Journal of Applied Physiology
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J Appl Physiol (December 27, 2002). doi:10.1152/japplphysiol.00789.2002
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Submitted on August 30, 2002
Accepted on December 18, 2002

REPERFUSION INJURY IS REDUCED IN SKELETAL MUSCLE BY INHIBITION OF INDUCIBLE NITRIC OXIDE SYNTHASE

Li Zhang1, Colin G Looney1, Wen-Ning Qi1, Long-En Chen1*, Anthony V Seaber2, Jonathan S Stamler3, and James R Urbaniak1

1 Department of Surgery, Duke University Medical Center, Durham, NC, USA
2 Department of Surgery, Duke University Medical Center, Durham, NC, USA; Howard Hughes Medical Institute, Durham, NC, USA
3 Department of Medicine, Duke University Medical Center, Durham, NC, USA; Howard Hughes Medical Institute, Durham, NC, USA

* To whom correspondence should be addressed. E-mail: chen0006{at}mc.duke.edu.

This study evaluated the effects of the selective iNOS inhibitor 1400W on the microcirculation in reperfused skeletal muscle. The cremaster muscles from 32 rats underwent 5-hr ischemia followed by 90-min reperfusion. Rats received either 3mg/kg 1400W or PBS subcutaneously prior to reperfusion. RESULTS. Blood flow in reperfused muscles was less than 45% of baseline in controls but sharply recovered to near baseline levels in 1400W-treated animals. There was a significant (p<0.01 to < 0.001) difference between the two groups at each time point throughout the 90-min of reperfusion. Vessel diameters remained less than 80% of baseline in controls during reperfusion, but recovered to the baseline level in the 1400W group by 20 min, and reached a maximum of 121±14% (mean±SD) of baseline in 10-20µm arterioles, 121±6% in 21-40µm arterioles, and 115±8% in 41-70µm arteries (p<0.01 to <0.001). The muscle weight ratio between ischemia/reperfused (left) and non-ischemia/reperfused (right) cremaster muscles was 193±42% of normal in controls and 124±12% in the 1400W group (p<0.001). Histology showed that neutrophil extravasation and edema were markedly reduced in 1400W-treated muscles when compared to controls. CONCLUSIONS. I/R leads to increased generation of NO from iNOS in skeletal muscle, and the selective iNOS inhibitor 1400W reduces the negative effects of ischemia/reperfusion on vessel diameter and muscle blood flow. Thus, 1400W may have therapeutic potential in treatment of I/R injury.




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