Bazal Vasküler Tonusun Düzenlenmesinde Rol Alan Mekanizmaların Sıçan Torasik Aort Modelinde İncelenmesi
Yıl 2021,
, 423 - 430, 01.12.2021
Serdar Şahintürk
,
Naciye İşbil
Öz
Bu çalışmada, endotelyal nitrik oksit sentaz (eNOS)/nitrik oksit (NO), siklooksijenaz (COX), AMP ile aktive olan protein kinaz (AMPK), mitojen ile aktive edilen protein kinaz (MAPK) ve apelin reseptörü (APJ) sinyal ileti yolakları ile potasyum kanallarının vasküler tonus üzerindeki etkisinin belirlenmesi amaçlandı. Wistar Albino erkek sıçanların torasik aortlarından elde edilen 4 mm’lik damar halkaları izole organ banyosu sistemine yerleştirildi. Damar gerimi 1 gram olarak ayarlandı. Sinyal ileti yolaklarının ve potasyum kanallarının bazal damar tonusu üzerindeki etkilerini belirlemek için 1 saatlik dengelenme periyodunu takiben inhibitör madde uygulamaları yapıldı. İnhibitör madde uygulamalarından önceki ve sonraki periyodlardaki gerim değerleri kaydedildi. Nω-Nitro-L-arginin metil ester ve tetraetilamonyum uygulamaları bazal damar gerim değerlerinde istatistiksel olarak anlamlı düzeyde artışa neden oldu (sırasıyla: p < 0,001; p < 0,05). İndometazin ve dorsomorfin uygulamaları bazal damar gerim değerlerinde istatistiksel olarak anlamlı düzeyde azalmaya neden oldu (p < 0,05). F13A ve U0126 uygulamaları bazal damar gerim değerlerinde istatistiksel olarak anlamlı düzeyde bir değişikliğe neden olmadı. Bu çalışmanın verileri eNOS/NO, COX ve AMPK sinyal ileti yolakları ile potasyum kanallarının bazal vasküler tonus regülasyonunda önemli birer etken olduğunu göstermektedir. Buna karşın MAPK ve APJ sinyal ileti yolaklarının sıçan torasik aortundaki bazal vasküler tonus düzenlenmesinde önemli birer faktör olmadığı düşünülmektedir.
Teşekkür
Bu çalışma Bursa Uludağ Üniversitesi Tıp Fakültesi Fizyoloji Anabilim Dalı’nın imkanları ile gerçekleştirilmiştir.
Kaynakça
- 1. Barrett KE, Barman SM, Boitano S, Brooks HL, (eds.). Ganong’un Tıbbi Fizyolojisi. 24. baskı. İstanbul: Nobel Tıp Kitabevleri; 2015.
- 2. Hall JE, (ed.). Guyton ve Hall Tıbbi Fizyoloji. 13. Baskı. Ankara: Güneş Tıp Kitabevleri; 2017.
- 3. Zhao Y, Vanhoutte PM, Leung SWS. Vascular nitric oxide: Beyond eNOS. Journal of Pharmacological Sciences 2015;129(2):83-94.
- 4. Sahinturk S, Demirel S, Ozyener F, Isbil N. [Pyr1]apelin-13 relaxes the rat thoracic aorta via APJ, NO, AMPK, and potassium channels. General Physiology and Biophysics 2021;40(5):427-34.
- 5. Barutcigil A, Tasatargil A. Effects of nesfatin-1 on atrial contractility and thoracic aorta reac-tivity in male rats. Clinical and Experimental Hypertension 2018;40(5):414-20.
- 6. 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.
- 7. Wang Z, Yu D, Wang M, Wang Q, Kouznetsova J, Yang R, et al. Elabela-apelin receptor signaling pathway is functional in mammalian systems. Scientific Reports 2015;5:8170.
- 8. Zhu L, Zhang Y, Guo Z, Wang M. Cardiovascular Biology of Prostanoids and Drug Disco-very. Arteriosclerosis, Thrombosis, and Vascular Biology 2020;40;1454–63.
- 9. Koller A, Kaley G. Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation. Circulation Research 1990;67:529–34.
- 10. Corriu C, Félétou M, Canet E, Vanhoutte PM. Endothelium-derived factors and hyperpola-risations of the isolated carotid artery of the guinea-pig. British Journal of Pharmacology 1996;119:959–64.
