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 (P<0.05) inhibited the DABK-induced response (pA2=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%, 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).
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, 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.
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.
British Journal of Pharmacology (1999) 128, 275–282; doi:10.1038/sj.bjp.0702743