Dokument: Einfluss der lokalen Applikation von Nitroglycerin und Carbachol auf die mitochondriale Funktion des Colons im septischen Rattenmodell
| Titel: | Einfluss der lokalen Applikation von Nitroglycerin und Carbachol auf die mitochondriale Funktion des Colons im septischen Rattenmodell | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=62848 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20230614-143436-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Eitner-Pchalek, Jeanne Christine [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Picker, Olaf [Gutachter] Dr. Heinen, André [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Trotz des medizinischen Fortschrittes der vergangenen Dekade bleibt die Sepsis eine der häufigsten Ursachen für Mortalität im Krankenhaus. Als Hauptursache für die Entwicklung eines septischen Multiorganversagens (MOV) werden Mikrozirku-lationsstörungen und mitochondriale Dysfunktionen, insbesondere im Gastrointesti-naltrakt, angesehen. Systemisch applizierte Substanzen konnten zwar die Sauer-stoffversorgung im Gastrointestinaltrakt verbessern, führten aber häufig zu gravie-renden Nebenwirkungen. Eine erste Untersuchung zeigt, dass die lokale Therapie mit Nitroglycerin, im hämorrhagischen Hundemodell, zu einer verbesserten Oxyge-nierung der Magenschleimhaut führt. In einer in vitro Untersuchung unseres Ar-beitskreises konnte im gesunden Rattenmodell gezeigt werden, dass Nitroglycerin den mitochondrialen Sauerstoffverbrauch vermindert und die Effizienz der oxidati-ven Phosphorylierung in intestinalen Mitochondrien verbessert. Andere in vitro Untersuchungen zeigten außerdem, dass Carbachol die intestinale Barrierefunktion erhalten kann. Ziel dieser Arbeit war es zu untersuchen, ob die lokale Applikation von Nitroglycerin und Carbachol in vivo die mitochondriale Funktion (MF) intesti-naler Zellen während einer abdominellen Sepsis im Rattenmodell beeinflusst. Eine Verbesserung der MF intestinaler Zellen könnte prognostisch sehr günstig sein.
An insgesamt 109 männlichen Wistar-Ratten wurde in randomisierter Reihenfolge entweder eine abdominelle Sepsis mittels einer Colon ascendens stent peritonitis (CASP) - Operation induziert oder eine Sham (sterile Laparotomie) - Operation als Kontrolle durchgeführt. 24 Stunden nach erfolgter CASP- oder Sham - Operation wurde das Colon, entsprechend den Gruppeneinteilungen, mit Nitroglycerin, Carba-chol, der Kombination beider Medikamente oder der Trägersubstanz Natriumchlo-rid (NaCl) behandelt. Im Anschluss wurde Colongewebe entnommen und für die respirometrische Messung aufbereitet. Die Quantifizierung der MF erfolgte über die kontinuierliche Messung der Sauerstoffkonzentration und des Sauerstoffver-brauchs in der Messprobe. Aus diesen Werten wurden anschließend respiratorische Atmungsquotienten ermittelt. Die statistische Datenanalyse wurde mittels Kruskal-Wallis und Dunn’s Korrektur durchgeführt und die Ergebnisse als Mittelwert ± Standardabweichung dargestellt. Als statistisch signifikant wurde p<0,05 betrachtet. Die Parameter der MF im Colon blieben in allen behandelten Gruppen unverändert gegenüber der Kontrolle sowohl nach CASP- als auch nach Sham-Operation. Folg-lich veränderte die lokale Applikation von Nitroglycerin und Carbachol die MF weder unter septischen noch unter nicht septischen Bedingungen.Despite medical advances in the past decade, sepsis remains one of the most com-mon causes of in-hospital mortality. Microcirculatory and mitochondrial dysfunc-tion, particularly in the gastrointestinal tract, are considered to be the main causes of septic multiorgan failure. Systemically applied agents could improve oxygena-tion in the gastrointestinal tract, but often result in serious side effects. A first study shows that local therapy with nitroglycerin leads to improved oxygenation of the gastric mucosa in a hemorrhagic dog model. In an in vitro study by our group, ni-troglycerin was shown to decrease mitochondrial oxygen consumption and to im-prove the efficiency of oxidative phosphorylation in intestinal mitochondria in a healthy rat model. Other in vitro studies also showed that carbachol can preserve barrier function. The aim of this work was to investigate whether local application of nitroglycerin and carbachol in vivo affects mitochondrial function (MF) of intes-tinal cells during abdominal sepsis in a rat model. Improvement in MF of intestinal cells could be highly beneficial in new therapeutic approaches. A total of 109 male Wistar rats were randomized to undergo either abdominal sep-sis induced by a colon ascendens stent peritonitis- (CASP) surgery or sham- sur-gery (sterile laparotomy) as a control. Twenty-four hours after CASP or Sham sur-gery, the colon was treated with nitroglycerin, carbachol, a combination of both drugs, or solely the carrier substance of nitroglycerin (NaCl) according to the group classification. Colon tissue was then collected and processed for respirometric measurement. MF was quantified by continuous measurement of oxygen concentra-tion and oxygen consumption in the sample. Respiratory quotients were then calcu-lated from these values. Statistical data analysis was performed using Kruskal-Wallis and Dunn's correction, and results were presented as mean ± standard devia-tion. P<0.05 was considered to be statistically significant. The parameters of MF in the colon remained unchanged in all treated groups com-pared to the control group after both Sham and CASP surgery. Consequently, local application of nitroglycerin and carbachol did not alter MF under either physiologi-cal or septic conditions. | |||||||
| Quelle: | 1. Fleischmann C, Thomas-Rueddel DO, Hartmann M, Hartog CS, Welte T, Heublein S, et al. Hospital Incidence and Mortality Rates of Sepsis. Dtsch Arztebl Int. 2016;113(10):159-166.
2. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259-272. 3. Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40(3):754-761. 4. Eissa D, Carton EG, Buggy DJ. Anaesthetic management of patients with severe sepsis. Br J Anaesth. 2010;105(6):734-743. 5. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167-1174. 6. Prescott HC, Angus DC. Enhancing Recovery From Sepsis: A Review. JAMA. 2018;319(1):62-75. 7. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794. 8. Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE. Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med. 2010;38(5):1276-1283. 9. Schmidt KF, Schwarzkopf D, Baldwin LM, Brunkhorst FM, Freytag A, Heintze C, et al. Long-Term Courses of Sepsis Survivors: Effects of a Primary Care Management Intervention. Am J Med. 2020;133(3):381-385 e385. 10. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. 11. Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med. 2007;35(10):2408-2416. 12. Grip J, Jakobsson T, Tardif N, Rooyackers O. The effect of plasma from septic ICU patients on healthy rat muscle mitochondria. Intensive Care Med Exp. 2016;4(1):20. 13. Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004;32(9):1825-1831. 14. Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9 Suppl 4:S13-19. 15. De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, et al. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med. 2013;41(3):791-799. 16. De Backer D, Orbegozo Cortes D, Donadello K, Vincent JL. Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence. 2014;5(1):73-79. 17. Lipinska-Gediga M. Sepsis and septic shock-is a microcirculation a main player? Anaesthesiol Intensive Ther. 2016;48(4):261-265. 18. Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial Responses in Sepsis. Am J Respir Crit Care Med. 2020;202(3):361-370. 19. Vallet B, Wiel E. Endothelial cell dysfunction and coagulation. Crit Care Med. 2001;29(7 Suppl):S36-41. 20. Dhillon SS, Mahadevan K, Bandi V, Zheng Z, Smith CW, Rumbaut RE. Neutrophils, nitric oxide, and microvascular permeability in severe sepsis. Chest. 2005;128(3):1706-1712. 21. Buwalda M, Ince C. Opening the microcirculation: can vasodilators be useful in sepsis? Intensive Care Med. 2002;28(9):1208-1217. 22. Hotchkiss RS, Tinsley KW, Swanson PE, Karl IE. Endothelial cell apoptosis in sepsis. Crit Care Med. 2002;30(5 Suppl):S225-228. 23. Garrabou G, Moren C, Lopez S, Tobias E, Cardellach F, Miro O, et al. The effects of sepsis on mitochondria. J Infect Dis. 2012;205(3):392-400. 24. Galley HF. Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth. 2011;107(1):57-64. 25. Balestra GM, Legrand M, Ince C. Microcirculation and mitochondria in sepsis: getting out of breath. Curr Opin Anaesthesiol. 2009;22(2):184-190. 26. Jeger V, Djafarzadeh S, Jakob SM, Takala J. Mitochondrial function in sepsis. Eur J Clin Invest. 2013;43(5):532-542. 27. Elbers PW, Ince C. Mechanisms of critical illness--classifying microcirculatory flow abnormalities in distributive shock. Crit Care. 2006;10(4):221. 28. Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care. 2002;6(6):491-499. 29. Rosser DM, Manji M, Cooksley H, Bellingan G. Endotoxin reduces maximal oxygen consumption in hepatocytes independent of any hypoxic insult. Intensive Care Med. 1998;24(7):725-729. 30. King CJ, Tytgat S, Delude RL, Fink MP. Ileal mucosal oxygen consumption is decreased in endotoxemic rats but is restored toward normal by treatment with aminoguanidine. Crit Care Med. 1999;27(11):2518-2524. 31. Boekstegers P, Weidenhofer S, Kapsner T, Werdan K. Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med. 1994;22(4):640-650. 32. Takeyama N, Itoh Y, Kitazawa Y, Tanaka T. Altered hepatic mitochondrial fatty acid oxidation and ketogenesis in endotoxic rats. Am J Physiol. 1990;259(4 Pt 1):E498-505. 