- 11. Zygmunt PM, Plane F, Paulsson M, Garland CJ, Högestätt ED. Interactions between en-dothelium-derived relaxing factors in the rat hepatic artery: focus on regulation of EDHF. Bri-tish Journal of Pharmacology 1998;124:992–1000.
- 12. Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. British Journal of Pharmacology 2011;164(3):894-912.
- 13. Gutterman DD, Chabowski DS, Kadlec AO, Durand MJ, Freed JK, Ait-Aissa K, Beyer AM. The human microcirculation: regulation of flow and beyond. Circulation Research 2016;118: 157–72.
- 14. Gwóźdź P, Drelicharz L, Kozlovski VI, Chlopicki S. Prostacyclin, but not nitric oxide, is the major mediator of acetylcholine-induced vasodilatation in the isolated mouse heart. Pharma-cological Reports 2007;59:545–52.
- 15. Corriu C, Félétou M, Edwards G, Weston AH, Vanhoutte PM. Differential effects of Pros-tacyclin and Iloprost in the isolated carotid artery of the guinea-pig. European Journal of Phar-macology 2001;426:89–94.
- 16. Félétou M, Vanhoutte PM. Endothelium-dependent hyperpolarizations: past beliefs and pre-sent facts. Annals of Medicine 2007;39:495–516.
- 17. Wong SL, Leung FP, Lau CW, Au CL, Yung LM, Yao X, et al. Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging. Circulation Research 2009;104:228–35.
- 18. Smith JB, Araki H, Lefer AM. Thromboxane A2, prostacyclin and aspirin: effects on vas-cular tone and platelet aggregation. Circulation 1980;62(6 pt 2):(V19–V25).
- 19. Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predo-minant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disea-se. Hypertension 2009;54(3):598–604.
- 20. Salcedo A, Garijo J, Monge L, Fernández N, García-Villalón AL, Turrión VS, et al. Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids. Regulatory Peptides 2007;144:50–5.
- 21. Verma T, Sinha M, Bansal N, Yadav SR, Shah K, Chauhan NS. Plants Used as Antihyper-tensive. Natural Products and Bioprospecting 2021;11(2):155-84.
- 22. Ewart MA, Kennedy S. AMPK and vasculoprotection. Pharmacology & Therapeutics 2011;131:242-53.
- 23. Salt IP, Hardie DG. AMPK, AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the Cardiovascular System. Circulation Research 2017;120(11): 1825-41.
- 24. Ford RJ, Teschke SR, Reid EB, Durham KK, Kroetsch JT, Rush JW. AMP-activated pro-tein kinase activator AICAR acutely lowers blood pressure and relaxes isolated resistance arte-ries of hypertensive rats. Journal of Hypertension 2012;30,725-33.
- 25. Goirand F, Solar M, Athea Y, Viollet B, Mateo P, Fortin D, et al. Activation of AMP kina-se alpha1 subunit induces aortic vasorelaxation in mice. The Journal of Physiology 2007;581:1163-71.
- 26. Buhl ES, Jessen N, Pold R, Ledet T, Flyvbjerg A, Pedersen SB, et al. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying fea-tures of the insulin resistance syndrome. Diabetes 2002;51:2199–206.
- 27. Schneider H, Schubert KM, Blodow S, Kreutz CP, Erdogmus S, Wiedenmann M, et al. AMPK dilates resistance arteries via activation of SERCA and BKCa channels in smooth musc-le. Hypertension 2015;66:108–16.
- 28. Banes A, Florian JA, Watts SW. Mechanisms of 5-hydroxytryptamine2A receptor activa-tion of the mitogen-activated protein kinase pathway in vascular smooth muscle. Journal of Pharmacology and Experimental Therapeutics 1999;291(3):1179–87.
- 29. Roberts RE. Role of the extracellular signal-regulated kinase (ERK) signal transduction cas-cade in α2-adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein. British Journal of Pharmacology 2001;133(6):859–66.
- 30. Oeckler RA, Kaminski PM, Wolin MS. Stretch enhances contraction of bovine coronary arteries via an NADPH oxidase-mediated activation of the extracellular signal-regulated mito-gen-activated protein kinase cascade. Circulation Research 2003;92(1):23–31.
- 31. Dessy C, Kim I, Sougnez CL, Laporte R, Morgan KG. A role for MAP kinase in differenti-ated smooth muscle contraction evoked by α-adrenoceptor stimulation. American Journal of Physiology 1998;275(4 Pt 1):C1081–C1086.
