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Effects of PAF-receptor antagonist and eicosanoid synthesis inhibitors on adrenaline-induced pulmonary edema in mice
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I Effects of PAF-receptor antagonist and eicosanoid synthesis inhibitors on adrenaline- induced pulmonary edema in mice Fonteles, M.C. and Rao,
V.S.
Department of Physiology and Pharmacology, Center of Health Sciences. Federal University of Ceard. PO Box 657. 60425 Fortaleza, Ceard, Brazil
Pulmonary edema may occl~r ~,~ond3ry to drug exposure to heroin, propoxyphene, methadone and hydrochiorothiazide (Anderson, 1987). The mechanism responsible for pulmonary edema to these drugs has not been cle~,.r. Experimentally, pulmonary edema can be induced by IV adrenaline in several animal species which include rabbits, cats, dogs, rats and mice. However, the mechanism of adrenaline induced puhnonary edema (APE) is not yet well established. Previous reports to establish the role of adrenoceptors in APE are controversial. Since platelet-activating factor (PAF, PAF-acether) and the metabolites of arachidonate play an important role as mediators of Vascular permeability and in edema formation (Braquet, 1987; Siwadlowski, 1970), we have investigated their participation in the mouse model of pulmonary edema using specific PAF antagonists and Eicosanoid synthesis inihibitors. Groups of mice (ten in each) were treated with the PAF antagonists BN 52021 (10 mg/kg, ip), PCA 4248 (10 mg/kg, PO) or WEB 2170 (10 mg/kg, PO), the lipoxygenase inhibitor EP 10161 (10 mg/kg, ip); the cyclooxygenase inhibitor Aspirin (5 mg/kg, PO); the dual cyclooxygenase/5- lipoxygenase inhibitor BW 755C (50 mg/kg, ip) or with the vehicle (5% DMSO in 154 mM Saline) 30 to 60 min before induction of pulmonary edema. Pulmonary edema was induced by IV administration of adrenaline (2 mg/kg). One hour later, the mice were sacrificed, lungs were isolated and weighed. The lung body index (LBI) was taken as the criterion to compare the exten~ of p,.dmonary edema between groups. BN52021, PCA 4248 and WEB 2170 were without significant effect on pulmonary edema. In contrast, EP 10161, Aspirin and BN 755C significantly inhibited pulmonary edema by 49%, 28% and 27% respectively. Conclusion: The results suggest that arachidonic acid metabolites, but not PAF may be relevant to adrenaline induced pulmonary edema in mice. References Anderson, J.A., 1987, J.A.M.A. 258, 2891. Braquet, P., 1987, Pharmacol. Rev. 39, 97. Siwadlowski, W., 1970, Chest. 57, 554.
IS.we.22.4] The relative influence of SCH 39370, a neutral endopeptidase inhibitor, and C-ANF on the pharmacokinetics of iZSlI-ANF in rats Chiu, P.J.S., Tetzloff, G., Romano, M., Foster, C. and Sybertz, E.J. Dept. of Pharmacology, Schering-Piough Research, 60 Orange Street. Bloomfield, Nea, Jerse): U.S.A.
The C-ANF receptors which mediate endocytosis and ensuing degradation of ANF,and the neutral endopeptidase (NEP;EC 3.4.24.11)~which rapidly inactivates atrial natriuretic factor (ANF), have been implicated in the metabolism of circulating ANF (Almeida et al., 1989; Gros et al., 1989). The present study was designed to evaluate the relative role of C-ANF receptors and NEP in the pharmacogenetics and hydrolysis of ~251-1abeled AN F-(99-126) in rats by using des[GinIs, Ser 19, Gly !°, Leu zl, GlyZZ]r ANF (4-23) NH z (C-ANF) and N-[N-[l-(S)-carboxyl-3-phenylpropyl](S)-phenylalanyl]-(S)-isoserine (SCH 39370) to block the non-enzymatic and enzymatic pathways, respectively. C-ANF is a C-terminal ring-deleted analogue of ANF that binds C-receptors with high affinity, whereas SCH 39370 is a potent
I Effects of PAF-receptor antagonist and eicosanoid synthesis inhibitors on adrenaline- induced pulmonary edema in mice Fonteles, M.C. and Rao,
V.S.
