Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,456

Background. Arterial diameter changes in response to how. Chronic flow-medi ated arterial enlargement may be mediated through metalloproteinase activit y in the extracellular matrix of the arterial wall. We examined flow-mediat ed enlargement in the setting of increasing competitive matrix metalloprote inase (MMP) inhibition and with respect to gelatinase A and B expression an d activity. Methods. Left common femoral arteriovenous fistulas (AVFs) were created in dose-response (52) and time course (34) cohorts of rats. Dose-response rats received either vehicle alone or 12.5, 25, or 37.5 mg/kg b.i.d. RS 113,456 , a competitive MMP inhibitor. Heart rate, blood pressure, and weight were measured at intervals following AVF construction. Aortic and common iliac d iameters were measured on postoperative day (POD) 21. Untreated time course rats were sacrificed on PODs 0 (no AVF), 3, 7, 14, and 21. Aortic diameter was measured and the vessels were harvested for tissue analysis. Equal amo unts of aortic RNA underwent reverse transcription and polymerase chain rea ction with primers for MMP-2, MMP-9, and GAPDH. Zymography was performed on iliac artery tissue to measure gelatinolytic activity. Results. A significant, stepwise reduction in flow-mediated aortic and left common iliac enlargement following left femoral AVF creation was noted wit h progressively higher doses of RS 113,456 without apparent hemodynamic or toxic effects. Right common iliac diameter was unchanged. Over 21 days foll owing AVF creation, there was an upward trend in expression and activity fo r MMP-2 not evident for MMP-9. Conclusion. Flow-mediated arterial enlargement is limited by competitive MM P inhibition in a dose-dependent fashion. MMP-dependent flow-mediated enlar gement may involve differential expression and activity of MMP-2 and MMP-9. (C) 1999 Academic Press.