- 32. Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA. Regulation of cell motility by mitogen-activated protein kinase. Journal of Cell Biology 1997;137(2):481–92.
- 33. Roberts RE. The role of Rho kinase and extracellular regulated kinase-mitogen-activated protein kinase in α2-adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein. Journal of Pharmacology and Experimental Therapeutics 2004;311(2):742–7.
- 34. Demirel S, Sahinturk S, Isbil N, Ozyener F. Irisin relaxes rat thoracic aorta: MEK1/2 signa-ling pathway, KV channels, SKCa channels, and BKCa channels are involved in irisin-induced vasodilation. Canadian Journal of Physiology and Pharmacology 2021; doi: 10.1139/cjpp-2021-0500.
- 35. Perjés Á, Kilpiö T, Ulvila J, Magga J, Alakoski T, Szabó Z, et al. Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart. Basic Research in Cardiology 2016;111:2.
- 36. Isbil N, Sahinturk S, Demirel S. Vascular Functional Effects of the Apelinergic System. Journal of Literature Pharmacy Sciences 2021;10(1):12-20.
- 37. Rikitake Y. The apelin/APJ system in the regulation of vascular tone: friend or foe?. The Journal of Biochemistry 2020;0(0):1–4.
- 38. Mughal A, O'Rourke ST. Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacology & Therapeutics 2018;190:139-47.
- 39. Yang P, Read C, Kuc RE, Buonincontri G, Southwood M, Torella R., et al. Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expres-sion in Pulmonary Arterial Hypertension. Circulation 2017;135(12):1160-73.
- 40. Jackson WF. Ion Channels and Vascular Tone. Hypertension 2000;35(1 Pt 2):173-8.
- 41. Tykocki NR, Boerman EM, Jackson WF. Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Comprehensive Physiology 2017;7(2):485–581.
- 42. Ganitkevich VY, Isenberg G. Membrane potential modulates inositol 1,4,5-trisphosphate-mediated Ca2+ transients in guinea-pig coronary myocytes. The Journal of Physiology 1993;470:35–44.
- 43. Okada Y, Yanagisawa T, Taira N. BRL 38227 (levcromakalim)-induced hyperpolarization reduces the sensitivity to Ca2+ of contractile elements in canine coronary artery. Naunyn-Schmiedeberg's Archives of Pharmacology 1993;347:438–44.
- 44. Demirel S, Sahinturk S, Isbil N, Ozyener F. Physiological role of K+ channels in irisin-induced vasodilation in rat thoracic aorta. Peptides 2022;147:170685.
Investigation of Mechanisms Involved in the Regulation of Basal Vascular Tone in a Rat Thoracic Aortic Model
Yıl 2021,
, 423 - 430, 01.12.2021
Serdar Şahintürk
,
Naciye İşbil
Öz
In this study, it was aimed to determine the effect of endothelial nitric oxide synthase (eNOS)/nitric oxide (NO), cyclooxygenase (COX), AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and apelin receptor (APJ) signal-transducing pathways and potassium channels on vascular tone. 4 mm vascular rings obtained from the thoracic aorta of Wistar Albino male rats were placed in the isolated organ bath system. Vascular tension was adjusted to 1 gram. To determine the effects of signal-transducing pathways and potassium channels on basal vessel tone, inhibitors were administered after a 1-hour equilibration period. The tension values in the periods before and after the inhibitor application were recorded. Nω-Nitro-L-arginine methyl ester and tetraethylammonium administrations caused a statistically significant increase in basal vascular tension values (in order: p < 0.001; p < 0.05). Indomethacin and dorsomorphin administrations caused a statistically significant decrease in basal vascular tension values (p < 0.05). F13A and U0126 administrations didn’t cause a statistically significant change in basal vascular tension values. The data of this study show that eNOS/NO, COX, and AMPK signal-transducing pathways and potassium channels have significant effects on the regulation of basal vascular tone. On the other hand, it is thought that MAPK and APJ signaling pathways aren’t important factors in the regulation of basal vascular tone in the rat thoracic aorta.
Kaynakça
- 1. Barrett KE, Barman SM, Boitano S, Brooks HL, (eds.). Ganong’un Tıbbi Fizyolojisi. 24. baskı. İstanbul: Nobel Tıp Kitabevleri; 2015.
