Journal of Chest Surgery

The Korean Society for Thoracic and Cardiovascular Surgery (대한심장혈관흉부외과학회)
권호 표지

The Change of Vascular Reactivity in Rat Thoracic Aorta 3 Days after Acute Myocardial Infarction

흰쥐에서 급성심근경색 3일 후 흉부 대동맥 혈관 반응성의 변화

  • Lee, Sub (Department of Thoracic and Cardiovascular Surgery, Daegu Catholic University Medical Center) ;
  • Roh, Woon-Seok (Department of Anesthesiology and Pain Medicine, School of Medicine, Catholic University of Daegu) ;
  • Jang, Jae-Seok (Department of Thoracic and Cardiovascular Surgery, Daegu Catholic University Medical Center) ;
  • Bae, Chi-Hoon (Department of Thoracic and Cardiovascular Surgery, Daegu Catholic University Medical Center) ;
  • Park, Ki-Sung (Department of Thoracic and Cardiovascular Surgery, Daegu Catholic University Medical Center) ;
  • Lee, Jong-Tae (Department of Thoracic and Cardiovascular Surgery, Kyungpook University Hospital)
  • 이섭 (대구가톨릭대학교병원 흉부외과) ;
  • 노운석 (대구가톨릭대학교 의과대학 마취통증의학과교실) ;
  • 장재석 (대구가톨릭대학교병원 흉부외과) ;
  • 배지훈 (대구가톨릭대학교병원 흉부외과) ;
  • 박기성 (대구가톨릭대학교병원 흉부외과) ;
  • 이종태 (경북대학교병원 흉부외과)
  • Published : 2009.10.05
Download PDF
⟨ Previous Next ⟩

Abstract

Background: The up-regulation of the nitric oxide (NO)-cGMP pathway might be involved in the change of vascular reactivity in rats 3 days after they suffer acute myocardial infarction. However, the underlying mechanism for this has not been clarified. Material and Method: Acute myocardial infarction (AMI) was induced by occluding the left anterior descending coronary artery (LAD) for 30 min (Group AMI), whereas the sham-operated control rats were treated similarly without LAD occlusion (Group SHAM), The concentration-response relationships for phenylephrine (PE), KCl, acetylcholine (Ach) and sodium nitroprusside (SNP) were determined in the endothelium intact E(+) and endothelium denuded E(-) thoracic aortic rings from the rats 3 days after AMI or a SHAM operation. The concentration-response relationships of PE in the E(+) rings from the AMI rats were compared with those relationships in the rings pretreated with nitric oxide synthase (NOS) inhibitor $N{\omega}$-nitro-L-arginine methyl ester (L-NAME) or the cyclooxygenase inhibitor indomethacin. The plasma nitrite/nitrate concentrations were checked via a Griess reaction. The cyclic GMP content in the thoracic aortic rings was measured by radioimmunoassay and the endothelial nitric oxide synthase (eNOS) mRNA expression was assessed by real time PCR. Result: The mean infarct size (%) in the rats with AMI was $21.3{\pm}0.62%$. The heart rate and the systolic and diastolic blood pressure were not significantly changed in the AMI rats. The sensitivity of the contractile response to PE and KCl was significantly decreased in both the E(+) and E(-) aortic rings of the AMI group (p<0.05). L-NAME completely reversed these contractile responses whereas indomethacin did not (p<0.05). Moreover, the sensitivity of the relaxation response to Ach was also significantly decreased in the AMI group (p<0.05). The plasma nitrite and nitrate content (p<0.05), the basal cGMP content (p<0.05) and the eNOS mRNA expression (p=0.056) in the AMI rats were increased as compared with the SHAM group. Conclusion: Our findings indicate that the increased eNOS activity and the up-regulation of the NO-cGMP pathway can be attributed to the decreased contractile or relaxation response in the rat thoracic aorta 3 days after AMI.

