Function of vascular endothelium and vasomotor nerve in atherosclerotic animals

为了研究动脉粥样硬化和高脂血症对血管功能的影响，我们首先检查了正常动物的内皮功能（1,2）。然后，在Watanabe遗传性高脂血症（WHHL）兔(3)和高胆固醇饮食喂养的高脂血症猴子(4)中，研究了动脉粥样硬化和高脂血症对内皮细胞和血管舒缩神经功能的影响。在离体猴舌动脉中，乙酰胆碱诱导的舒张是由一氧化氮（NO）和Ca^<2+>-依赖性K^<+>-通道打开基质介导的，这些基质来自于内皮细胞色素P450 3A4异构体产生的四烯酸。在离体犬海绵体中，乙酰胆碱诱导的松弛是由NO和打开Ca^<2+>-依赖性K^<+>-小电导通道的物质介导的。所有WHHL兔颈动脉均可见明显的斑块状动脉粥样硬化病变。乙酰胆碱诱导的内皮依赖性松弛在有动脉粥样硬化病变的WHHL兔颈动脉中明显被抑制。相反，P物质在有动脉粥样硬化和无动脉粥样硬化的WHHL兔动脉中的内皮依赖性松弛作用大于日本白兔动脉。因此，动脉粥样硬化可能抑制毒蕈碱受体的功能。长期暴露于高脂血症可能导致内皮中P物质的受体超敏。从高胆固醇饮食喂养的高脂血症猴子中分离的大脑中动脉（MCA）未观察到动脉粥样硬化病变。与对照组相比，内皮细胞NO介导的组胺诱导的舒张在高脂血症猴子的MCA中显著增强，而Ca^<2+>离子离子A23187的舒张在对照组和高脂血症猴子之间没有差异。高脂血症不影响尼古丁诱导的中动脉舒张，这种舒张是由一氧化氮神经释放的一氧化氮介导的。因此，高脂血症不影响猴MCA的内皮和氮氧能神经功能，但增强了组胺引起的no介导的松弛，可能与内皮中组胺受体介导的功能上调有关。从高脂血症兔和猴子的研究结果来看，动脉粥样硬化和高脂血症可能改变内皮细胞的特异性受体功能，但不会普遍影响内皮细胞和支配神经的功能。少

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