1993 Fiscal Year Final Research Report Summary
Studes on the L-arginine-derived, endothelium-independent relaxing factor
| Project/Area Number |
03671054
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Dept. of Pharmacol., Fac. of Pharmaceutical Sci., Univ. of Tokushima |
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Principal Investigator |
MORITOKI Hideki Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 教授 (10035545)
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| Co-Investigator(Kenkyū-buntansha) |
HORIO Shuuhei Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 助手 (80145010)
FUKUZAWA Kennji Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 教授 (90035551)
HISAYAMA Tetsuhiro Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 助教授 (70130383)
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| Project Period (FY) |
1991 – 1993
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| Keywords | L-Arginine / Nitric Oxide / NO synthase / Enzyme induction / Endotoxin / Cytokine / Vasorelaxation |
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| Research Abstract |
1. We examined whether endotoxin contributes to L-arginine-induced relaxation of endothelium-denuded rat thoracic aorta, which apears to be mediated by nitric oxide synthase in the vascular smooth muscle.
2. In the absence of endotoxin, L-arginine induced scarcely any relaxation of the arteries. Treatment of the arteries with endotoxin initiated ralaxation in response to 10 muM L-arginine with lag periods of 2-4 hr, and degree of relaxation increased on repeated application of L-arginine to reach a consistent level in several hours. Increase in the concentration of endotoxin shortened the lag period, enhanced the degree of relaxation and lowered the threshold concentration of L-arginine required to relax the arteries. In endotoxin-primed arteries, L-arginine at concentrations necessary to induce relaxation stimulated cyclic GMP production.
3. Prophylactic appliction of actinomycin D or dexamethasone, which inhibits induction of nitric oxide synthase, prevented induction by endotoxin of L
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-arginine-induced relaxation and cyclic GMP formation. Polymyxin B, which inhibits the action of endotoxin, also prevented development of endotoxin-sensitized relaxation and cyclic GMP formation inducded by L-arginine.
4. When the Krebs solution was prepared using de-ionized water, the amount of endotoxin in the reservoir was above the level required to initiate L-arginine-induced relaxation and cyclic GMP fotmation.
5. These results suggest that endotoxin triggered time-dependent development of L-arginine-induced relaxation by expressing nitric oxide synthase in the vascular smooth muscle.
6. We examined the effects of tyrosine kinase inhibitors on the endotoxin(LPS)-primed, L-arginine-induced relaxation of rat thoracic aorta.
7. Prophylactic application of the tyrosine kinase inhibitors herbimycin A, genistein and erbstatin analog selectively prevented the initiation by LPS of L-arginine-induced relaxation and cyclic GMP formation.
8. These results suggest that tyrosine kinase mediates the L-arginine-induced relaxation of the arteries, probably through protein tyrosine phosphorylation in the LPS-triggered signaling pathway that triggers expression of an inducible NO synthase producing NO. Less
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