| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Prostanoids, the prostaglandin (PGs) and thromboxane (TXs), are the cyclooxygenase metabolites of arachidonic acids and exert a range of actions in the body. These actions are mediated by their respective receptors expressed in the targe cells, which are generally present in the vicinity of prostanoid production. The receptors include the DP, EP, FP, IP and TP respectively. Moreover, there are four subtypes of the EPs: EP_1, EP_2 EP_3, and EP_4. The PGE_2, the common prostanoid in the cardiovascular system, is produced during cardiac ischemia/reperfusion (I/R). We intended to clarify the roles of PGE_2 in cardiac I/R injury using mice lacking the PGE_2 receptor EP_1, EP_2, or EP_3. Mice were subjected to coronary occlusion followed by reperfusion.
Myocardial infarct size in EP_3^<-/-> mice was significantly larger than that in wild-type (WT) mice. In contrast, there was no such difference among EP_1^<-/->, EP_2^<-/-> and WT mice. To further determine whether PGE_2 acts directly on the heart or indirectly through their action on blood constituents, we examined I/R injury ex vivo. Excised hearts were perfused according to Langendorff technique and were subjected to I/R. In EP_3^<-/-> mice, developed pressure during reperfusion was significantly lower, and release of creatine kinase was significantly augmented than those in WT mice. These results indicate the possibility that endogenous PGE_2 acts on the EP_3 in the heart and plays a cardioprotection role in I/R injury. In in vivo study, when the EP_3 agonist was administered 1 hour before coronary occlusion, it reduced infarct size significantly in wild-type mice. The potent cardioprotective effects of the EP_3 agonist suggest that the compound would be useful for treatment of acute myocardial infarction.
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