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The Journal of Cardiovascular Surgery 2003 February;44(1):37-49

language: English

Role of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts

Yamashiro S. 1, Noguchi K. 2, Kuniyoshi Y. 1, Koja K. 1, Sakanashi M. 2

1 2ndDe­part­ment of Sur­gery School of Med­i­cine, ­Faculty of Med­i­cine Uni­ver­sity of the ­Ryukyus, Nish­i­hara, Oki­nawa, ­Japan
2 Department of Pharmacology School of Medicine, Faculty of Medicine University of the Ryukyus, Nishihara, Okinawa, Japan


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Aim. It has ­recently ­been ­shown ­that ­nitric ­oxide syn­thase in the pres­ence of sub­op­timal ­levels of tet­ra­hy­dro­bi­op­terin (BH4), an essen­tial ­cofactor of ­nitric ­oxide syn­thase, may ­favor ­increased pro­duc­tion of ­oxygen ­free rad­i­cals. ­This ­study was ­designed to ­define the ­role of BH4 in myo­car­dial ­ischemia-reper­fu­sion ­injury.
­Methods. Iso­lated per­fused rat ­hearts ­were sub­jected to 37°C ­ischemia and reper­fu­sion. ­Hearts ­were ­received ­with BH4 or ­vehicle for 5 min ­just ­before ­ischemia and ­during the ­first 5 min of the reper­fu­sion ­period. The ­effects of BH4 on ­left ven­tric­ular func­tion, myo­car­dial con­tents of ­lipid per­ox­i­da­tion and ­high ­energy phos­phates, and ­levels of lac­tate dehy­drog­e­nase and ­nitrite ­plus ­nitrate in per­fu­sate ­before ­ischemia and ­after reper­fu­sion ­were esti­mated. More­over, the ­effect of BH4 ­given ­with 2,4-dia­mino-6-hydrox­y­py­rim­i­dine (­DAHP), a selec­tive inhib­itor of BH4 pro­duc­tion, intra­per­it­o­neally 24 h ­before the experi­ments ­were esti­mated.
­Results. BH4 ­improved con­trac­tile and meta­bolic abnor­mal­ities in reper­fused ­hearts. Fur­ther­more, BH4 sig­nif­i­cantly alle­vi­ated ­ischemic con­trac­ture ­during ­ischemia, and ­restored dimin­ished per­fu­sate ­levels of ­nitrite ­plus ­nitrate ­after reper­fu­sion. On the ­other ­hand, ­DAHP-treat­ment aggra­vated ­ischemia-reper­fu­sion ­induced func­tional and meta­bolic abnor­mal­ities. Admin­is­tra­tion of BH4 im­proved ­DAHP-­induced func­tional and meta­bolic abnor­mal­ities.
Con­clu­sion. ­Results dem­on­strated ­that BH4 ­lessens ­ischemia-reper­fu­sion ­injury in iso­lated per­fused rat ­hearts. Con­versely, defi­ciency of BH4 ­seems to accel­erate endo­the­lial dys­func­tion and myo­car­dial ­ischemia-reper­fu­sion ­injury. ­Present ­data may be com­pat­ible ­with the hypoth­esis ­that ­nitric ­oxide syn­thase in the pres­ence of insuf­fi­ciency of BH4 ­serve as the ­cause of oxi­da­tive ­injury.

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