- 2. Hall JE, (ed.). Guyton ve Hall Tıbbi Fizyoloji. 13. Baskı. Ankara: Güneş Tıp Kitabevleri; 2017.
- 3. Zhao Y, Vanhoutte PM, Leung SWS. Vascular nitric oxide: Beyond eNOS. Journal of Pharmacological Sciences 2015;129(2):83-94.
- 4. Sahinturk S, Demirel S, Ozyener F, Isbil N. [Pyr1]apelin-13 relaxes the rat thoracic aorta via APJ, NO, AMPK, and potassium channels. General Physiology and Biophysics 2021;40(5):427-34.
- 5. Barutcigil A, Tasatargil A. Effects of nesfatin-1 on atrial contractility and thoracic aorta reac-tivity in male rats. Clinical and Experimental Hypertension 2018;40(5):414-20.
- 6. 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.
- 7. Wang Z, Yu D, Wang M, Wang Q, Kouznetsova J, Yang R, et al. Elabela-apelin receptor signaling pathway is functional in mammalian systems. Scientific Reports 2015;5:8170.
- 8. Zhu L, Zhang Y, Guo Z, Wang M. Cardiovascular Biology of Prostanoids and Drug Disco-very. Arteriosclerosis, Thrombosis, and Vascular Biology 2020;40;1454–63.
- 9. Koller A, Kaley G. Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation. Circulation Research 1990;67:529–34.
- 10. Corriu C, Félétou M, Canet E, Vanhoutte PM. Endothelium-derived factors and hyperpola-risations of the isolated carotid artery of the guinea-pig. British Journal of Pharmacology 1996;119:959–64.
- 11. Zygmunt PM, Plane F, Paulsson M, Garland CJ, Högestätt ED. Interactions between en-dothelium-derived relaxing factors in the rat hepatic artery: focus on regulation of EDHF. Bri-tish Journal of Pharmacology 1998;124:992–1000.
- 12. Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. British Journal of Pharmacology 2011;164(3):894-912.
- 13. Gutterman DD, Chabowski DS, Kadlec AO, Durand MJ, Freed JK, Ait-Aissa K, Beyer AM. The human microcirculation: regulation of flow and beyond. Circulation Research 2016;118: 157–72.
- 14. Gwóźdź P, Drelicharz L, Kozlovski VI, Chlopicki S. Prostacyclin, but not nitric oxide, is the major mediator of acetylcholine-induced vasodilatation in the isolated mouse heart. Pharma-cological Reports 2007;59:545–52.
- 15. Corriu C, Félétou M, Edwards G, Weston AH, Vanhoutte PM. Differential effects of Pros-tacyclin and Iloprost in the isolated carotid artery of the guinea-pig. European Journal of Phar-macology 2001;426:89–94.
- 16. Félétou M, Vanhoutte PM. Endothelium-dependent hyperpolarizations: past beliefs and pre-sent facts. Annals of Medicine 2007;39:495–516.
- 17. Wong SL, Leung FP, Lau CW, Au CL, Yung LM, Yao X, et al. Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging. Circulation Research 2009;104:228–35.
- 18. Smith JB, Araki H, Lefer AM. Thromboxane A2, prostacyclin and aspirin: effects on vas-cular tone and platelet aggregation. Circulation 1980;62(6 pt 2):(V19–V25).
- 19. Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predo-minant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disea-se. Hypertension 2009;54(3):598–604.
- 20. Salcedo A, Garijo J, Monge L, Fernández N, García-Villalón AL, Turrión VS, et al. Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids. Regulatory Peptides 2007;144:50–5.
- 21. Verma T, Sinha M, Bansal N, Yadav SR, Shah K, Chauhan NS. Plants Used as Antihyper-tensive. Natural Products and Bioprospecting 2021;11(2):155-84.
- 22. Ewart MA, Kennedy S. AMPK and vasculoprotection. Pharmacology & Therapeutics 2011;131:242-53.
- 23. Salt IP, Hardie DG. AMPK, AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the Cardiovascular System. Circulation Research 2017;120(11): 1825-41.
- 24. Ford RJ, Teschke SR, Reid EB, Durham KK, Kroetsch JT, Rush JW. AMP-activated pro-tein kinase activator AICAR acutely lowers blood pressure and relaxes isolated resistance arte-ries of hypertensive rats. Journal of Hypertension 2012;30,725-33.
