MAST-CELL CHYMASE-LIKE PROTEASE(S) MODULATES ESCHERICHIA-COLI LIPOPOLYSACCHARIDE-INDUCED VASOMOTOR DYSFUNCTION IN SKELETAL-MUSCLE IN-VIVO

This study investigated whether short-term exposure to Escherichia coi l lipopolysaccharide (LPS) elicits vasomotor dysfunction in skeletal m uscle in vivo and, if so, whether perivascular mast cell proteases par tly modulate this response. With intravital microscopy, we found that suffusion of E. coil LPS on the in situ hamster spinotrapezius muscle for 60 min elicits immediate vasoconstriction followed by vasodilation . Vasoconstriction is abrogated by SK&F 108566, a selective, nonpeptid e angiotensin II (AT II) subtype 1 receptor antagonist, chymostatin an d soybean trypsin inhibitor. These compounds also attenuate E. coil LP S-induced vasodilation. By contrast, superoxide dismutase, catalase an d indomethacin attenuate only E. coli LPS-induced vasodilation. Endoth elin receptor antagonists, lisinopril, leupeptin, Bestatin and DL-2-me rcaptomethyl-3-guanidinoethylthiopropanoic acid are ineffective. Histo chemical analysis of the spinotrapezius muscle reveals abundant periva scular mast cells with chymostatin-inhibitable chymase-like activity. Pretreatment of hamsters with compound 48/80 for 4 days curtails E. co li LPS-induced vasoconstriction and converts vasodilation to vasoconst riction. On balance, these data indicate that E. coil LPS stimulates p erivascular mast cells in the in situ hamster spinotrapezius muscle to release an AT Ii-producing chymase-like protease(s). AT II thus produ ced elicits local vasoconstriction and elaborates reactive oxygen spec ies which, in turn, generate vasodilator prostaglandins.