Effects of the combination of rapamycin with tacrolimus or cyclosporin on experimental intimal hyperplasia.
BACKGROUND
Allograft vasculopathy remains the leading cause of late allograft failure following transplantation and can be inhibited by the antiproliferative drug rapamycin. This study assessed the efficacy of combining rapamycin therapy with calcineurin inhibition.


METHODS
Male Sprague-Dawley rats received rapamycin 0.05 mg/kg daily and either tacrolimus 0.1 mg/kg or cyclosporin 5 mg/kg daily, and findings were compared with those in an untreated control group. Animals underwent left common carotid artery balloon angioplasty; the artery was explanted after 2 weeks. Morphometric analysis was performed on transverse sections and the intima : media ratio was calculated. Profibrotic gene expression was measured with competitive reverse transcriptase-polymerase chain reaction at 14 and 28 days. Proliferation was determined with proliferating cell nuclear antigen at 14 and 28 days. Extracellular matrix deposition was quantified with Sirius red.


RESULTS
The combination of rapamycin and tacrolimus was associated with the greatest reduction in intimal thickening. Furthermore, treatment with rapamycin and tacrolimus significantly attenuated extracellular matrix deposition compared with rapamycin and cyclosporin (P < 0.02).


CONCLUSIONS
The effects of rapamycin in combination with tacrolimus were better than those observed with rapamycin and cyclosporin.
Waller
J R
JR
Division of Transplant Surgery, University of Leicester, Leicester, UK. julian@waller720.fsnet.co.uk
Murphy
G J
GJ
Bicknell
G R
GR
Toomey
D
D
Nicholson
M L
ML
D000818:Animals; D065095:Calcineurin Inhibitors; D017536:Carotid Artery, Common / Q000637:transplantation; D002455:Cell Division; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D019715:Tissue Inhibitor of Metalloproteinase-1; D016572:Cyclosporine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020123:Sirolimus; D016559:Tacrolimus