- 25. Goirand F, Solar M, Athea Y, Viollet B, Mateo P, Fortin D, et al. Activation of AMP kina-se alpha1 subunit induces aortic vasorelaxation in mice. The Journal of Physiology 2007;581:1163-71.
- 26. Buhl ES, Jessen N, Pold R, Ledet T, Flyvbjerg A, Pedersen SB, et al. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying fea-tures of the insulin resistance syndrome. Diabetes 2002;51:2199–206.
- 27. Schneider H, Schubert KM, Blodow S, Kreutz CP, Erdogmus S, Wiedenmann M, et al. AMPK dilates resistance arteries via activation of SERCA and BKCa channels in smooth musc-le. Hypertension 2015;66:108–16.
- 28. Banes A, Florian JA, Watts SW. Mechanisms of 5-hydroxytryptamine2A receptor activa-tion of the mitogen-activated protein kinase pathway in vascular smooth muscle. Journal of Pharmacology and Experimental Therapeutics 1999;291(3):1179–87.
- 29. Roberts RE. Role of the extracellular signal-regulated kinase (ERK) signal transduction cas-cade in α2-adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein. British Journal of Pharmacology 2001;133(6):859–66.
- 30. Oeckler RA, Kaminski PM, Wolin MS. Stretch enhances contraction of bovine coronary arteries via an NADPH oxidase-mediated activation of the extracellular signal-regulated mito-gen-activated protein kinase cascade. Circulation Research 2003;92(1):23–31.
- 31. Dessy C, Kim I, Sougnez CL, Laporte R, Morgan KG. A role for MAP kinase in differenti-ated smooth muscle contraction evoked by α-adrenoceptor stimulation. American Journal of Physiology 1998;275(4 Pt 1):C1081–C1086.
- 32. Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA. Regulation of cell motility by mitogen-activated protein kinase. Journal of Cell Biology 1997;137(2):481–92.
- 33. Roberts RE. The role of Rho kinase and extracellular regulated kinase-mitogen-activated protein kinase in α2-adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein. Journal of Pharmacology and Experimental Therapeutics 2004;311(2):742–7.
- 34. Demirel S, Sahinturk S, Isbil N, Ozyener F. Irisin relaxes rat thoracic aorta: MEK1/2 signa-ling pathway, KV channels, SKCa channels, and BKCa channels are involved in irisin-induced vasodilation. Canadian Journal of Physiology and Pharmacology 2021; doi: 10.1139/cjpp-2021-0500.
- 35. Perjés Á, Kilpiö T, Ulvila J, Magga J, Alakoski T, Szabó Z, et al. Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart. Basic Research in Cardiology 2016;111:2.
- 36. Isbil N, Sahinturk S, Demirel S. Vascular Functional Effects of the Apelinergic System. Journal of Literature Pharmacy Sciences 2021;10(1):12-20.
- 37. Rikitake Y. The apelin/APJ system in the regulation of vascular tone: friend or foe?. The Journal of Biochemistry 2020;0(0):1–4.
- 38. Mughal A, O'Rourke ST. Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacology & Therapeutics 2018;190:139-47.
- 39. Yang P, Read C, Kuc RE, Buonincontri G, Southwood M, Torella R., et al. Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expres-sion in Pulmonary Arterial Hypertension. Circulation 2017;135(12):1160-73.
- 40. Jackson WF. Ion Channels and Vascular Tone. Hypertension 2000;35(1 Pt 2):173-8.
- 41. Tykocki NR, Boerman EM, Jackson WF. Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Comprehensive Physiology 2017;7(2):485–581.
- 42. Ganitkevich VY, Isenberg G. Membrane potential modulates inositol 1,4,5-trisphosphate-mediated Ca2+ transients in guinea-pig coronary myocytes. The Journal of Physiology 1993;470:35–44.
- 43. Okada Y, Yanagisawa T, Taira N. BRL 38227 (levcromakalim)-induced hyperpolarization reduces the sensitivity to Ca2+ of contractile elements in canine coronary artery. Naunyn-Schmiedeberg's Archives of Pharmacology 1993;347:438–44.
- 44. Demirel S, Sahinturk S, Isbil N, Ozyener F. Physiological role of K+ channels in irisin-induced vasodilation in rat thoracic aorta. Peptides 2022;147:170685.