Sevtap HAN, Mecit Orhan ULUDAĞ, EMİNE DEMİREL YILMAZ

Deneysel Hipertansiyon Modelinde Farklı DOCA-tuz Uygulama Sürelerinin Kan Basıncı ve Damar Cevapları Üzerine Etkisi

Amaç: Hipertansiyon, gelişiminde pek çok faktörün etkili olması nedeniyle araştırılması zor bir hastalıktır.Deoksikortikosteron asetat (DOCA)-tuz hipertansiyon modeli, oldukça sık kullanılan ve insanlardaki esansiyelhipertansiyonu başarılı bir şekilde taklit edebilen bir deneysel modeldir. Hipertansiyon çalışmalarında, hayvanmodelinin seçimi kadar seçilen modelinin ne kadar süreyle uygulanacağı da büyük önem taşımaktadır. Bu çalışmada,DOCA-tuz hipertansiyon modelinin farklı sürelerde uygulanmasının, kan basıncı ve damar cevapları üzerine etkileri,araştırılmıştır.Yöntemler: Deneylerde 8 haftalık, erkek Wistar albino sıçanlar kullanılmıştır. DOCA-tuz hipertansiyon modelinioluşturmak için, hayvanlara tek taraflı nefrektomi uygulanmış ardından haftada iki kez DOCA enjeksiyonu (15 mg/kg,s.c.) yapılmış ve %1 NaCl ile %0,2 KCl içeren içme suyu verilmiştir. Uygulamalara farklı hayvan gruplarına 4 hafta ve 8hafta boyunca devam edilmiş ve kan basınçları ölçülmüştür. Süre sonunda, hayvanların torasik aortları izole edilmişve damar cevapları izole organ banyosunda kaydedilmiştir.Bulgular: 4 veya 8 hafta DOCA-tuz uygulaması, hayvanların kan basıncını yükseltmiş ve aortanın endotele bağımlıgevşeme cevaplarını azaltmıştır. 4 haftalık DOCA-tuz grubunda aortun KCl kasılma cevapları değişmezken, alfa-1reseptör agonisti fenilefrin (FE) ile uyarılan kasılma cevapları azalmıştır. 8 haftalık DOCA-tuz grubunda ise, hem KClhem de FE ile oluşan damar kasılmaları azalmıştır.Sonuç: DOCA-tuz hipertansiyon modelinin erken döneminde, endotel işlevinde ve reseptör aracılı damarkasılmalarında bozukluklar ortaya çıkmaktadır. Daha uzun süreli uygulama sonucunda ise, kan basıncı daha fazlayükselmekte, hem endotel hem de damar düz kasının işlevlerinde bozukluklar görülmektedir. Elde edilen sonuçlar,deneysel hipertansiyon modelinde farklı DOCA-tuz uygulama sürelerinin, damarların işlevleri üzerine farklı etkileriolduğunu göstermektedir.

The Effect of Different Application Periods of DOCA-salt on Blood Pressure and Vascular Response in the Experimental Model of Hypertension

Objective: Hypertension is a difficult disease to study because of the many factors involved in its development. The deoxycorticosterone acetate (DOCA)-salt hypertension model is a frequently used experimental model and mimics essential hypertension in humans. In hypertension studies, it is of great importance to choose how long the model will be applied as well as the selection of the animal model. In this study, it was investigated whether the administration of DOCA-salt hypertension model at different times would have different effects on blood pressure and vessel responses. Method: 8-week-old male Wistar albino rats were used in the experiments. DOCA-salt hypertension model was induced through unilateral nephrectomy, DOCA injection (15 mg/kg, s.c.) twice a week and 1% NaCl and 0.2% KCl added to drinking water. The applications were performed for 4 weeks or 8 weeks in different animal groups and blood pressures were measured. At the end of the period, thoracic aortas of the animals were isolated and the vessel responses were recorded in the isolated tissue bath. Results: 4 or 8 weeks DOCA-salt administration resulted in a significant increase in blood pressure and a reduction in endothelium-dependent relaxation responses. In the 4-week DOCA-salt group, KCl-induced contractile responses remained unchanged, whereas the alpha-1 receptor agonist phenylephrine (FE)-induced contractile responses were decreased. In the 8-week DOCA-salt group, both contractile contractions with KCl and FE were reduced. Conclusion: DOCA-salt hypertension model leads to endothelial dysfunction and impaired receptor-mediated smooth muscle contractions in the early-stage. The longer-term administration results in higher blood pressure and both endothelial and vascular smooth muscle dysfunction. These findings suggest that different DOCA-salt application times may have different effects on smooth muscle functions in experimental hypertension model.

