., De Caprio, L., Verde, R., Mastropasqua, L., 1995. Effect of oral captopril (SQ 14225) on intraocular pressure in man. Eur. J. Ophthalmol. 5, 19–25. Costagliola, C., Verolino, M., Iaccarino, G., de Rosa, M.L., Ciancaglini, M., Mastropasqua, L., 1999. Effect of Losartan potassium oral administration on intraocular pressure in humans. Clin. Drug. Invest. 29, 329–332.
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