Elsevier

Surgery

Volume 124, Issue 2, August 1998, Pages 328-335
Surgery

Society of University Surgeons
Matrix metalloproteinase inhibition limits arterial enlargement in a rodent arteriovenous fistula model,☆☆

Presented at the Fifty-ninth Annual Meeting of the Society of University Surgeons, Milwaukee, Wis., Feb. 12-14, 1998.
https://doi.org/10.1016/S0039-6060(98)70138-2Get rights and content

Abstract

Background: We administered a specific, nonselective matrix metalloproteinase (MMP) inhibitor (RS-113,456) to examine the effect of MMP inhibition on flow-mediated arterial enlargement in a rodent arteriovenous fistula (AVF) model. Methods: Four groups of male Sprague-Dawley rats were created: sham (sham operated; n = 10), control (2.0 mm left common femoral AVF alone; n = 16), vehicle (AVF plus 0.5 mL vehicle orally twice a day; n = 20), and treatment (AVF plus 25 mg/kg RS-113,456 in 0.5 mL vehicle orally twice a day; n = 16). Heart rate, mean arterial pressure, and body weight were recorded on postoperative days 0, 7, 14, and 21. On day 21, AVF patency was confirmed, the infrarenal aorta and common iliac arteries were exposed, blood flow velocity and external diameter were measured, and wall shear stress (WSS) was calculated. Analysis was performed by paired, two-tailed Student t test, one-way analysis of variance, and the Bonferroni/Dunn procedure for post hoc testing. Results: Heart rate, mean arterial pressure, and weight did not vary at any time between groups. Aortic and left iliac diameter was larger in the AVF groups than in sham groups (P < .001), and control and vehicle groups were larger than treatment groups (P < .0001). Changes in aortic and left iliac flow were also significant (AVF was more than sham and control, and vehicle was more than treatment). No difference in aortic and left iliac artery velocity and WSS or right iliac diameter, velocity, flow, or WSS was observed between groups. Conclusions: MMP inhibition diminishes flow-mediated arterial enlargement in the rat AVF model. (Surgery 1998;124:328-35.)

Section snippets

Material and methods

Adult male Sprague-Dawley rats (weight 350 to 450 g) were used for this experiment. Clean surgical technique was used for all procedures. Anesthetic (50 mg/kg sodium pentobarbital; Abbott Laboratories, Chicago, Ill.) was administered through intraperitoneal injection. Fistula construction was performed after intravenous injection of 100 units/kg beef lung heparin (The Upjohn Co, Kalamazoo, Mich.). Animals recovered from the operation in separate cages with free access to food and water. All

Results

All results are expressed as means ± SD. Three rats died during the initial surgical procedure, 3 were killed after unsuccessful AVF creation, 4 did not survive measurement of the aorta and iliac arteries, and 4 AVFs were found to be occluded during the final surgical procedure. Thus 48 rats were available for comparison at the final surgical procedure, including 10 in the sham, 10 in the control, 14 in the vehicle, and 14 in the treatment groups.

Discussion

Administration of RS-113,456 to rats with increased left CFA blood flow caused by an AVF prevented abdominal aortic enlargement compared with control AVF rats or AVF rats treated with vehicle alone. Treatment with RS-113,456 did not completely inhibit aortic enlargement; the average aortic diameter in the treatment group was significantly larger than in rats who did not have an AVF (sham group).

To our knowledge, prevention of flow-mediated arterial enlargement has not been attempted with other

Acknowledgements

We thank Byron Brown, PhD, for reviewing the statistical analyses, Michelle Bendeck, PhD, for assistance with references and manuscript preparation, and Sarika C. Joshi and Joshua M. Hull for their technical assistance in animal husbandry and performance of procedures as described. Material support was provided by the Inflammatory Diseases Section, Roche Bioscience, Palo Alto, Calif.

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Supported in part by the American Heart Association, California affiliate grant 95-255, the Office of Technology and Licensing, Stanford University, and the Lifeline Foundation 1997 Student Fellowship Award.

☆☆

Reprint requests: Ronald L. Dalman, MD, Surgical Service, Palo Alto Veterans Affairs Health Care System, Palo Alto, CA 94304.

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