| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Pathogenicity of vasculature with chronically increased hemodynamics such as hypertension and arteriosclerosis may be attributable in part to biological responses of cardiovascular tissues against mechanical stimuli. The research purpose of this study is to find a new therapeutic target for experimental pulmonary hypertension through pharmacological regulation of mechanotransduction mechanisms of pulmonary artery.
Mechanical stretching to 180% of initial muscle length produces the excessive arterial tension, which is considered to be similar degree in the pulmonary hypertension. The stretching of the pulmonary artery activates downstream signal of integrin, a putative mechanosensor; nevertheless, the stretching augments productions of prostanoids in an integrin-dependent (TXA_2 and PGF_<2α>) and independent (untransformed (ut-)PGH_2, PGE_2, and PGI_2) manner. Of these prostanoids, moreover, the ut-PGH_2 was primarily responsible for the stretch-induced contraction of the pulmonary arter
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y. Assuming that integrin-independent pathway of PG-production might be mediated by secretory phospholipase A_2 (sPLA_2), the effects of indoxam, a highly selective inhibitor for sPLA_2, on the contraction of pulmonary artery and the production of ut-PGH_2 in response to stretching were examined. In a normal rabbit pulmonary artery, indoxam preferentially inhibit the stretch-induced contraction (IC_<50>=0.513 μM), which was about 20-fold more effective than acetylcholine-induced contraction (IC_<50>=10.25 μM). Production of ut-PGH_2 was abolished by indoxam at this time. In the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PH rats), a significant increase in the steady-state mRNA level for group X sPLA_2 was observed. Indoxam (1-3 μM) completely abolished rhythmic contraction as well as concomitant production of ut-PGH_2 during the prolonged stretching, which is an aberrant character of the pulmonary artery of MCT-PH rats.
These results suggest that sPLA_2-mediated production of ut-PGH_2 causes stretch-induced contraction and/or increasing vascular tone of the pulmonary arteries in both normal and the pulmonary hypertension. Successful blockade by Indoxam of ut-PGH_2-production and contractile responses of the pulmonary arteries in both normal and diseased status suggest that sPLA_2 would become a new therapeutic target for experimental pulmonary hypertension. Less
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