Inducible expression of the kinin B 1 receptor in the endotoxemic heart: mechanisms of des‐Arg 9 bradykinin‐induced coronary vasodilation

We have investigated the role of kinin B 1 receptor induction in the endotoxemic rat heart and elucidated the mechanisms underlying B 1 receptor‐mediated coronary vasodilation. We also investigated the role of these receptors in endotoxin‐induced hypotension. Endotoxin treatment induced cardiac B 1 receptor mRNA expression and promoted a coronary vasodilation response to des‐Arg 9 bradykinin (DABK; ED 50 =149.4 pmol, n =9) ex vivo peaking at 6 h. The B 1 receptor antagonist des‐Arg 9 ‐[Leu 8 ]‐BK (DALBK, 30 n M ) significantly ( P <0.05) inhibited the DABK‐induced response (pA 2 =8.4, n =5) whilst HOE140 (B 2 receptor antagonist, 10 n M ) was inactive ( n =4). Removal of the endothelium or infusion with indomethacin (5 μ M ), but not L ‐NAME (300 μ M ) or ODQ (1 μ M ), inhibited (>85%, P <0.05, n =5) the DABK‐induced response. DABK caused a dose‐dependent release of the prostacyclin metabolite, 6‐keto‐PGF 1a (E max =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 B 1 receptor mRNA expression and promoted a time‐dependent vasodilation response to DABK. Endotoxin treatment (6 h) in vivo promoted a hypotensive response to DABK (ED 50 =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‐Arg 10 HOE140 (B 1 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. In summary, we have shown that in endotoxemia activation of B 1 receptors causes coronary vasodilation via endothelial prostacyclin release. Additionally, B 1 receptor antagonists partially reversed endotoxin‐induced hypotension. Therefore activation of B 1 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