Reperfusion injury is reduced in skeletal muscle by inhibition of inducible nitric oxide synthase.
This study evaluated the effects of the selective inducible nitric oxide synthase (iNOS) inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400W) on the microcirculation in reperfused skeletal muscle. The cremaster muscles from 32 rats underwent 5 h of ischemia followed by 90 min of reperfusion. Rats received either 3 mg/kg 1400W or PBS subcutaneously before reperfusion. We found that blood flow in reperfused muscles was <45% of baseline in controls but sharply recovered to near baseline levels in 1400W-treated animals. There was a significant (P < 0.01 to P < 0.001) difference between the two groups at each time point throughout the 90 min of reperfusion. Vessel diameters remained <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- to 20-micro m arterioles, 121 +/- 6% in 21- to 40-micro m arterioles, and 115 +/- 8% in 41- to 70-micro m arteries (P < 0.01 to P < 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 compared with controls. We conclude that ischemia-reperfusion leads to increased generation of NO from iNOS in skeletal muscle and that 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 ischemia-reperfusion injury.
Zhang
Li
L
Orthopaedic Microsurgery Laboratory, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Looney
Colin G
CG
Qi
Wen-Ning
WN
Chen
Long-En
LE
Seaber
Anthony V
AV
Stamler
Jonathan S
JS
Urbaniak
James R
JR
D000005:Abdomen; D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D015656:Respiratory Mechanics / Q000187:drug effects; D014664:Vasodilation
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat