Endothelium regulation problems in pathogenesis of primary glaucoma

PURPOSE: To study the state of the endothelial vasomotor mediators system (endothelin and nitric oxide), as well as the marker of endothelial damage - von Willebrand factor - in the dynamics of glaucoma modeling in rabbits, to identify ion-calcium regulation of these mediators. METHODS: The research was conducted on 60 rabbits, aged 2-3 years. Glaucoma model was induced by intravenous administration of 0.18% solution of adrenalin hydro- tartrat each week on days 1, 3 and 5. Developed scheme included 40 injections. A single drug dose depended on the weight of the animal and amounted to the following values: 12.5 mcg/kg for the first three injections, 20 mcg/kg from the fourth to the sixth injection and 25 mcg/kg for further injections. Endothelial dysfunction was estimated by blood serum levels of endothelin-1 (ET-1), nitric oxide and von Willebrand factor (EF). ET-1 level was determined by ELISA. The level of nitric oxide in peripheral blood was assessed by the level of its stable metabolite nitrite-ion NO₂ in citrate blood serum by means of The Griess Reagent System. The level of von Willebrand factor was determined by ristomycin reaction. RESULTS: An imbalance of endothelial mediators, marking an endothelial dysfunction was observed in glaucoma rabbit models induced by the introduction of the stress hormone adrenaline. The system of vasomotor mediators - endothelin (ET-1) and nitric oxide (NO) - shifted towards strengthening vasoconstriction. The level of ET-1 was increased by 70%, NO - reduced by 39%, the index of the ability to dilatation (IAD) was reduced by half in long-term modelling of glaucoma. Endothelial dysfunction in experimental glaucoma is the Ca²+-dependent process, so it was corrected with calcium channel blocker verapamil. In the course of its 4-month administration vasoconstrictor response in animals with glaucoma was reduced, the level of ET-1 declined by 58%, IAD increased threefold. CONCLUSION: The endothelium is one of the main target organs in the formation of primary glaucoma, and endothelial dysfunction plays a significant role in its pathogenesis. Directed action on this pathogenesis link can be of significant interest in the development of therapeutic treatment of glaucoma.

глаукома, эндотелиальная дисфункция, эндотелин, оксид азота, фактор Виллебранда, верапамил, glaucoma, endothelial dysfunction, endothelin, nitric oxide, von Willebrand factor, verapamil

1. Бувальцев В.И. Дисфункция эндотелия как новая концепция профилактики и лечения сердечно-сосудистых заболеваний. Международный медицинский журнал 2001; 3:1-10. [Buvalcev V.I. Endothelial dysfunction as a new concept of prevention and treatment of cardiovascular diseases. International Medical Journal 2001; 3:1-10. (In Russ.)].

2. Ребров А.П., Кароли Н.А., Юдакова Ю.П. Дисфункция эндотелия сосудов у больных хроническими обструктивными болезнями легких. Проблемы туберкулеза и болезней легких 2004; 4:19-23. [Rebrov A.P., Karoli N.A., Yudakova Yu.P. Dysfunction of endothelium in patients with chronic obstructive lung disease. J Problems of Tuberculosis and Lung Diseases 2004; 4:19-23. (In Russ.)].

3. Смагина Л.В., Аметова А.С., Демидова Т.Ю. Эндотелий как мишень терапевтического воздействия антигипертензивной терапии у больных сахарным диабетом 2 типа. Кардиоваскулярная терапия и профилактика 2004; 5:81-87. [Smagina L.V., Ametova A.S., Demidova T.Yu. Endothelium as a therapeutic target of antihypertensive therapy in patients with diabetes mellitus type 2. Cardiovascular Therapy and Prevention 2004; 5:81-87. (In Russ.)].

