Abstract
This study investigated whether short-term exposure toEscherichia coli lipopolysaccharide (LPS) elicits vasomotor dysfunction in skeletal muscle in vivo and, if so, whether perivascular mast cell proteases partly modulate this response. With intravital microscopy, we found that suffusion ofE. coli 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, nonpeptide angiotensin II (AT II) subtype 1 receptor antagonist, chymostatin and soybean trypsin inhibitor. These compounds also attenuate E. coli LPS-induced vasodilation. By contrast, superoxide dismutase, catalase and indomethacin attenuate only E. coli LPS-induced vasodilation. Endothelin receptor antagonists, lisinopril, leupeptin, Bestatin anddl-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid are ineffective. Histochemical analysis of the spinotrapezius muscle reveals abundant perivascular mast cells with chymostatin-inhibitable chymase-like activity. Pretreatment of hamsters with compound 48/80 for 4 days curtails E. coli LPS-induced vasoconstriction and converts vasodilation to vasoconstriction. On balance, these data indicate that E. coli LPS stimulates perivascular mast cells in the in situ hamster spinotrapezius muscle to release an AT II-producing chymase-like protease(s). AT II thus produced elicits local vasoconstriction and elaborates reactive oxygen species which, in turn, generate vasodilator prostaglandins.
Footnotes
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Send reprint requests to: Dr. Israel Rubinstein, Department of Medicine (M/C 787), University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60612-7323.
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↵1 This study was supported, in part, by grants from the National Institutes of Health (DE10347 and HL24136), American Heart Association of Metropolitan Chicago and Laerdal Foundation for Acute Medicine.
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↵2 Recipient of a Career Investigator Award from the American Lung Association.
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↵3 Recipient of a Research Career Development Award from the National Institutes of Health (DE00386) and a University of Illinois Scholar Award.
- Abbreviations:
- LPS
- lipopolysaccharide
- AT II
- angiotensin II
- AT1 RA
- angiotensin II subtype 1 receptor antagonist
- SOD
- superoxide dismutase
- ACE
- angiotensin I-converting enzyme
- ET
- endothelin
- NASDCA
- naphthol AS-D chloroacetate
- Received May 22, 1997.
- Accepted November 12, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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