Inducible expression of the kinin B1 receptor in the endotoxemic heart: mechanisms of des‐Arg9bradykinin‐induced coronary vasodilation

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Abstract
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. 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 (P2=8.4, n=5) whilst HOE140 (B2 receptor antagonist, 10 nM) was inactive (n=4). Removal of the endothelium or infusion with indomethacin (5 μM), but not L‐NAME (300 μM) or ODQ (1 μM), inhibited (>85%, Pn=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). In vitro perfusion of hearts with endotoxin (1 μg ml−1, n=6) or interleukin‐1β (5 ng ml−1, n=6) induced B1 receptor mRNA expression and promoted a time‐dependent vasodilation response to DABK. 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, Pn=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, Pn=5, P1 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. British Journal of Pharmacology (1999) 128, 275–282; doi:10.1038/sj.bjp.0702743