4. Кашинцева Л.Т. Открытоугольная глаукома как локальное проявление общих сосудистых изменений. Труды VI Всесоюзного съезда офтальмол. М., 1985; 37-38. [Kashintceva L.T. Open-angle glaucoma as a local manifestation of common vascular changes. Proceedings of VI Ophthalmology Congress. Moscow, 1985; 37-38. (In Russ.)].

5. Малая Л.Т., Корж А.Н., Балковская Л.Б. Эндотелиальная дисфункция при патологии сердечно-сосудистой системы. Харьков: 2000; 432. [Malaya L.T., Korzh A.N., Balkovskaya L.B. Endotelial’naya disfunktsiya pri patologii serdechno-sosudistoi sistemy [Endothelial dysfunction in cardiovascular pathology] - Khar’kov, 2000. 432 p. (In Russ.)].

6. Коркушко О.В., Лишневская В.Ю. Эндотелиальная дисфункция. Кровообіг та гемостаз 2003; 2: 4-15. [Korkushko O.V., Lishnevskaya B.U. Endothelial dysfunction. Circulation and Haemostasis 2003; 2: 4-15. (In Russ.)].

7. Абрагамович О.О., Файник А.Ф., Нечай О.В. и др. Механізми розвитку дисфункції ендотелію та її роль у патогенезі ішемічної хвороби серця. Український кардіологічний журнал 2007; 4:81-87. [Abragamovich O.O., Faynik A.F., Nechay O.V. et al. Mechanisms of endothelium dysfunction development and its role in the pathogenesis of ischemic heart disease. Ukranian Cardiology Journal 2007; 4:81-87 (In Ukr.)].

8. Katz S.D., Hryniewiez K., Hriljac I. et al. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation 2005; 111(3): 310-314.

9. Коркушко О.В., Лишневская В.Ю., Дужак Г.В. Возрастные особенности функционального состояния эндотелия микрососудов. Кровообіг та гемостаз 2007; 4:5-11. [Korkushko O.V., Lishnevskaya B.U., Dujak G.V. Age specifics of the functional state of microvascular endothelium. Circulation and Haemostasis 2007; 4:5-11 (In Russ.)].

10. Flammer J., Mozaffarieh J.M. Autoregulation, a balancing act between supply and demand. Canadian J Ophthalmol 2008; 43(3):317-321.

11. Flammer J. The role of ocular blood flow in the pathogenesis of glaucomatous damage. US Ophthalmic Review 2011; l4(2):84-87.

12. Михейцева И.Н. Патент України на корисну модель №61478. 2011; Бюл. № 14. Спосіб моделювання адреналін- індукованої глаукоми у кролів. [Mikheytseva I.N. Patent of Ukraine № 61478. 2011; Bull. № 14. A method of adrenaline- induced glaucoma modelling in rabbits (In Ukr.)].

13. Marasciulo F.L., Montagnani M., Potenza M.A. Endothe- lin-1: the yin and yang on vascular function. Current Medical Chemistry 2006; 13(14):1655-1665.

14. Blann A.D. Von Willebrand factor as a marker of injury to the endothelium in inflammatory vascular disease. J Reumatol 1993; 20(9):1469-1471.

15. Jansson J.H., Nilsson T.K., Jonsson O. Von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66(6):351-355.

16. Thomas P.C., Simonson M.S., Dunn W.J. Endothelin: receptors and transmembrane signals. News Physiology Sci 1992; 7:207-211.

17. Mikheytseva I., Lipovetskaya E., Kopp O., Moraffarieh M., Flammer J., Meyer P. Adrenalin-induced chronic ocular hypertension in adult rabbits. Klinsche Monatsblatter Augen- heilkunde 2009; 226(4):332-336.

18. Grossman E., Messerli F.H. Calcium antagonists. Progress in Cardiovascular Diseases 2004; 47(1):34-57.

19. Pashe M., Flammer J. A sick eye in a sick body? Systemic findings in patients with primary open-angle glaucoma. Surv Ophthalmol 2006; 51(3):179-212.