33. Kantrow SP, Taylor DE, Carraway MS, Piantadosi CA. Oxidative metabolism in rat hepatocytes and mitochondria during sepsis. Arch Biochem Biophys. 1997;345(2):278-288. 34. Kozlov AV, Staniek K, Haindl S, Piskernik C, Ohlinger W, Gille L, et al. Different effects of endotoxic shock on the respiratory function of liver and heart mitochondria in rats. Am J Physiol Gastrointest Liver Physiol. 2006;290(3):G543-549. 35. Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol. 2004;286(3):R491-497. 36. Larche J, Lancel S, Hassoun SM, Favory R, Decoster B, Marchetti P, et al. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol. 2006;48(2):377-385. 37. Nin N, Cassina A, Boggia J, Alfonso E, Botti H, Peluffo G, et al. Septic diaphragmatic dysfunction is prevented by Mn(III)porphyrin therapy and inducible nitric oxide synthase inhibition. Intensive Care Med. 2004;30(12):2271-2278. 38. Geller ER, Jankauskas S, Kirkpatrick J. Mitochondrial death in sepsis: a failed concept. J Surg Res. 1986;40(5):514-517. 39. Mittal A, Hickey AJ, Chai CC, Loveday BP, Thompson N, Dare A, et al. Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis. HPB (Oxford). 2011;13(5):332-341. 40. Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004;364(9433):545-548. 41. Herminghaus A, Papenbrock H, Eberhardt R, Vollmer C, Truse R, Schulz J, et al. Time-related changes in hepatic and colonic mitochondrial oxygen consumption after abdominal infection in rats. Intensive Care Med Exp. 2019;7(1):4. 42. Correa TD, Vuda M, Blaser AR, Takala J, Djafarzadeh S, Dunser MW, et al. Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis. Crit Care Med. 2012;40(10):2841-2849. 43. Regueira T, Djafarzadeh S, Brandt S, Gorrasi J, Borotto E, Porta F, et al. Oxygen transport and mitochondrial function in porcine septic shock, cardiogenic shock, and hypoxaemia. Acta Anaesthesiol Scand. 2012;56(7):846-859. 44. Spronk PE, Zandstra DF, Ince C. Bench-to-bedside review: sepsis is a disease of the microcirculation. Crit Care. 2004;8(6):462-468. 45. Vollmer C, Weber APM, Wallenfang M, Hoffmann T, Mettler-Altmann T, Truse R, et al. Melatonin pretreatment improves gastric mucosal blood flow and maintains intestinal barrier function during hemorrhagic shock in dogs. Microcirculation. 2017;24(4). 46. Truse R, Hinterberg J, Schulz J, Herminghaus A, Weber A, Mettler-Altmann T, et al. Effect of Topical Iloprost and Nitroglycerin on Gastric Microcirculation and Barrier Function during Hemorrhagic Shock in Dogs. J Vasc Res. 2017;54(2):109-121. 47. Russell DH, Barreto JC, Klemm K, Miller TA. Hemorrhagic shock increases gut macromolecular permeability in the rat. Shock. 1995;4(1):50-55. 48. Haussner F, Chakraborty S, Halbgebauer R, Huber-Lang M. Challenge to the Intestinal Mucosa During Sepsis. Front Immunol. 2019;10:891. 49. Trzeciak S, McCoy JV, Phillip Dellinger R, Arnold RC, Rizzuto M, Abate NL, et al. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med. 2008;34(12):2210-2217. 50. Schwarte LA, Schwartges I, Scheeren TWL, Schober P, Picker O. The differential effects of recombinant brain natriuretic peptide, nitroglycerine and dihydralazine on systemic oxygen delivery and gastric mucosal microvascular oxygenation in dogs. Anaesthesia. 2012;67(5):501-507. 51. Ewert R, Glaser S, Bollmann T, Schaper C. Inhaled iloprost for therapy in pulmonary arterial hypertension. Expert Rev Respir Med. 2011;5(2):145-152. 52. Cihan AO, Bicakci U, Tander B, Rizalar R, Kandemir B, Ariturk E, et al. Effects of intraperitoneal nitroglycerin on the strength and healing attitude of anastomosis of rat intestines with ischemia-reperfusion injury. Afr J Paediatr Surg. 2011;8(2):206-210. 53. Khanna, Khanna A, Rossman J, Caty M, Fung H-L. Beneficial effects of intraluminal nitroglycerin in intestinal ischemia-reperfusion injury in rats. The Journal of surgical research. 