| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2005: ¥3,100,000 (Direct Cost: ¥3,100,000)
|
|---|
| Research Abstract |
Kynurenic acid (KYN) is an endogenous glutamate antagonist. Kynurenine aminotransferase-1 (KAT-1) catalyzes the conversion of kynurenine to KYN. It has been reported that a missense (E61G) mutation exists in the KAT-1 gene of spontaneously hypertensive rat (SHR), an experimental model of metabolic syndrome. Our previous report indicated that this missense mutation reduces KAT-1 activity within rostral ventrolateral medulla (RVLM) and play a key role in the maintenance of hypertension in SHR. To determine how exogenous expression of the KAT-1 gene in the RVLM can affect arterial pressure (AP) and insulin resistance in SHR, adenovirus vector encoding either KAT-1 (AdKAT-1) or β-galactosidase (AdLacZ) were transfected bilaterally into RVLM of SHR. At days 7,14 and 21 after gene transfer, the expression of KAT-1 in the RVLM was increased in AdKAT-1, AP decreased from day 7 in AdKAT-1. Microinjection of KYN into the RVLM at day 7 decreased AP less significantly in the AdKAT-1. Urinary excre
… More
tion of catecholamines was also decreased in AdKAT-1. These results suggest that bilateral KAT-1 transfection in the RVLM decreased AP and sympathetic nerve activity in SHR. Additionally, insulin resistance tended to shift to normal in AdKAT-1. Since excitatory amino acid neurotransmission in RVLM is important in central cardiovascular regulation, the reduced KAT-1 activity due to missense mutation should contribute to maintenance of both elevated AP and sympathetic nerve activity observed in metabolic syndrome.
We have also previously reported that the balance between EAA-mediated excitation and inhibition of RVLM neurons was shifted to excitation in salt-sensitive hypertension (SSH). From this background, we also hypothesized that SSH may be caused by the decrease of KAT-1 activity within RVLM. In this study, antisnse of KAT-1 gene is transfected into normotensive Wistar-Kyoto Rat (WKY) RVLM on high or normal salt diet to examine the effect of KAT-1 activity within RVLM in SSH. Twelve weeks-old WKY rats were fed with high or normal salt diet. At day 14, Ad KAT-1 antisense were transfected into bilateral RVLM of both groups. KAT-1 activity localized in RVLM was decreased by KAT-1 antisense transfection. AP and HR were not changed by KAT-1 antisense transfection in WKY on normal salt diet. In contrast, in high salt group AP and HR were increased by KAT-1 antisense transfection. Thus, decreased KAT-1 activity within RVLM seems to increase salt-sensitivity. These results suggest that the combination of decreased KAT-1 activity within RVLM and high salt diet may cause the imbalance between EAA-mediated excitatory and inhibitory input to RVLM. Missense mutation of KAT-1 gene may play a key role in SSH. Less
|
