Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,456.
BACKGROUND
Arterial diameter changes in response to flow. Chronic flow-mediated arterial enlargement may be mediated through metalloproteinase activity in the extracellular matrix of the arterial wall. We examined flow-mediated enlargement in the setting of increasing competitive matrix metalloproteinase (MMP) inhibition and with respect to gelatinase A and B expression and 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 diameters 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 amounts of aortic RNA underwent reverse transcription and polymerase chain reaction 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 with progressively higher doses of RS 113,456 without apparent hemodynamic or toxic effects. Right common iliac diameter was unchanged. Over 21 days following AVF creation, there was an upward trend in expression and activity for MMP-2 not evident for MMP-9.


CONCLUSIONS
Flow-mediated arterial enlargement is limited by competitive MMP inhibition in a dose-dependent fashion. MMP-dependent flow-mediated enlargement may involve differential expression and activity of MMP-2 and MMP-9.
Karwowski
J K
JK
Vascular Section, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94303, USA.
Markezich
A
A
Whitson
J
J
Abbruzzese
T A
TA
Zarins
C K
CK
Dalman
R L
RL
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D001166:Arteriovenous Shunt, Surgical; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D011714:Pyrans / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011714:Pyrans; C113899:RS 113456; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9