Microvascular transport is associated with TNF plasma levels and protein synthesis in postischemic muscle.
To better understand the mechanisms of ischemia-reperfusion (I/R) injury, we tested the hypothesis that protein synthesis is involved in the production of tumor necrosis factor (TNF) and in the microvascular transport changes in I/R. To evaluate the hypothesis, we inhibited protein synthesis with topically applied actinomycin D (AMD), measured I/R-induced changes in microvascular transport, and bioassayed the venous plasma levels of TNF. The rat cremaster muscle I/R model consisted of 4 h of ischemia followed by 2 h of reperfusion. Changes in transport were determined by integrated optical intensity (IOI) using FITC-Dextran 150 as tracer. Animals were separated into four groups: 1) control (C), 2) control treated with AMD (C + AMD), 3) I/R, and 4) I/R treated with AMD (I/R + AMD). The mean (+/-SE) maximal IOI in C and C + AMD were 3.0 +/- 1.0 and 3. 7 +/- 0.7 units, respectively. I/R elevated mean maximal IOI to 21.8 +/- 1.9 units (P < 0.05 vs. C, C + AMD, I/R + AMD). Treatment with AMD reduced the I/R-induced mean maximal IOI to 9.7 +/- 2.0 units (P < 0.05 vs. I/R). In I/R group, plasma TNF levels increased (relative to preischemia baseline) immediately after the release of the vascular occlusion to 250 pg/ml and reached a peak value of 342 pg/ml at 60 min of reperfusion. In the I/R + AMD group, AMD reduced TNF increase to 44 pg/ml. The C and C + AMD groups showed no differences in TNF values during the 6 h of observation. We conclude that protein synthesis and TNF generation are at least partially involved in I/R-induced changes in microvascular transport.
Takenaka
H
H
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
Oshiro
H
H
Kim
D D
DD
Thompson
P N
PN
Seyama
A
A
Hobson
R W
RW
Duran
W N
WN
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003609:Dactinomycin / Q000494:pharmacology; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D011920:Rats, Inbred WF; D015427:Reperfusion Injury / Q000097:blood / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015415:Biomarkers; D009124:Muscle Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin