Kinin-B1 receptors in ischaemia-induced pancreatitis: functional importance and cellular localisation.
In this study we compare the role of kinin-B1 and B2 receptors during ischaemia/reperfusion of rat pancreas. Our investigations were prompted by the observation that infusion of a kinin-B2 receptor antagonist produced significant improvement in acute experimental pancreatitis. In an acute model with two hours of ischaemia/two hours of reperfusion, application of the kinin-B1 receptor antagonist (CP-0298) alone, or in combination with kinin-B2 receptor antagonist (CP-0597), significantly reduced the number of adherent leukocytes in post-capillary venules. In a chronic model with five days of reperfusion, the continuous application of kinin-B1 receptor antagonist or a combination of kinin-B1 and B2 receptor antagonists markedly reduced the survival rate. In kinin-receptor binding studies kinin-B1 receptor showed a 22-fold increase in expression during the time of ischaemia/reperfusion. Carboxypeptidase M activity was up-regulated 10-fold following two hours of ischaemia and two hours of reperfusion, provided the appropriate specific ligand, des-Arg10-kallidin and/or des-Arg9-bradykinin, was used. The occurrence of kinin-B1 receptor binding sites on acinar cell membranes was demonstrated by micro-autoradiography. With a specific antibody, the localisation of kinin-B1 receptor protein was confirmed at the same sites. In conclusion, we have demonstrated the up-regulation of the pancreatic acinar cell kinin-B1 receptors during ischaemia/reperfusion. The novel functional finding was that antagonism of the kinin-B1 receptors decreased the survival rate in an experimental model of pancreatitis.
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D002448:Cell Adhesion; D058851:GPI-Linked Proteins; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D010195:Pancreatitis / Q000209:etiology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000378:metabolism / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism / Q000502:physiology; D015427:Reperfusion Injury; D015996:Survival Rate; D015854:Up-Regulation; D014699:Venules / Q000166:cytology
D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D058851:GPI-Linked Proteins; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C024626:bradykinin, des-Arg(9)-; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; C058479:carboxypeptidase M; D008666:Metalloendopeptidases; D001920:Bradykinin