2003;114(1):15-24. 54. Herminghaus A, Eberhardt R, Truse R, Schulz J, Bauer I, Picker O, et al. Nitroglycerin and Iloprost Improve Mitochondrial Function in Colon Homogenate Without Altering the Barrier Integrity of Caco-2 Monolayers. Front Med (Lausanne). 2018;5:291. 55. Alican I, Kubes P. A critical role for nitric oxide in intestinal barrier function and dysfunction. Am J Physiol. 1996;270(2 Pt 1):G225-237. 56. Kubes P. Nitric oxide modulates epithelial permeability in the feline small intestine. Am J Physiol. 1992;262(6 Pt 1):G1138-1142. 57. Takizawa Y, Kishimoto H, Kitazato T, Tomita M, Hayashi M. Effects of nitric oxide on mucosal barrier dysfunction during early phase of intestinal ischemia/reperfusion. Eur J Pharm Sci. 2011;42(3):246-252. 58. Wu LL, Chiu HD, Peng WH, Lin BR, Lu KS, Lu YZ, et al. Epithelial inducible nitric oxide synthase causes bacterial translocation by impairment of enterocytic tight junctions via intracellular signals of Rho-associated kinase and protein kinase C zeta. Crit Care Med. 2011;39(9):2087-2098. 59. Hu S, Che JW, Tian YJ, Sheng ZY. Carbachol promotes gastrointestinal function during oral resuscitation of burn shock. World J Gastroenterol. 2011;17(13):1746-1752. 60. Bao C, Hu S, Zhou G, Tian Y, Wu Y, Sheng Z. Effect of carbachol on intestinal mucosal blood flow, activity of Na+-K+-ATPase, expression of aquaporin-1, and intestinal absorption rate during enteral resuscitation of burn shock in rats. J Burn Care Res. 2010;31(1):200-206. 61. Lesko S, Wessler I, Gabel G, Petto C, Pfannkuche H. Cholinergic modulation of epithelial integrity in the proximal colon of pigs. Cells Tissues Organs. 2013;197(5):411-420. 62. Khan RI, Yazawa T, Anisuzzaman AS, Semba S, Ma Y, Uwada J, et al. Activation of focal adhesion kinase via M1 muscarinic acetylcholine receptor is required in restitution of intestinal barrier function after epithelial injury. Biochim Biophys Acta. 2014;1842(4):635-645. 63. Traeger T, Koerner P, Kessler W, Cziupka K, Diedrich S, Busemann A, et al. Colon ascendens stent peritonitis (CASP)--a standardized model for polymicrobial abdominal sepsis. J Vis Exp. 2010(46). 64. Lustig MK, Bac VH, Pavlovic D, Maier S, Grundling M, Grisk O, et al. Colon ascendens stent peritonitis--a model of sepsis adopted to the rat: physiological, microcirculatory and laboratory changes. Shock. 2007;28(1):59-64. 65. Zantl N, Uebe A, Neumann B, Wagner H, Siewert JR, Holzmann B, et al. Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis. Infect Immun. 1998;66(5):2300-2309. 66. Schoneborn S, Vollmer C, Barthel F, Herminghaus A, Schulz J, Bauer I, et al. Vasopressin V1A receptors mediate the stabilization of intestinal mucosal oxygenation during hypercapnia in septic rats. Microvasc Res. 2016;106:24-30. 67. Stubs CC, Picker O, Schulz J, Obermiller K, Barthel F, Hahn AM, et al. Acute, short-term hypercapnia improves microvascular oxygenation of the colon in an animal model of sepsis. Microvasc Res. 2013;90:180-186. 68. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-275. 69. Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Mark W, Steurer W, et al. Mitochondrial defects and heterogeneous cytochrome c release after cardiac cold ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2004;286(5):H1633-1641. 70. Herminghaus A, Barthel F, Heinen A, Beck C, Vollmer C, Bauer I, et al. Severity of polymicrobial sepsis modulates mitochondrial function in rat liver. Mitochondrion. 2015;24:122-128. 71. Wichterman KA, Baue AE, Chaudry IH. Sepsis and septic shock--a review of laboratory models and a proposal. J Surg Res. 1980;29(2):189-201. 72. Maier S, Traeger T, Entleutner M, Westerholt A, Kleist B, Huser N, et al. Cecal ligation and puncture versus colon ascendens stent peritonitis: two distinct animal models for polymicrobial sepsis. Shock. 2004;21(6):505-511. 73. Parker SJ, Watkins PE. Experimental models of gram-negative sepsis. Br J Surg. 2001;88(1):22-30. 74. Ait-Oufella H, Maury E, Lehoux S, Guidet B, Offenstadt G. The endothelium: physiological functions and role in microcirculatory failure during severe sepsis. Intensive Care Med. 2010;36(8):1286-1298. 75. Pecinova A, Drahota Z, Nuskova H, Pecina P, Houstek J. Evaluation of basic mitochondrial functions using rat tissue homogenates. Mitochondrion. 2011;11(5):722-728. 76. Colgan SP, Campbell EL, Kominsky DJ. Hypoxia and Mucosal Inflammation. Annu Rev Pathol. 2016;11:77-100. 77. Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev. 1997;77(3):731-758. 78. Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest. 2004;114(8):1098-1106. 79. Carre JE, Singer M. Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta. 2008;1777(7-8):763-771. 80. Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011;435(2):297-312. 81. Sadio A, Amaral AL, Nunes R, Ricardo S, Sarmento B, Almeida R, et al. A Mouse Intra-Intestinal Infusion Model and its Application to the Study of Nanoparticle Distribution. Front Physiol. 2016;7:579. 82. Yang L. Biorelevant dissolution testing of colon-specific delivery systems activated by colonic microflora. J Control Release. 2008;125(2):77-86. 83. Sutton SC, Evans LA, Fortner JH, McCarthy JM, Sweeney K. Dog colonoscopy model for predicting human colon absorption. Pharm Res. 2006;23(7):1554-1563. 84. Sousa T, Paterson R, Moore V, Carlsson A, Abrahamsson B, Basit AW. The gastrointestinal microbiota as a site for the biotransformation of drugs. Int J Pharm. 2008;363(1-2):1-25. 85. Sousa T, Yadav V, Zann V, Borde A, Abrahamsson B, Basit AW. On the colonic bacterial metabolism of azo-bonded prodrugsof 5-aminosalicylic acid. J Pharm Sci. 2014;103(10):3171-3175. 86. Gericke A, Sniatecki JJ, Goloborodko E, Steege A, Zavaritskaya O, Vetter JM, et al. Identification of the muscarinic acetylcholine receptor subtype mediating cholinergic vasodilation in murine retinal arterioles. Invest Ophthalmol Vis Sci. 2011;52(10):7479-7484. 87. Tangsucharit P, Takatori S, Zamami Y, Goda M, Pakdeechote P, Kawasaki H, et al. Muscarinic acetylcholine receptor M1 and M3 subtypes mediate acetylcholine-induced endothelium-independent vasodilatation in rat mesenteric arteries. J Pharmacol Sci. 2016;130(1):24-32. 88. Takenaga M, Kawasaki H, Wada A, Eto T. Calcitonin gene-related peptide mediates acetylcholine-induced endothelium-independent vasodilation in mesenteric resistance blood vessels of the rat. Circ Res. 1995;76(6):935-941. 89. Vasquez-Vivar J, Martasek P, Whitsett J, Joseph J, Kalyanaraman B. The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. Biochem J. 2002;362(Pt 3):733-739. 90. Wang WZ, Fang XH, Stephenson LL, Khiabani KT, Zamboni WA. Effects of supplementation of BH4 after prolonged ischemia in skeletal muscle. Microsurgery. 2007;27(3):200-205. 91. Maglione M, Hermann M, Hengster P, Schneeberger S, Mark W, Obrist P, et al. Tetrahydrobiopterin attenuates microvascular reperfusion injury following murine pancreas transplantation. Am J Transplant. 2006;6(7):1551-1559. 92. Tyml K, Li F, Wilson JX. Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med. 2008;36(8):2355-2362. 93. Fitzal F, Redl H, Strohmaier W, Werner ER, Bahrami S. A 4-amino analogue of tetrahydrobiopterin attenuates endotoxin-induced hemodynamic alterations and organ injury in rats. Shock. 2002;18(2):158-162. 94. Secor D, Li F, Ellis CG, Sharpe MD, Gross PL, Wilson JX, et al. Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries. Intensive Care Med. 2010;36(11):1928-1934. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 14.06.2023 | |||||||
| Dateien geändert am: | 14.06.2023 | |||||||
| Promotionsantrag am: | 16.07.2018 | |||||||
| Datum der Promotion: | 11.05.2023 |
