| Co-Investigator(Kenkyū-buntansha) |
OKAMURA Tomio Shiga University qo Medical Science, Pharmacology, Professor, 医学部, 教授 (70152337)
FUJIOKA Hideyuki Shiga University of Medical Science, Pharmacology, Research Associate, 医学部, 助手 (50228970)
|
|---|
| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
|
|---|
| Research Abstract |
In order to examine the effects of atherosclerosis and hyperlipidemia on vascular function, endothelial function in normal animals was firstly examined (1, 2). Then, the effects of atherosclerosis and hyperlipidemia on the functions of endothelium and vasomotor nerves were examined in Watanabe heritable hyperlipidemic (WHHL) rabbits (3) and hyperlipidemic monkeys fed by a high cholesterol diet (4).
1. In isolated monkey lingual arteries, acetylcholine-induced relaxation was mediated by nitric oxide (NO) and Ca^<2+>-dependent K^<+>-channel opening substarice(s) from arachidonic acid produced by cytochrome P450 3A4 isoform in the endothelium.
2. In isolated dog corpus cavernosum, acetylcholine-induced relaxation was mediated by NO and substance(s) which opens Ca^<2+>-dependent K^<+>-channel of small conductance.
3. Marked, patchy atherosclerotic lesions were observed in all WHHL rabbit carotid arteries. Endothelium-dependent relaxations induced by acetylcholine were significantly inhibited
… More
in the WHHL rabbit carotid arteries with atherosclerotic lesions. Inversely, endothelium-dependent relaxations by substance P were greater in the arteries with and without atherosclerosis from WHHL rabbits than those in the arteries from Japanese white rabbits. Therefore, atherosclerosis may inhibit the muscarinic receptor function. Long exposure to hyperlipidemia was expected to cause receptor-hypersensitivity of substance P in the endothelium.
4. Atherosclerotic lesions were not observed in middle cerebral arteries (MCA) isolated from hyperlipidemic monkeys fed by a high cholesterol diet. Histamine-induced relaxation, which was mediated by endothelial NO, was significantly potentiated in the hyperlipidemic monkey MCA, compared to that in the arteries from control monkeys whereas the relaxation by Ca^<2+> ionophore A23187 did not differ between control and hyperlipidemic monkeys. Nicotine- induced relaxation in MCA, which was mediated by NO released from nitroxidergic (nitrergic) nerves, was not affected by hyperlipidemia. Therefore, hyperlipidemia did not affect endothelial and nitroxidergic nerve functions of monkey MCA, but enhanced NO-mediated relaxation caused by histamine, possibly due to upregulation of histamine receptor-mediated function in the endothelium.
From the findings using hyperlipidemic rabbits and monkeys, atherosclerosis and hyperlipidemia may modify the specific receptor functions in the endothelium, but not generally affect the functions of endothelium and innervating nerves. Less
|
