Neurokinin receptor mediated plasma extravasation in guinea pig and rat airways: comparison of 125I-labelled human fibrinogen and 99mTc-labelled human serum albumin as markers of leakage.
In the present study we have characterized NK-1 and NK-2 receptor induced microvascular leakage in guinea pig and rat airways, using 125I-labelled human fibrinogen ([125I]FN) versus 99mTc-labelled human serum albumin ([99mTc]HSA) as markers for plasma protein extravasation. Intravenous administration of the selective NK-1 agonist [Sar9, Met(O2)11]SP (1 nmol kg-1) caused a dose-dependent increase of [125I]FN extravasation in guinea pig trachea, main bronchi, secondary bronchi, and intraparenchymal airways. Extravasation of [125I]FN increased by up to 192 (trachea), 284 (main bronchi), 368 (secondary bronchi), and 271% (intraparenchymal bronchi) over control levels in these regions of the airways. Pretreatment of the animals with CP 99,994 and RP 67,580, two NK-1 nonpeptide antagonists, caused a dose-dependent inhibition of [Sar9, Met(O2)11]SP-induced leakage of [125I]FN. [Sar9, Met(O2)11]SP (1 nmol kg-1) did not induce specific leakage of [99mTc]HSA in the intraparenchymal bronchi. Specific NK-2 receptor induced leakage was detected in the lower airways but only when using [125I]FN as a marker. We have also compared the ability of CP 99,994 and RP 67,580 to inhibit [Sar9, Met(O2)11]SP induced extravasation of [125I]FN in rat airways. CP 99,994 was 40-50 (tracheobronchial region) to 75 (lower airways) times more potent in the guinea pig than the rat airways. In contrast, RP 67,580 had higher affinity for rat airways compared with guinea pig airways. The results of this study highlight the superiority of [125I]FN as a sensitive marker of plasma extravasation over [99mTc]HSA.(ABSTRACT TRUNCATED AT 250 WORDS)
Tousignant
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Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Canada.
Chan
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Young
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Guevremont
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Rodger
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D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001980:Bronchi / Q000098:blood supply*; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000097:blood*; D005340:Fibrinogen / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D013668:Technetium Tc 99m Aggregated Albumin / Q000493:pharmacokinetics*; D014132:Trachea / Q000098:blood supply*
D015415:Biomarkers; D007457:Iodine Radioisotopes; D018040:Receptors, Neurokinin-1; D013668:Technetium Tc 99m Aggregated Albumin; D005340:Fibrinogen