Role of BH4 in resistance to myocardial ischemia in the BN/Mcw vs. SS/Mcw rats

BH4, an essential cofactor for NOS was shown to contribute to ischemia/reperfusion (I/R) injury. Provision of Sepiapterin (Sep), an intermediate in the salvage pathway of BH4, improved cardioprotection. In contrast, inhibiting GTP cyclohydrolase I (GCH1), the rate‐limiting enzyme for BH4 synthesis by 2, 4‐Diamino‐6‐hydroxypyrimidine (DAHP) increased I/R injury. We previously showed SS/Mcw rats were more susceptible to myocardial I/R than BN/Mcw rats due to reduced •NO production. This study is testing if decreased BH4 levels are responsible for the increased susceptibility to I/R injury in SS/Mcw rats, and if Sep supplementation in SS/Mcw hearts or GCH1 inhibition by DAHP in BN/Mcw hearts could increase/decrease resistance to I/R injury, respectively. Hearts were perfused with Sep or DAHP for 40 min before I/R. Cardiac BH4 levels were much lower in SS/Mcw hearts than in BN/Mcw hearts (27.1±2.2 vs. 37.3±5.5 pmols/mg protein). After I/R, BH4 levels were decreased and this decrease was even more in SS/Mcw hearts. Real‐time PCR revealed that GCH‐1 mRNA was transcribed less in SS/Mcw hearts than BN/Mcw hearts. Sep increased recovery of left ventricular developed pressure (RVDP) following I/R in SS/Mcw hearts (from 37.1±4.3% to 54.3±6.4%). DAHP decreased RVDP in BN/Mcw hearts compared to controls (38.2±4.4% vs. 59.6±4.1%). These results indicate that BH4 plays a crucial role in •NO‐mediated resistance to I/R in rat.