Phenytoin can accelerate the healing process after experimental myocardial infarction?
BACKGROUND
Over-degradation and/or inadequate accumulation of extracellular matrix after myocardial infarction (MI) may lead to adverse ventricular remodeling, even ventricular aneurysm or rupture. Phenytoin can increase gingival overgrowth by stimulating the proliferation of connective tissue, which implies a novel way to hasten the healing process after MI.


METHODS
Experimental MI was induced by permanent coronary ligation. Surviving rats after MI were randomly divided into phenytoin, captopril, phenytoin plus captopril, operation control and sham operation group. Picrosirius red staining plus polarized microscopy was used for collagen analysis. Left ventricular passive pressure-volume relationship was determined ex vivo. The effects of phenytoin concentration gradient (0, 1.25, 2.5, 5.0, 10.0, and 20.0 microg/mL) on transforming growth factor-beta1 (TGF-beta1) mRNA and protein expression by neonatal rat cardiac fibroblast were determined using semi-quantitative RT-PCR and ELISA, respectively. Peritoneal macrophage was incubated with same gradient of phenytoin concentration. Then the supernatant was harvested to stimulate another 6 groups of cardiac fibroblast, to investigate possible role mediated by macrophage.


RESULTS
Phenytoin treatment could promote type I collagen cross-linking level and ratio of type I/III collagen in the infarcted region and had no obvious side effect on interstitial collagen volume fraction, subtype ratio and distribution in non-infarcted region. Phenytoin-treated hearts exhibited attenuation of global ventricular dilation. Phenytoin alone had no direct effects on rat cardiac fibroblast proliferation and collagen production in vitro, but phenytoin-stimulated macrophage could exert a positive influence on cardiac fibroblast TGF-beta1 mRNA and protein production, which exhibited a dose-dependent manner.


CONCLUSIONS
Phenytoin can accelerate the healing process in the infarcted region and has no obviously detrimental influence on collagen accumulation in non-infarcted region, which implies a potential benefit to patients undergoing early post-infarction ventricular remodeling process.
Institute of Cardiovascular Disease, Pingjin Hospital, Medical College of Armed Police Forces, Cheng-lin-zhuang Street, Hedong District, Tianjin, 300162, China.
Xin
X
Zhou
Yu-Ming
YM
Li
Wen-Jie
WJ
Ji
Tie-Min
TM
Jiang
Xiao-Nan
XN
Sun
Yong
Y
Zhu
Rui
R
Shi
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000187:drug effects; D024061:Collagen Type III / Q000187:drug effects; D003238:Connective Tissue / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects; D014945:Wound Healing / Q000502:physiology*
D000927:Anticonvulsants; D024042:Collagen Type I; D024061:Collagen Type III; D010672:Phenytoin