Inducible expression of the kinin B1 receptor in the endotoxemic heart: mechanisms of des-Arg9bradykinin-induced coronary vasodilation.
1 We have investigated the role of kinin B1 receptor induction in the endotoxemic rat heart and elucidated the mechanisms underlying B1 receptor-mediated coronary vasodilation. We also investigated the role of these receptors in endotoxin-induced hypotension. 2 Endotoxin treatment induced cardiac B1 receptor mRNA expression and promoted a coronary vasodilation response to des-Arg9bradykinin (DABK; ED50 = 149.4 pmol, n = 9) ex vivo peaking at 6 h. The B1 receptor antagonist des-Arg9-[Leu8]-BK (DALBK, 30 nM) significantly (P<0.05) inhibited the DABK-induced response (pA2 = 8.4, n = 5) whilst HOE140 (B2 receptor antagonist, 10 nM) was inactive (n = 4). 3 Removal of the endothelium or infusion with indomethacin (5 microM), but not L-NAME (300 microM) or ODQ (1 microM), inhibited (>85%, P<0.05, n = 5) the DABK-induced response. DABK caused a dose-dependent release of the prostacyclin metabolite, 6-keto-PGF1a (Emax = 0.3 ng ml-1, n = 6). 4 In vitro perfusion of hearts with endotoxin (1 microg ml-1, n = 6) or interleukin-1beta (5 ng ml-1, n = 6) induced B1 receptor mRNA expression and promoted a time-dependent vasodilation response to DABK. 5 Endotoxin treatment (6 h) in vivo promoted a hypotensive response to DABK (ED50 = 29.7 nmol kg-1, n = 10) which was antagonised by DALBK (3-6 nmol kg-1 min-1, P<0.05, n = 7). DALBK (3 nmol kg-1 min-1) and des-Arg10HOE140 (B1 receptor antagonist, 30 nmol kg-1 min-1) produced a 5.3% (n = 6, P<0.05) and 8.8% (n = 5, P<0.05) reversal, respectively, of endotoxin-induced hypotension. 6 In summary, we have shown that in endotoxemia activation of B1 receptors causes coronary vasodilation via endothelial prostacyclin release. Additionally, B1 receptor antagonists partially reversed endotoxin-induced hypotension. Therefore activation of B1 receptors may have a role to play in the vascular changes associated with endotoxemia.
McLean
P G
PG
Center for Clinical Pharmacology, Department of Medicine, University College London, WC1E 6JJ. p.mclean@ucl.ac.uk
Perretti
M
M
Ahluwalia
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000502:physiology; D019446:Endotoxemia / Q000378:metabolism* / Q000503:physiopathology; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology; D008297:Male; D009129:Muscle Tonus / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014664:Vasodilation / Q000187:drug effects*
D065168:Bradykinin Receptor Antagonists; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; C024626:bradykinin, des-Arg(9)-; D009569:Nitric Oxide; D001920:Bradykinin