Davit SABA, Zehra SERDAR, Melahat DİRİCAN, Hayati ÖZKAN, Hasan YAVUZ, Işık ŞENKAYA, Ziya ÖZER, Musa AĞRIŞ, Hülya ÖZTÜRK

Kalsiyum dobesilatın iskelet kası iskemi-reperfüzyon hasarındaki rolü

Kalsiyum dobesilatın kapiller fonksiyon bozukluklarını düzelttiği, lenfatik akımı arttırdığı, trombosit agregasyonu ve trombogenezi inhibe ettiği bilinmektedir. Bu deneysel çalışmada venotonik bir ajan olarak kullanılan kalsiyum dobesilatın, iskelet kasında iskemi - reperfüzyon hasarına etkileri araştırılmıştır. Materyal ve Metod: Sprague - Dawley cinsi 25 rat 5 gruba ayrıldı. Grup 1'de sadece anestezi, Grup'2 de turnike yöntemiyle sağ arka ekstremiteye 4 saat iskemi uygulandı. İskemi lazer dopler ile gösterildi. Grup 3 ve Grup 4'de 5 gün süre ile oral kalsiyum dobesilat verildi. Grup 3'de 4 saat iskemi, Grup 4 ve Grup 5'de 4 saat iskemiyi takiben 2 saat reperfüzyon yapıldı. Tüm gruplarda soleus kası, akciğer ve karaciğer dokusu lipit peroksidasyonunun son ürünü olan malondialdehit seviyelerinin ölçümü için çıkarıldı. Serum kreatin fosfokinaz düzeyleri çalışıldı. Ayrıca histopatolojik inceleme amacıyla soleus kasından alınan doku kesitleri nitroblue tetrazolium boyası ile boyanarak oksidatif enzimlerde kullanımı gösteren menekşe renkli hücrelerin sayımı yapıldı. Bulgular:İlaçsız iskemi grubu ile kalsiyum dobesilat alan iskemi grubu karşılaştırıldığında, kalsiyum dobesilatlı iskemik grupta adale ve karaciğer malondialdehit düzeylerinde ve kreatin fosfokinaz düzeylerinde istatistiksel anlamlı azalma vardı(p < 0.05). Kalsiyum dobesilatlı iskemi - reperfüzyon ile ilaçsız iskemi - reperfüzyon grupları karşılaştırıldığında, kalsiyum dobesilatlı iskemi - reperfüzyon grubunda serum kreatin fosfokinaz ve adale malondialdehit düzeylerinde anlamlı azalma görüldü ( p < 0.05 ). Sonuç:Şu anda klinik kullanımda yalnızca oral formu bulunan ve venöz hastalıkların tedavisinde kullanılan bu ilacın iskeminin etkilerini ayrıca kladikasyonun oluşturduğu iskemi reperfüzyon hasarını azaltabileceği için kronik arteriyel iskemili hastaların tedavisinde kullanılabileceği sonucuna varıldı.

The effects of calcium dobesilate on skeletal muscle ischemia reperfusion injury

It's known that calcium dobesilate improves capillary dysfunction and lymphatic flow, inhibits thrombogenesis and thrombocytic aggregation. In this experimental study the effects of calcium dobesilate, a venotonic agent, on skeletal muscle ischemia -reperfusion injury is investigated. Method: Sprague-Dawley type 25 rats were divided into 5 groups. In Group 1 only anesthesia was performed. Ischemia was obtained in right lower extremity using tourniquet method in Group 2. Ischemia was documented by laser doppler. In group 3 and 4 , oral calcium dobesilate was given for five days. In Group 3 four hours of ischemia, in Group 4 and 5 two hours of reperfusion following 4 hours of ischemia was performed. Soleus muscle, lung and liver tissues were extracted for measurement of malondialdehyde levels which is the last product of lipid peroxidation. Serum creatine phospokinase levels were also studied. In addition , tissue samples of soleus muscle were dyed with nitroblue tetrazolium and then purple colored cells were counted in order to show the usage of oxidative enzymes. Results: When ischemia groups without calcium dobesilate and with calcium dobesilate were compared, in latter group there was a decrease in malondialdehyde levels of soleus muscle and liver tissues and also in serum creatine phosphokinase levels, which was statistically significant (p < 0.05). When comparing ischemia-repefusion groups with and without calcium dobesilate, there was statistically significant decrease in serum creatine phosphokinase and muscular malondialdehyde levels in the former group (p < 0.05). Conclusion: Even though calcium dobesilate is available only in oral form and used in treatment of venous diseases, it can also be used in the treatment of patients with chronic arterial disease to prevent ischemia and ischemia-reperfusion injury induced by claudication.

