sr-142801 and Pulmonary-Edema

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 (125)I-albumin in wild-type and tachykinin NK(1) receptor knockout mice. Intradermal NKB (30-300 pmol) caused dose-dependent plasma extravasation in wild-type (P < 0.05) but not NK(1) knockout mice, indicating an essential role for the NK(1) 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 NK(1) knockout mice. By comparison, the tachykinin substance P induced only minimal plasma extravasation in the lungs of wild-type mice. The plasma extravasation produced by NKB in the lungs of NK(1) receptor knockout mice was unaffected by treatment with the NK(2) receptor antagonist SR48968 (3 mg kg(-1)), by the NK(3) 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 endothelial nitric oxide synthase (eNOS), produced only a partial inhibition. We conclude that NKB is a potent stimulator of plasma extravasation through two distinct pathways: via activation of NK(1) 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.

Topics: Animals; Antipsychotic Agents; Benzamides; Cyclooxygenase Inhibitors; Edema; Enzyme Inhibitors; Extravascular Lung Water; Female; Indomethacin; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurokinin B; Neurokinin-1 Receptor Antagonists; NG-Nitroarginine Methyl Ester; Piperidines; Plasma; Pulmonary Edema; Receptors, Neurokinin-1; Substance P