PDF

___

1. Sözmen K, Ergör G, Ünal B. Hipertansiyon sıklığı, farkındalığı, tedavi alma ve kan basıncı kontrolünü etkileyen etmenler. Dicle Medical Journal / Dicle Tip Dergisi. 2015;42:199-207.
2. Basting T, Lazartigues E. DOCA-Salt Hypertension: an Update. Curr Hypertens Rep. 2017;19:32.
3. Lerman LO, Kurtz TW, Touyz RM, et al. Animal Models of Hypertension: A Scientific Statement From the American Heart Association. Hypertension. 2019:HYP0000000000000090.
4. Carretero OA, Oparil S. Essential hypertension. Part I: definition and etiology. Circulation. 2000;101:329-35.
5. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006;7:335-46.
6. Crowley SD, Coffman TM. In hypertension, the kidney breaks your heart. Curr Cardiol Rep. 2008;10:470-6.
7. Takeda K, Nakamura Y, Hayashi J, et al. Effects of Salt and Doca on Hypothalamic and Baroreflex Control of Blood-Pressure. Clinical and Experimental Hypertension Part a-Theory and Practice. 1988;10:289- 99.
8. Takeda K, Nakamura Y, Oguro M, et al. Central Attenuation of Baroreflex Precedes the Development of Hypertension in Doca-Salt-Treated Rats. American Journal of Hypertension. 1988;1:S23-S5.
9. Takeda K, Nakamura Y, Okajima H, et al. AttenuatedCardiovascularandSympathetic-Nerve Responses to Aortic Nerve-Stimulation in Doca-Salt Hypertensive Rats. Journal of Hypertension. 1988;6:559-63.
10. Ueno Y, Mohara O, Brosnihan KB, Ferrario CM. Characteristics of hormonal and neurogenic mechanisms of deoxycorticosterone-induced hypertension. Hypertension. 1988;11:I172-7.
11. Sapouckey SA, Deng G, Sigmund CD, Grobe JL. Potential mechanisms of hypothalamic reninangiotensin system activation by leptin and DOCA-salt for the control of resting metabolism. Physiol Genomics. 2017;49:722-32.
12. Han S, Bal NB, Sadi G et al. Inhibition of endoplasmic reticulum stress protected DOCA-salt hypertensioninduced vascular dysfunction. Vascul Pharmacol. 2019;113:38-46.
13. Han S, Bal NB, Sadi G, et al. Theeffects of LXR agonist GW3965 on vascular reactivity and inflammation in hypertensive rat aorta. Life Sci. 2018;213:287-93.
14. Han S, Uludag MO, Usanmaz SE, et al. Resveratrol affects histone 3 lysine 27 methylation of vessels and blood biomarkers in DOCA salt-induced hypertension. Mol Biol Rep. 2015;42:35-42.
15. Cassinotti LR, Guil MJ, Scholler MI, et al. Chronic Blockade of Brain Endothelin ReceptorType-A (ETA) Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats. Int J Mol Sci. 2018;19.
16. Bae EH, Kim IJ, Song JH et al. Renoprotective Effect of the Histone Deacetylase Inhibitor CG200745 in DOCASalt Hypertensive Rats. Int J MolSci. 2019;20.
17. Kubacka M, Zadrozna M, Nowak B, et al. Reversal of cardiac, vascular, andrenal dysfunction by nonquinazoline alpha1-adrenolytics in DOCA-salt hypertensive rats: a comparison with prazosin, a quinazoline-based alpha1-adrenoceptor antagonist. Hypertens Res. 2019.
18. Jamwal S, Sharma S. Vascular endothelium dysfunction: a conservative target in metabolic disorders. Inflamm Res. 2018;67:391-405.
19. Ye F, Wu Y, Chen Y, Xiao D, Shi L. Impact of moderateand high-intensity exercise on the endothelial ultrastructure and function in mesenteric arteries from hypertensive rats. Life Sci. 2019;222:36-45.
20. Niazi ZR, Silva GC, Ribeiro TP, et al. EPA:DHA 6:1 prevents angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidaseand COX-derived oxidative stress. Hypertens Res. 2017;40:966-75.
21. Mordi I, Mordi N, Delles C, Tzemos N. Endothelial dysfunction in human essential hypertension. J Hypertens. 2016;34:1464-72.
22. Bockman CS, Jeffries WB, Pettinger WA, Abel PW. Enhanced release of endothelium-derived relaxing factor in mineralocorticoid hypertension. Hypertension. 1992;20:304-13.
23. Galisteo M, Garcia-Saura MF, Jimenez R, et al. Effects of quercetin treatment on vascular function in deoxycorticosteroneacetate-salt hypertensive rats. Comparative study with verapamil. Planta Med. 2004;70:334-41.
24. Goulopoulou S, Webb RC. Symphony of Vascular Contraction How Smooth Muscle Cells Lose Harmony to Signal Increased Vascular Resistance in Hypertension. Hypertension. 2014;63:E33-E9.
25. Sonkusare S, Palade PT, Marsh JD, et al. Vascular calcium channels and high blood pressure: Pathophysiology and therapeutic implications. Vascular Pharmacology. 2006;44:131-42.