Department of Physiology and Pharmacology, Center of Health Sciences. Federal University of Ceard. PO Box 657. 60425 Fortaleza, Ceard, Brazil
Pulmonary edema may occl~r ~,~ond3ry to drug exposure to heroin, propoxyphene, methadone and hydrochiorothiazide (Anderson, 1987). The mechanism responsible for pulmonary edema to these drugs has not been cle~,.r. Experimentally, pulmonary edema can be induced by IV adrenaline in several animal species which include rabbits, cats, dogs, rats and mice. However, the mechanism of adrenaline induced puhnonary edema (APE) is not yet well established. Previous reports to establish the role of adrenoceptors in APE are controversial. Since platelet-activating factor (PAF, PAF-acether) and the metabolites of arachidonate play an important role as mediators of Vascular permeability and in edema formation (Braquet, 1987; Siwadlowski, 1970), we have investigated their participation in the mouse model of pulmonary edema using specific PAF antagonists and Eicosanoid synthesis inihibitors. Groups of mice (ten in each) were treated with the PAF antagonists BN 52021 (10 mg/kg, ip), PCA 4248 (10 mg/kg, PO) or WEB 2170 (10 mg/kg, PO), the lipoxygenase inhibitor EP 10161 (10 mg/kg, ip); the cyclooxygenase inhibitor Aspirin (5 mg/kg, PO); the dual cyclooxygenase/5- lipoxygenase inhibitor BW 755C (50 mg/kg, ip) or with the vehicle (5% DMSO in 154 mM Saline) 30 to 60 min before induction of pulmonary edema. Pulmonary edema was induced by IV administration of adrenaline (2 mg/kg). One hour later, the mice were sacrificed, lungs were isolated and weighed. The lung body index (LBI) was taken as the criterion to compare the exten~ of p,.dmonary edema between groups. BN52021, PCA 4248 and WEB 2170 were without significant effect on pulmonary edema. In contrast, EP 10161, Aspirin and BN 755C significantly inhibited pulmonary edema by 49%, 28% and 27% respectively. Conclusion: The results suggest that arachidonic acid metabolites, but not PAF may be relevant to adrenaline induced pulmonary edema in mice. References Anderson, J.A., 1987, J.A.M.A. 258, 2891. Braquet, P., 1987, Pharmacol. Rev. 39, 97. Siwadlowski, W., 1970, Chest. 57, 554.
IS.we.22.4] The relative influence of SCH 39370, a neutral endopeptidase inhibitor, and C-ANF on the pharmacokinetics of iZSlI-ANF in rats Chiu, P.J.S., Tetzloff, G., Romano, M., Foster, C. and Sybertz, E.J. Dept. of Pharmacology, Schering-Piough Research, 60 Orange Street. Bloomfield, Nea, Jerse): U.S.A.
The C-ANF receptors which mediate endocytosis and ensuing degradation of ANF,and the neutral endopeptidase (NEP;EC 3.4.24.11)~which rapidly inactivates atrial natriuretic factor (ANF), have been implicated in the metabolism of circulating ANF (Almeida et al., 1989; Gros et al., 1989). The present study was designed to evaluate the relative role of C-ANF receptors and NEP in the pharmacogenetics and hydrolysis of ~251-1abeled AN F-(99-126) in rats by using des[GinIs, Ser 19, Gly !°, Leu zl, GlyZZ]r ANF (4-23) NH z (C-ANF) and N-[N-[l-(S)-carboxyl-3-phenylpropyl](S)-phenylalanyl]-(S)-isoserine (SCH 39370) to block the non-enzymatic and enzymatic pathways, respectively. C-ANF is a C-terminal ring-deleted analogue of ANF that binds C-receptors with high affinity, whereas SCH 39370 is a potent