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Received February 15, 2002
Accepted after revision June 24, 2002
1 Centre for Cardiovascular Biology and Medicine, New Hunt's House, Guy's Campus, King's College, London, SE1 1UL, UK
2 Perlmutter Laboratory, The Children's Hospital, Boston, Massachusetts 02115, USA
3 Centre for Cardiovascular Biology and Medicine, New Hunt's House, Guy's Campus, King's College, London SE1 1UL, UK
* To whom correspondence should be addressed. E-mail: sue.brain{at}kcl.ac.uk.
The tachykinin neurokinin B (NKB) has been implicated in the hypertension that characterises pre-eclampsia, a condition where tissue oedema is also observed. The ability of NKB, administered intradermally or intravenously, to induce oedema formation (assessed as plasma extravasation) was examined by extravascular accumulation of intravenously injected 125I-albumin in wild-type and tachykinin NK1 receptor knockout mice. Intradermal NKB (30-300 pmol) caused dose-dependent plasma extravasation in wild-type (P < 0.05) but not NK1 knockout mice, indicating an essential role for the NK1 receptor in mediating NKB-induced skin oedema. Intravenous administration of NKB to wild-type mice produced plasma extravasation in skin, uterus, liver (P < 0.05) and particularly in the lung (P < 0.01). Surprisingly, the same doses of NKB led to plasma extravasation in the lung and liver of NK1 knockout mice. By comparison substance P induced only minimal plasma extravasation in the lungs of wild-type mice. The plasma extravasation produced by NKB in the lungs of NK1 receptor knockout mice was unaffected by treatment with the NK2 receptor antagonist SR48968 (3 mg kg-1), by the NK3 receptor antagonists SR142801 (3 mg kg-1) and SB-222200 (5 mg kg-1) or by the cyclo-oxygenase (COX) inhibitor indomethacin (20 mg kg-1). L-nitro-arginine methyl ester (15 mg kg-1), an inhibitor of eNOS, produced only a partial inhibition. We conclude that NKB is a potent stimulator of plasma extravasation through two distinct pathways: via activation of NK1 receptors, and via a novel neurokinin receptor-independent pathway specific to NKB that operates in the mouse lung. These findings are in keeping with a role for NKB in mediating plasma extravasation in diseases such as pre-eclampsia.
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