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1. Hinder RA, Stein HJ. Oxygen derived free radicals. Arch Surg 1991;126:104-5.
2. Welbourn CRB, Goldman G, Paterson IS, et al. Pathophysiology of ischemia reperfusion injury: Centralf ole of the neutrophil. Br J Surg 1991;78:651-5.
3. Weinbroum AA, Hochhauser E, Rudick V, et al. Multiple organ dysfunction after remote circulatuar arrest: Common pathway of radical oxygen species. J Trauma 1999;47:691-8.
4. Braithwaite B, Ouinnes - Baldrich W, Earnshaw J. Skeletal muscle reperfusion syndrome. Hosp Update 1995;50:27-33.
5. Jeffrey T, Michael E, Garry L, et al. The role of glutamine in skeletal muscle ischemia / reperfusion injury in the rat hind limb model. Ann J Surg 1999;178:147-50.
6. Androulakis G, Panoysis PA. Pletysmographic confirmation of the beneficial effect of calcium dobesilate in primary varicose veins. Angiology 1989;40:1-4.
7. Angen F. On behalf of the Swiss study group. Efficacy and safety of calcium dobesilate in patients with chronic venous insufficiency. Curr Ther Res 1995;56:346-7.
8. Hardy SC, Gough MJ. Pharmacological manipulation of gastrocnemius muscle blood flow in an animal model of reperfusion injury. J Biomed Eng 1991;13:263-6.
9. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxidation in animal tissue by thiobarbutiric acid reaction. Analy Biochem 1979;95:351-5.
10. Bancroft JD and Stewens A, eds. Theory and Practice of Histological Techniques. New York: Churchill Livingstone, 1982:395-6.
11. Hobson II RW, Milazzo VJ, Duran WN. Pathophysiology of skeletal muscle ischemia - reperfusion injury. In Haimovici H ed. Vascular Surgery New York: Blackwell Science, 1996:497-508.
12. Hardy SC, Homer - Vanniaskinkam S, Gough MJ. The triphasic pattern of skeletal muscle blood flow in reperfusion injury: An experimental model with implications for surgery on the acutely ischaemic lower limb. Eur J Vasc Surg 1990;4:587-90.
13. Hong RW, Rounds JD, Helton WS, et al. Glutamine preserves liver glutathione after hepatic injury. Ann Surg 1992;215:114-9.
14. Diamantopoulos EJ, Dionisios C, Georgopoulos V, et al. Oxgen free radicals and the effect of a free radical scavenger in patients with intermittent claudication. Vasc Surg 2000;34:167-74.
15. Szlavy L, Repa I, Lengye I, et al. Effects of intravenous streptokinase and CLS 2210 ( Calcium Dobesilate ) on the biochemical markers of early acute myocardial infarction: A historic comprasion with both studies. Angiology 1992; 43:741-7.
16. Windsor ACJ, Mullen PG, Fowler AA, et al. Role of neutrophil in adult respiratory distress syndrome. Br J Surg 1993;80:10-7.
17. Seekap A, Warren JS, Remick DG, et al. Requirements for tumor necrosis factor - alpha and interleukin - 1 in limb ischemia -reperfusion injury and associated lung injury. Am J Pathol 1993;143:453-63.
18. Tassiopoulos AP, Carlýn RE, Gao Y, et al. Role of nitric oxide and tumor necrosis factor on lung injury caused byischemia / reperfusion of the lower extremities. J Vasc Endovasc Surg 1997;26:647-56.
19. Gaines GC, Welborn BM III, Moldawer LL, et al. Attenuation of skeletal muscle ischemia / reperfusion injury by inhibition of tumor necrosis factor. J Vasc Surg 1999;29:370-5