Pravastatin AMPK Yolağının ve Potasyum Kanallarının Aktivasyonu Yoluyla Sıçan Torasik Aortunu Gevşetir

Öz

Bu çalışma kolesterol düşürücü bir ilaç olan pravastatinin sıçan torasik aortundaki fonksiyonel etkilerini ve etki mekanizmalarını belirlemeyi amaçladı. Erkek Wistar Albino sıçanların torasik aortlarından izole edilen damar segmentleri, izole organ banyosu sistemindeki bölmelere yerleştirildi. Dinlenim gerimi 1 g olarak ayarlandı. Dengelenme sürecinden sonra torasik aorta halkaları 10-6 M fenilefrin ile kasıldı. Stabil bir kasılma sağlandıktan sonra damar halkalarına kümülatif (10-8-10-4 M) pravastatin uygulandı. Pravastatinin vazoaktif etki mekanizmalarını belirlemek için, belirtilen deney protokolü, spesifik sinyal yolağı inhibitörleri ve potasyum kanal blokörlerinin inkübasyonundan sonra tekrarlandı. Pravastatin, önceden kasılmış sıçan torasik aort halkalarında konsantrasyona bağımlı bir gevşeme gösterdi (p<0,001). Endotelin çıkarılması, L-NAME uygulaması ve indometazin inkübasyonu, pravastatinin vazorelaksan etki düzeyini anlamlı ölçüde azalttı (p<0,001). Pravastatin kaynaklı vazorelaksasyon seviyeleri, TEA, 4-Aminopiridin, XE-991, dorsomorfin ve anandamid uygulamalarından sonra anlamlı ölçüde azaldı (p<0,001). Gliburid ve baryum klorür uygulamaları pravastatinin vazorelaksan etki düzeyinde istatistiksel olarak anlamlı bir değişikliğe neden olmadı (p=1,000). Pravastatin sıçan torasik aortunda belirgin bir vazorelaksan etkiye sahiptir. Pravastatinin vazorelaksan etkisinde sağlam endotel, nitrik oksit, prostanoidler, AMPK ve potasyum kanalları (BKCa, SKCa, KV ve K2p kanalları) rol oynamaktadır.

Anahtar Kelimeler

• AMPK
• Kolesterol
• Nitrik oksit
• Potasyum kanalları
• Pravastatin
• Sıçan aortu

Pravastatin Relaxes Rat Thoracic Aorta via Activation of AMPK Pathway and Potassium Channels

Öz

This study aimed to determine the functional effects and mechanisms of action of pravastatin, a cholesterol-lowering drug, in rat thoracic aorta. Vessel segments isolated from the thoracic aortas of male Wistar Albino rats were placed in chambers within an isolated tissue bath system. The resting tension was set to 1 g. After an equilibration period, the thoracic aorta rings were contracted with 10-6 M phenylephrine. Once a steady contraction was obtained, cumulative pravastatin (10-8-10-4 M) was applied to the vascular rings. To identify the vasoactive effect mechanisms of pravastatin, the specified experimental protocol was repeated after incubation with specific signaling pathway inhibitors and potassium channel blockers. Pravastatin showed a concentration-dependent relaxation in precontracted rat thoracic aorta rings (p<0.001). The vascular relaxant effect levels of pravastatin were significantly reduced by removal of the endothelium, L-NAME application, and indomethacin incubation (p<0.001). Pravastatin-induced vasorelaxation levels were also significantly reduced following TEA, 4-Aminopyridine, XE-991, apamin, dorsomorphin, and anandamide administrations (p<0.001). However, applications of glyburide and barium chloride did not cause a statistically significant change in the vasorelaxant effect level of pravastatin (p=1.000). Pravastatin has a prominent vasorelaxant effect in rat thoracic aorta. Intact endothelium, nitric oxide, prostanoids, AMPK, and potassium channels (BKCa, SKCa, KV, and K2p channels) play a role in the vascular relaxant effect of pravastatin.

