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NITRIC OXIDE AND CARBON MONOXIDE: MODULATION OF INTRAOCULAR PRESSURE

NITRIC OXIDE AND CARBON MONOXIDE: MODULATION OF INTRAOCULAR PRESSURE. Claudio Bucolo and Filippo Drago*. Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Catania, Italy *Director PhD School of Neuropharmacology. NADPH. NADPH. O 2. H 2 O.

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NITRIC OXIDE AND CARBON MONOXIDE: MODULATION OF INTRAOCULAR PRESSURE

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  1. NITRIC OXIDE AND CARBON MONOXIDE: MODULATION OF INTRAOCULAR PRESSURE Claudio Bucolo and Filippo Drago* Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Catania, Italy *Director PhD School of Neuropharmacology

  2. NADPH NADPH O2 H2O NADP NADP HEME NADPH Cytocrome C (P450) Reductase Heme Oxygenase Fe CO BILIVERDIN Biliverdin reductase BILIRUBIN

  3. sGC Soluble guanilyl cyclase Heat shock Cellular stress U.V. Transition metals Metalloporphirine Adrenal glucocorticoids Phorbol esters Cytokines HO-2/3 HO-1 + Lypopolysaccaride + Costitutive Inducible HEME Apoptosis MAPK pathway Cytoprotection Vasomotor tone CO Endothelin-1 + Ca2+activated K+channels cGMP Platelet aggregation Vascular cell growth and proliferation GTP

  4. HO System (isoforms:HO-1, HO-2, HO-3) NOS System (isoforms: NOS-1, NOS-2,NOS-3) CO NO sGC cGMP

  5. CO NO - HO-2 HEME HO-1 - + NOS L-Arginine

  6. Inhibition of Nitric Oxide Synthase by L-NAME reduces IOP of rabbits • Taniguchi et al. Curr Eye Res 1998 • Kiel et al. Exp Eye Res 2001 • Giuffrida et al. J Ocular Pharmacol Ther 2003

  7. CARBON MONOXIDE MAY MODULATE THE INTRAOCULAR PRESSURE ?

  8. Experimental Models of Ocular Hypertension - Alpha-Chymotrypsyn • Single intraocular injection of -chymotrypsyn • After 4 weeks the rabbits in which the IOP became 15 mmHg higher than in untreated controlateral eye were admitted • Measurements: IOP (TonoPen) and PD (caliper) - Betamethasone • Multiple injection of betamethasone (subconjunctival) • After 4 weeks the rabbits in which the IOP became 15 mmHg higher than in untreated controlateral eye were admitted • Measurements: IOP and PD

  9. Experimental Design Ocular Hypertension α-chymotrypsin or betamethasone -6 0 6 12 24 48 hours Hemin 50, 75, 100 mg/Kg i.v. IOP ZnPP-IX 0.1 mg/Kg i.p.

  10. Pupil Diameter in Ocular Normotensive Rabbit PD (mm) at various time intervals after drug administration TREATMENT PD (mm) b.t.* 0.5h 1h 2h 3h 6h 12h 24h 48h Vehicle 6.800.20 6.850.20 6.800.15 6.850.20 6.850.20 6.800.30 6.850.20 6.850.15 6.850.20 Hemin 50mg/kg 6.950.30 6.980.15 6.950.30 7.010.25 6.950.15 6.980.25 6.900.20 7.000.30 6.980.30 Hemin 75mg/kg 6.900.15 6.900.20 6.900.30 6.950.15 6.950.30 6.920.30 6.940.20 6.900.25 6.910.30 Hemin 100mg/kg 6.850.20 6.850.20 6.800.20 6.820.25 6.850.30 6.830.25 6.850.20 6.850.30 6.850.25 * b.t.: before treatment • No change on Pupil Diameter has been observed

  11. CO NO - HO-2 HEME HO-1 + - + HEMIN NOS L-Arginine

  12. HO-1 AND RETINAL NEUROPROTECTION: RELEVANT STUDIES • HO-1 has cytoprotective effects on Müller cells and • plays an anti-inflammatory, anti-oxidative role • against the ischemia-reperfusion injury in rat • (Arai-Gaun et al. IOVS, 45, 2004) • HO-1-related carbon monoxide production • induced by flavonoids showed a protective effect • against ischemia-reperfusion injury in the rat retina • (Szabo et al. IOVS, 45, 2004) • Flavonoids protect human RPE cells from • oxidative-stress-induced death also through a • robust expression of HO-1 • (Hanneken et al. IOVS, 47, 2006)

  13. CONCLUSIONS • Hemin reduces IOP in rabbit with intraocular • hypertension. • This effect is possibly mediated by reduced • availability of ocular NO as a result of • increased production of CO by hemin • Hemin, and in general the HO-1 inducers • (i.e. phenolic compounds), may offer a • novel class of agents potentially effective • in the modulation of ocular hypertension • and retinal protection

  14. Acknowledgements Collaborators • Giovanna Privitera • Gian Marco Leggio • Department of Experimental and Clinical • Pharmacology, School of Medicine, • University of Catania, Catania, Italy • Marta Potenza • School of Ophthalmology, • University of Palermo, • Palermo, Italy Sponsorship This work was supported by a grant from M.I.U.R. Misura III.4 PON.RST

  15. Thanks and see you …

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