Sandmann Steffen, Kaschina Elena, Blume Annegret, Kruse Marie Luise, Unger Thomas
Institute of Pharmacology, University of Kiel, Hospitalstrasse 4, 24105, Kiel, Germany.
Eur J Pharmacol. 2003 Jan 1;458(1-2):3-16. doi: 10.1016/s0014-2999(02)02656-0.
Bradykinin B(1) and B(2) receptors are up-regulated in the infarcted myocardium, and both receptors are involved in the regulation of intracellular pH and Ca(2+). The present study investigated the role of bradykinin B(1) and B(2) receptors in the regulation of Na(+)-H(+) exchanger (NHE-1), Na(+)-Ca(2+) exchanger (NCE-1) and Na(+)-HCO(3)(-) symporter (NBC-1) in the infarcted myocardium. NHE-1, NCE-1 and NBC-1 mRNA expression was determined by Northern blot analysis and the protein levels by Western blot analysis. Measurements were performed 1, 7 and 14 days after induction of myocardial infarction. Localization of NHE-1, NCE-1 and NBC-1 within the myocardium was studied using confocal microscopy. Cardiac morphology was measured in picrosiris-red-stained hearts. Rats were treated with placebo, the bradykinin B(2) receptor antagonist icatibant (0.5 mg/kg/day) or the bradykinin B(1) receptor antagonist des-Arg(9)-[Leu(8)]bradykinin (1 mg/kg/day). Treatment was started 1 week prior to surgery and continued until 1, 7 and 14 days post infarction. NHE-1, NCE-1 and NBC-1 mRNA expression and protein levels were increased 1 day and reached maximum values on day 7 post infarction. NHE-1 was localized in the plasma membrane, NCE-1 in the membrane of the sarcoplasmatic reticulum and NBC-1 near the Z-line. Icatibant reduced NHE-1 and inhibited NCE-1 mRNA- and protein up-regulation, while des-Arg(9)-[Leu(8)]bradykinin had no effect on NHE-1 and NCE-1 expression and translation. Transcriptional and translational up-regulation of NBC-1 was unaffected by the bradykinin B(1) and B(2) receptor antagonists. Icatibant, but not des-Arg(9)-[Leu(8)]bradykinin, limited infarct size and reduced left ventricular dilation, septal thickening and interstitial fibrosis post infarction. Bradykinin B(2) receptors are involved in transcriptional and translational regulation of NHE-1 and NCE-1 in the ischemic myocardium. Chronic B(2) receptor blockade might exert an anti-ischemic effect via limitation of NHE-1-mediated acidosis and NCE-1-mediated Ca(2+)-overload.
缓激肽B(1)和B(2)受体在梗死心肌中上调，且两种受体均参与细胞内pH值和Ca(2+)的调节。本研究调查了缓激肽B(1)和B(2)受体在梗死心肌中对钠氢交换体（NHE-1）、钠钙交换体（NCE-1）和钠-碳酸氢根协同转运体（NBC-1）调节中的作用。通过Northern印迹分析测定NHE-1、NCE-1和NBC-1的mRNA表达，通过Western印迹分析测定蛋白质水平。在心肌梗死诱导后1、7和14天进行测量。使用共聚焦显微镜研究NHE-1、NCE-1和NBC-1在心肌内的定位。在苦味酸天狼星红染色的心脏中测量心脏形态。大鼠接受安慰剂、缓激肽B(2)受体拮抗剂艾替班特（0.5毫克/千克/天）或缓激肽B(1)受体拮抗剂去-精氨酸(9)-[亮氨酸(8)]缓激肽（1毫克/千克/天）治疗。治疗在手术前1周开始，持续至梗死后1、7和14天。NHE-1、NCE-1和NBC-1的mRNA表达和蛋白质水平在梗死后1天增加，并在第7天达到最大值。NHE-1定位于质膜，NCE-1定位于肌浆网膜，NBC-1定位于Z线附近。艾替班特降低NHE-1并抑制NCE-1的mRNA和蛋白质上调，而去-精氨酸(9)-[亮氨酸(8)]缓激肽对NHE-1和NCE-1的表达及翻译无影响。NBC-1的转录和翻译上调不受缓激肽B(1)和B(2)受体拮抗剂的影响。艾替班特而非去-精氨酸(9)-[亮氨酸(8)]缓激肽可限制梗死面积，并减少梗死后左心室扩张、室间隔增厚和间质纤维化。缓激肽B(2)受体参与缺血心肌中NHE-1和NCE-1的转录和翻译调节。慢性B(2)受体阻断可能通过限制NHE-1介导的酸中毒和NCE-1介导的Ca(2+)超载发挥抗缺血作用。