Anahtar Kelimeler

• AMPK
• Cholesterol
• Nitric oxide
• Potassium channels
• Pravastatin
• Rat aorta

Kaynakça

1. 1. Mendis S, Graham I, Narula J. Addressing the global burden of cardiovascular diseases; need for scalable and sustainable frameworks. Glob Heart. 2022;17(1):48.
2. 2. Abdul-Rahman T, Bukhari SMA, Herrera EC, et al. Lipid lowering therapy: an era beyond statins. Curr Probl Cardiol. 2022;47(12):101342.
3. 3. Vagelos PR. Are prescription drug prices high? Science. 1991252(5009):1080-4.
4. 4. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160-4.
5. 5. Okyay K. Pleiotropic effects of statins: new evidences. Türk Kardiyoloji Derneği Arşivi. 2021;49(7):533-5.
6. 6. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017;120(1):229-43. Erratum in: Circ Res. 2018;123(8):e20.
7. 7. Razavi AC, Mehta A, Sperling LS. Statin therapy for the primary prevention of cardiovascular disease: pros. Atherosclerosis. 2022;356:41-5.
8. 8. Wasim R, Ansari TM, Ahsan F, et al. Pleiotropic benefits of statins in cardiovascular diseases. Drug Res (Stuttg). 2022;72(9):477-86.

9. 9. López-Canales JS, Lozano-Cuenca J, López-Canales OA, et al. Pharmacological characterization of mechanisms involved in the vasorelaxation produced by rosuvastatin in aortic rings from rats with a cafeteria-style diet. Clin Exp Pharmacol Physiol. 2015;42(6):653-61. 10. Mukai Y, Shimokawa H, Matoba T, et al. Acute vasodilator effects of HMG-CoA reductase inhibitors: involvement of PI3-kinase/Akt pathway and Kv channels. J Cardiovasc Pharmacol. 2003;42(1):118-24.
10. 11. Alvarez De Sotomayor M, Herrera MD, Marhuenda E, Andriantsitohaina R. Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat. Br J Pharmacol. 2000;131(6):1179-87.
11. 12. Bravo L, Herrera MD, Marhuenda E, Perez-Guerrero C. Cardiovascular effects of lovastatin in normotensive and spontaneously hypertensive rats. Gen Pharmacol. 1998;30(3):331-6.
12. 13. Sonmez Uydes-Dogan B, Topal G, et al. Relaxant effects of pravastatin, atorvastatin and cerivastatin on isolated rat aortic rings. Life Sci. 2005;76(15):1771-86. 14. Verma K, Shukla R, Dwivedi J, Paliwal S, Sharma S. New insights on mode of action of vasorelaxant activity of simvastatin. Inflammopharmacology.2023;31(3):1279-1288.
13. 15. Pérez-Guerrero C, Alvarez de Sotomayor M, Herrera MD, Marhuenda E. Endothelium modulates contractile response to simvastatin in rat aorta. Z Naturforsch C J Biosci. 2000;55(1-2):121-4.
14. 16. Sahinturk S. Metformin relaxes rat thoracic aorta via nitric oxide, AMPK, potassium channels, and PKC. Iran J Basic Med Sci. 2023;26(9):1030-40.
15. 17. Şahintürk S. Kv7.1-7.5 Kanallarının Sıçan Torasik Aortundaki Apela Kaynaklı Vasorelaksasyondaki Rolü. Osmangazi Tıp Dergisi. 2023;45(5):639-50.
16. 18. Mitchell JA, Ali F, Bailey L, Moreno L, Harrington LS. Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. Exp Physiol. 2008;93(1):141-7.
17. 19. Jackson WF. Potassium channels in regulation of vascular smooth muscle contraction and growth. Adv Pharmacol.2017;78:89-144.
18. 20. Tykocki NR, Boerman EM, Jackson WF. Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles. Compr Physiol. 2017;7(2):485-581.
19. 21. Tan CS, Loh YC, Tew WY, Yam MF. Vasorelaxant effect of 3,5,4'-trihydroxy-trans-stilbene (resveratrol) and its underlying mechanism. Inflammopharmacology. 2020;28(4):869-75.
20. 22. Ulusoy KG, Dogan MF, Cam SA, Arslan SO, Yildiz O. Propofol relaxes isolated rat aorta through BKCa activation. Ann Vasc Surg. 2019;60:397-406.
21. 23. Shirwany NA, Zou MH. AMPK in cardiovascular health and disease. Acta Pharmacol Sin. 2010;31(9):1075-84.
22. 24. Bae JH, Kim JW, Kweon GR, et al. Corpus cavernosal smooth muscle relaxation effect of a novel AMPK activator, beta-lapachone. J Sex Med. 2011;8(8):2205-14.
23. 25. Sung JY, Choi HC. Metformin-induced AMP-activated protein kinase activation regulates phenylephrine-mediated contraction of rat aorta. Biochem Biophys Res Commun. 2012;421(3):599-604.
24. 26. Dehnavi S, Kiani A, Sadeghi M, et al. Targeting AMPK by statins: a potential therapeutic approach. Drugs. 2021;81(8):923-33.
25. 27. Sun W, Lee TS, Zhu M, et al. Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation. 2006;114(24):2655-62