sr-142801 and 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

In the present study we have investigated some of the mechanisms underlying B(1) kinin receptor-induced paw edema formation in rats that had been treated with LPS, paying special attention to the involvement of neurogenic inflammation. Intradermal (i.d.) injection of the B(1) receptor agonist des-Arg(9)-BK (100 nmol/paw) resulted in a marked increase in paw volume in animals pre-treated with LPS (0.40+/-0.06 ml). The co-injection of the selective NK(1) FK888 (1 nmol/paw) or NK(2) SR 48968 (3 nmol/paw) receptor antagonists resulted in a significant inhibition of the edema induced by des-Arg(9)-BK (30+/-4 and 25+/-7%, respectively). The NK(3) SR 142801 (3 nmol/paw) antagonist did not demonstrate any significant effect on B(1) receptor-mediated paw edema. The edema induced by des-Arg(9)-BK was also significantly inhibited (33+/-5%) by the co-injection of the CGRP-receptor antagonist CGRP 8-37 (1 nmol/paw) or by treatment of animals with capsaicin (50 mgkg(-1), s.c., 48 h, prior) (45+/-4%). The pre-treatment of animals with methysergide or with mianserin, 5-HT(1) and 5HT(2) antagonists, respectively (both 10 mgkg(-1), i.p. 30 min), resulted in a significant reduction of the edema mediated by B(1) receptors (23+/-5 and 20+/-3%, respectively). In addition, compound 48/80 (12 microg/paw, 24 h) significantly reduced des-Arg(9)-induced paw edema in rats pre-treated with LPS (23+/-3%), while the treatment of animals with the H(1) receptor antagonist pyrilamine (10 mgkg(-1), i.p., 30 min) failed to affect the edematogenic responses involving B(1) receptors. Finally, the co-injection of NOS inhibitors L-NAME (100 nmol/paw) or 7-NINA (10 nmol/paw) did not affect the rat paw edema caused by des-Arg(9)-BK, whereas they significantly inhibited BK-induced paw edema. Jointly, the results of the present study show that the edematogenic response mediated by the activation of B(1) receptors, in animals pre-treated with LPS, involves the release of tachykinins and CGRP, as well as serotonin, while NO and histamine seem not to be involved. Therefore, these data further support the notion that B(1) receptors have an important role in modulating the inflammatory processes.

Topics: Animals; Benzamides; Bradykinin; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Capsaicin; Edema; Histamine H1 Antagonists; Lipopolysaccharides; Male; Methysergide; Mianserin; Neurokinin-1 Receptor Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; p-Methoxy-N-methylphenethylamine; Peptide Fragments; Piperidines; Pyrazoles; Pyridines; Pyrilamine; Rats; Rats, Wistar; Receptor, Bradykinin B1; Receptors, Bradykinin; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Serotonin Antagonists

We examined the effect of SR 140333, a nonpeptide NK1 receptor antagonist, FK 888, a peptide NK1 antagonist, and SR 142801, a non-peptide NK3 antagonist, on ear oedema induced by topical application of capsaicin (250 micrograms/ear) in mice. SR 140333 (ED50:39 micrograms/kg, i.v.) dose-dependently inhibited the oedema response to capsaicin, whereas FK 888 (1.0 mg/kg, i.v.) and SR 142801 (3.0 mg/kg, i.v.) had no effect. Furthermore, SR 140333 significantly (p < 0.001) suppressed ear oedema in response to intradermal injection of substance P (SP) (100 pmol/site) by i.v. administration (0.1 mg/kg,) and co-injection (50 pmol/site). In contrast, FK 888 (1.0 mg/kg, i.v. and 500 pmol/site) was ineffective in the response to SP. The present results suggest that the difference in effects of the two NK1 receptor antagonists on the oedema response to capsaicin is due to species differences in affinities for the NK1 receptor in the mouse skin. Moreover, it seems unlikely that the NK3 receptor is involved primarily in capsaicin-induced mouse ear oedema.

Topics: Animals; Binding Sites; Capsaicin; Dipeptides; Disease Models, Animal; Ear Diseases; Edema; Indoles; Injections, Intravenous; Lethal Dose 50; Male; Mice; Piperidines; Quinuclidines; Receptors, Tachykinin; Skin; Stereoisomerism; Structure-Activity Relationship; Substance P