phosphoramidon and Edema

The involvement of tachykinin receptors in skin inflammation induced by substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) was investigated in mouse ears. Intradermal injection of tachykinins (0.1-100 pmol/site) into the ear skin produced oedema formation. RP 67580 (ED50: 0.34 mg/kg, i.v.) and SR 140333 (ED50: 0.19 mg/kg, i.v.), the non-peptide NK1 receptor antagonists, inhibited SP-induced oedema. SR 140333 was also effective in preventing NKA- and NKB-induced oedema. SR 48968 (1 mg/kg, i.v.), a non-peptide NK2 antagonist, induced a significant inhibition of NKA-induced oedema but had no effect on the response to SP and NKB. SR 142801 (3 mg/kg, i.v.), a non-peptide NK3 antagonist, prevented only NKB-induced oedema. In contrast, phosphoramidon (0.1 and 0.5 mg/kg, i.v.), an endopeptidase inhibitor, enhanced the oedema response to tachykinins. SR 140333, SR 48968, and SR 142801 blocked the enhancement by phosphoramidon of the response to SP, NKA, and NKB, respectively. Plasma extravasation in ear skin was induced by i.v. injection of tachykinins (0.7-17.6 nmol/kg). RP 67580 (ED50: 0.15 mg/kg, i.v. for SP) and SR 140333 (ED50: 14.3 micrograms/kg, i.v. for SP) inhibited tachykinin-induced plasma extravasation in ear skin. However, SR 48968 and SR 140281 had no effect on the vascular response to tachykinins. Chlorpheniramine (4 mg/kg, i.v.), a histamine H1 blocker, inhibited the response to local SP but not to i.v. SP. These results suggest that in addition to the NK1 receptors, functional NK2 and NK3 receptors may participate in the oedema response to local NKA and NKB in the ear skin. However, it appears that NK1 receptors on blood vessels are involved predominantly in plasma extravasation induced by i.v. tachykinins in the ear.

Topics: Animals; Capillary Permeability; Edema; Glycopeptides; Male; Mice; Neurokinin A; Neurokinin B; Piperidines; Quinuclidines; Receptors, Tachykinin; Substance P

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.

Topics: Albumins; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Capillary Permeability; Capsaicin; Captopril; Collagenases; Dose-Response Relationship, Drug; Edema; Glycopeptides; Hindlimb; Indoles; Inflammation; Isoindoles; Male; Matrix Metalloproteinase Inhibitors; Methysergide; Neurokinin-1 Receptor Antagonists; Oligopeptides; Organ Size; Protease Inhibitors; Rats; Rats, Wistar; Serotonin Antagonists; Substance P

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Edema; Glycopeptides; Humans; Hypertension; Natriuresis; Neprilysin; Substrate Specificity; Tissue Distribution