|Budget Amount *help
¥3,400,000 (Direct Cost : ¥3,400,000)
Fiscal Year 2004 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 2003 : ¥2,000,000 (Direct Cost : ¥2,000,000)
1)Negative inotropic response to α-receptor stimulation was examined with various selective antagonists. As a result, it was suggested that this response is mediated by tyrosine kinase, D-phosphatide phosphohydrolase pathway, and the activation of protein kinase C. Finally, as confirmed in the previous study, it is considered that the negative inotropy is produced by the augmentation of reverse mode of Na^+, Ca2+-exchange reaction.
2)In contrast to ventricular muscle, ET-1, AII, and PGF2α produces positive inotropic effect., the mechanism of which was examined. Since the positive inotropy produced by the above agents was inhibited by an inhibitor of Rho-associated kinase (ROCK), Y-27632, it was suggested that Rho/ROCK pathway is involved in this response.
3)As a mechanism underlying the specific nature of mouse myocardium including negative inotropy by α1-receptor stimulation of ET-1, etc., the involvement of Na+, Ca2+-exchange reaction (NCX) was suggested. This was able to be clarified with using a selective NCX inhibitor, SEA0400, which was developed by ourselves.
1.NCX is involved in the Ca extrusion during the late repolarization phase of mouse ventricular action potential.
2.Negative staircase phenomenon observed specifically in mouse ventricle can be explained by the augmented Ca extrusion via NCX at high frequency of contraction leading to the diminution of the amount of Ca which can be controlled by SR function.
3.Negative inotropy produced by α-stimulation, ATII and ET-1 is basically the same in their mechanism, i.e., activation of NCX.
4.Developmental change from positive to negative of the inotropic response to α-stimulation is explained by the decrease in the contribution of Na+,H+-exchange reaction to contractile function and the increase in the contribution of NCX.