Polyarginine and eosinophil-derived major basic protein increase microvascular permeability independently of histamine or nitric oxide release.
We tested the hypothesis that cationic peptides (polyarginine; poly-argn) and eosinophil-derived major basic protein (MaBP) increase permeability by stimulating the release of histamine and/or nitric oxide. We used intravital microscopy, clearance, and integrated optical intensity (IOI), using FITC-dextran 150 (FITC-dx 150) as a tracer, to evaluate changes in microvascular permeability in the hamster cheek pouch. Poly-argn at 1 microM (topical) increased the clearance of FITC-dx 150 from 610 to 3240 nl/60 min/g. In contrast, 1 microM polyglutamic acid (poly-glun; and anionic peptide) did not affect the clearance of FITC-dx 150 (605 nl/60 min/g). At 0.5 and 1.0 nM, poly-argn increased the clearance of FITC-dx 150 from 610 to 1722 and 2396 nl/60 min/g (P < 0.05). Similarly, 0.5 nM MaBP increased clearance from 591 +/- 38 to 1967 +/- 168 nl/60 min/g. L-NAME at 10(-4) M did not prevent the 0.5 nM MaBP-induced elevation in clearance (1784 +/- 350). Poly-argn at 1 nM increased net mean IOI by 21.5 +/- 7.2 units. This elevation was not inhibited by topical 10(-4) M L-NMMA (27.5 +/- 8.4). Using 0.5 nM poly-argn as agonist, we assayed suffusate samples for their histamine concentration using a competitive enzyme immunoassay and found no detectable histamine. Pyrilamine, an H1 antagonist, did not inhibit the 0.5 nM poly-argn-induced elevation in clearance of FITC-dx 150. We conclude that (1) cationic peptides and MaBP increase microvascular permeability and (2) the increase in microvascular permeability produced by low concentrations of poly-argn and by MaBP is independent of the release of histamine and does not require nitric oxide.
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001798:Blood Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects; D002610:Cheek / Q000098:blood supply; D006224:Cricetinae; D003911:Dextrans / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047091:Eosinophil Granule Proteins; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011738:Pyrilamine / Q000494:pharmacology; D012260:Ribonucleases; D019323:omega-N-Methylarginine
D001798:Blood Proteins; D003911:Dextrans; D004791:Enzyme Inhibitors; D047091:Eosinophil Granule Proteins; D006634:Histamine H1 Antagonists; D018836:Inflammation Mediators; D010455:Peptides; C015219:fluorescein isothiocyanate dextran; C015462:polyarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D012260:Ribonucleases; D011738:Pyrilamine; D016650:Fluorescein-5-isothiocyanate; D019331:NG-Nitroarginine Methyl Ester