The 2004 Annual Meeting (January 14-20, 2004) of OASYS_NEW

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Effects of nNOS Selective Inhibition on the Microcirculation of Denervated Skeletal Muscle During Reperfusion

Gowda C1, Chen LE1, Allen DM1, Seaber AV1, and Urbaniak JR2. (1) Division of Orthopaedics/Dept. of Surgery, Duke University Medical Center, Orthopaedic Research Laboratories, 375 Medical Sciences Research Bldg., Box 3093, Durham, NC, USA, (2) Division of Orthopaedic Surgery, Duke University Medical Center, Box 2912, Durham, NC, USA

INTRODUCTION: Nitric oxide (NO) and nitric oxide synthase (NOS) appears to play an important role in the development of skeletal muscle ischemia/reperfusion (I/R) injury. While endothelial and inducible NOS isoforms have been studied, the role of neuronal (nNOS) in I/R injury has not been established in skeletal muscle. This study examined the effects of selective inhibition of nNOS with N-propyl-L-arginine (NPA) on the microcirculation in reperfused skeletal muscle.

METHODS: Denervated cremaster muscles from 60 rats underwent 4 hrs of ischemia followed by 90 minutes of reperfusion. Each rat received intravenous infusion of phosphate buffered solution (control), low-dose (10 nmol per kg per hr), or high-dose (100 nmol per kg per hr) NPA starting 10 minutes prior to reperfusion. Blood vessel diameter from 3 vessel categories (10-20 µm, 21-40 µm, and 41-70 µm) and total blood flow into each muscle were measured at 10-minute intervals using intravital microscopy and laser Doppler flowmetry, respectively, during reperfusion.

RESULTS: In the 10-20 µm arterioles, average vessel diameters were significantly (p<0.05) greater in the low dose (92.5-97.9 percent of baseline) and high-dose (89.1-99.8 percent) NPA groups compared to control (66.3-75.0 percent) between 40-90 minutes of reperfusion. Vessel diameters in the 21-40 µm and 41-70 µm arteries showed similarly significant improvement in the two NPA groups between 40-90 minutes. Furthermore, total blood flow in the low-dose (63.6-110.8 percent of baseline) and high-dose NPA (73.8-107.3 percent) groups vs. control (38.6-79.8 percent) was also significantly (p<0.05) improved between 40-90 minutes. While improvement in vessel diameter and blood flow was found in the two NPA groups prior to 40 minutes, the difference was not significant compared to controls. In addition, there was no significant difference in vessel diameter or total blood flow between the two NPA groups.

CONCLUSION: These results show that NPA significantly increased vessel diameter and improved total blood flow in reperfused skeletal muscle. This suggests that NO produced by nNOS may have a detrimental role and exacerbate I/R injury. Thus, selective inhibition of nNOS may have the potential to improve clinical outcomes where I/R injury would be a limiting factor.


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