배경: Nitric oxide (NO)-cGMP 신호전달체계의 상향 조절(up-regulation)이 급성심근경색 3일 후 흰쥐의 혈관반응성의 변화에 관여한다고 알려져 있으나 그 기전에 대해서는 명확히 규명되지 않았다. 대상 및 방법: 좌전하행관상동맥을 30분간 폐쇄한 후 급성심근경색을 유도한 군을 AMI군으로, 동일한 모의 수술(sham operation)을 하였으나 관상동맥을 폐쇄하지 않은 군을 SHAM군으로 하였다 AMI 혹은 SHAM수술 3일 후 흰쥐의 대동맥 고리절편(내피를 보존한 대동맥 절편을 E(+), 내피를 제거한 대동맥 절편을 E(-))에서 phenylephrine (PE), KCl, acetylcholine (Ach) 및 sodium nitroprusside (SNP)에 대한 농도-반응 관계를 측정하였다 AMI군의 E(+) 대동맥 절편에서 PE의 농도-반응 관계를 NO synthase (NOS) 억제제인 $N{\omega}$-nitro-L-arginine methyl ester (L-NAME)와 cyclooxygenase 억제제인 indomethacin으로 각각 전처치한 대동맥 절편과 비교하였다. 혈장 nitrite/nitrate 농도는 Griess reaction으로 측정하였고, 방사면역 분석법을 이용한 흉부 대동맥 절편의 cGMP정량과 real time PCR을 이용한 endothelial nitric oxide synthase (eNOS) mRNA 발현양상 측정을 하였다. 결과: AMI군에서의 심근경색의 평균 크기는 $21.3{\pm}0.62%$였다. AMI군에서 심박수와 수축기 및 이완기 혈압은 의미있는 변화가 없었다. E(+)와 E(-) 대동맥 절편에서 PE와 KCl에 대한 수축반응의 민감도는 AMI군 대동맥 절편에서 의미 있게 감소하였다(p<0.05). L-NAME은 이러한 수축반응을 완전하게 역전시켰으나 indomethacin은 효과가 없었다(p<0.05). 또한 AMI군에서 Ach에 대한 이완반응의 민감도가 의미 있게 감소하였다(p<0.05). AMI군에서 SHAM군에 비해 혈장 nitrite/nitrate 농도(p<0.05), 기저 cGMP 농도(p<0.05), 및 eNOS mRNA 발현양상(p=0.056)이 증가하였다. 결론: 이상의 결과들로 보아 eNOS의 발현 증가와 NO-cGMP 신호전달체계의 상향조절이 급성심근경색 3일 후 흰쥐 흉부대동맥에서의 수축 및 이완 반응성 감소의 원인으로 생각된다.

Keywords

References

  1. Hansen PR. Myocardial reperfusion injury: experimental evidence and clinical relevance. Eur Heart J 1995;16:734-40 https://doi.org/10.1093/oxfordjournals.eurheartj.a060991
  2. Hess ML, Kukreja RC. Myocardial stunning. J Card Surg 1994;9:382-6 https://doi.org/10.1111/jocs.1994.9.3s.382
  3. Jeroudi MO, Hartley CJ, Bolli R. Myocardial reperfusion injury: role of oxygen radicals and potential therapy with antioxidants. Am J Cardiol 1994;73:2B-7B https://doi.org/10.1016/0002-9149(94)90257-7
  4. Zweier JL, Talukder MA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 2006;70:181- 90 https://doi.org/10.1016/j.cardiores.2006.02.025
  5. Kaiser L, Spickard RC, Olivier NB. Heart failure depresses endothelium-dependent responses in canine femoral artery. Am J Physiol 1989;256:H962-7
  6. Ceiler DL, Nelissen-Vrancken M, De Mey JG, Smits JF. Role of basal nitric oxide synthesis in vasoconstrictor hyporeactivity in the perfused rat hindlimb after myocardial infarction: effect of captopril. Cardiovasc Res 1999;43:779-87 https://doi.org/10.1016/S0008-6363(99)00147-9
  7. Valgimigli M, Merli E, Malagutti P, et al. Endothelial dysfunction in acute and chronic coronary syndromes: evidence for a pathogenetic role of oxidative stress. Arch Biochem Biophys 2003;420:255-61 https://doi.org/10.1016/j.abb.2003.07.006
  8. Sartorio CL, Pinto VD, Cutini GJ, Vassallo DV, Stefanon I. Effects of inducible nitric oxide synthase inhibition on the rat tail vascular bed reactivity three days after myocardium infarction. J Cardiovasc Pharmacol 2005;45:321-6 https://doi.org/10.1097/01.fjc.0000156822.58081.be
  9. Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA 1997;94:6954-8 https://doi.org/10.1073/pnas.94.13.6954
  10. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 2003;278:22546-54 https://doi.org/10.1074/jbc.M302227200
  11. Ohashi Y, Kawashima S, Hirata K, et al. Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 1998;102:2061-71 https://doi.org/10.1172/JCI4394
  12. Yamashita T, Kawashima S, Ohashi Y, et al. Mechanisms of reduced nitric oxide/cGMP-mediated vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. Hypertension 2000;36:97-102 https://doi.org/10.1161/01.HYP.36.1.97
  13. Lauer N, Suvorava T, Rüther U, et al. Critical involvement of hydrogen peroxide in exercise-induced up-regulation of endothelial NO synthase. Cardiovasc Res 2005;65:254-62 https://doi.org/10.1016/j.cardiores.2004.09.010
  14. Bauersachs J, Bouloumié A, Fraccarollo D, Hu K, Busse R, Ertl G. Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production. Circulation 1999;100:292-8 https://doi.org/10.1161/01.CIR.100.3.292
  15. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med 1999;341:577-85 https://doi.org/10.1056/NEJM199908193410806
  16. da Cunha V, Stefanon I, Mill JG. Role of nitric oxide in mediating cardiovascular alterations accompanying heart failure in rats. Can J Physiol Pharmacol 2004;82:372-9
  17. Teerlink JR, Clozel M, Fischli W, Clozel JP. Temporal evolution of endothelial dysfunction in a rat model of chronic heart failure. J Am Coll Cardiol 1993;22:615-20 https://doi.org/10.1016/0735-1097(93)90073-A
  18. Pinto VD, Cutini GJ, Sartório CL, Paigel AS, Vassallo DV, Stefanon I. Enhanced beta-adrenergic response in rat papillary muscle by inhibition of inducible nitric oxide synthase after myocardial infarction. Acta Physiol 2007;190:111-7 https://doi.org/10.1111/j.1748-1716.2007.01684.x
  19. Connelly L, Madhani M, Hobbs AJ. Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived no in vivo. J Biol Chem 2005;280:10040-6 https://doi.org/10.1074/jbc.M411991200
  20. Vanhoutte PM, Mombouli JV. Vascular endothelium: vasoactive mediators. Prog Cardiovasc Dis 1996;39:229-38 https://doi.org/10.1016/S0033-0620(96)80003-X
  21. Miller AA, Megson IL, Gray GA. Inducible nitric oxide synthase-derived superoxide contributes to hypereactivity in small mesenteric arteries from a rat model of chronic heart failure. Br J Pharmacol 2000;131:29-36 https://doi.org/10.1038/sj.bjp.0703528
  22. Stassen FR, Willemsen MJ, Janssen GM, DeMey JG. Alpha 1-adrenoceptor subtypes in rat aorta and mesenteric small arteries are preserved during left ventricular dysfunction post-myocardial infarction. Cardiovasc Res 1997;33:706-13 https://doi.org/10.1016/S0008-6363(96)00261-1
  23. da Silva-Santos JE, Terluk MR, Assreuy J. Differential involvement of guanylate cyclase and potassium channels in nitric oxide-induced hyporesponsiveness to phenylephrine in endotoxemic rats. Shock 2002;17:70-6 https://doi.org/10.1097/00024382-200201000-00012
  24. Terluk MR, da Silva-Santos JE, Assreuy J. Involvement of soluble guanylate cyclase and calcium-activated potassium channels in the long-lasting hyporesponsiveness to phenylephrine induced by nitric oxide in rat aorta. Naunyn Schmiedebergs Arch Pharmacol 2000;361:477-83 https://doi.org/10.1007/s002100000216
  25. Bauersachs J, Bouloumié A, Mülsch A, Wiemer G, Fleming I, Busse R. Vasodilator dysfunction in aged spontaneously hypertensive rats: changes in NO synthase III and soluble guanylyl cyclase expression, and in superoxide anion production. Cardiovasc Res 1998;37:772-9 https://doi.org/10.1016/S0008-6363(97)00250-2
  26. Bouloumié A, Bauersachs J, Linz W, et al. Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension 1997;30:934-41 https://doi.org/10.1161/01.HYP.30.4.934
  27. Zhen J, Lu H, Wang XQ, Vaziri ND, Zhou XJ. Upregulation of endothelial and inducible nitric oxide synthase expression by reactive oxygen species. Am J Hypertens 2008;21:28-34 https://doi.org/10.1038/ajh.2007.14
  28. Vaziri ND, Wang XQ. cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase expression by nitric oxide. Hypertension 1999;34:1237-41 https://doi.org/10.1161/01.HYP.34.6.1237