Bradykinin B1 and B2 receptors differentially regulate cardiac Na+-H+ exchanger, Na+-Ca2+ exchanger and Na+-HCO3- symporter.
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.
Sandmann
Steffen
S
Institute of Pharmacology, University of Kiel, Hospitalstrasse 4, 24105, Kiel, Germany. s.sandmann@pharmakologie.uni-kiel.de
Kaschina
Elena
E
Blume
Annegret
A
Kruse
Marie Luise
ML
Unger
Thomas
T
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D007150:Immunohistochemistry; D016623:Ion Pumps / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000502:physiology*; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D065168:Bradykinin Receptor Antagonists; D016623:Ion Pumps; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D027982:Sodium-Bicarbonate Symporters; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; C024626:bradykinin, des-Arg(9)-; C065679:icatibant; D001920:Bradykinin