Mode of Action of Endogenous Vasoactive Substances on Blood Vessels in Oral Region : Its Molecular Pharmacological Analysis

在本研究项目中，我们希望研究1)内毒素和氧自由基等血管活性物质对舌动脉血管反应性的相互作用，2)细胞内钙离子转导与氧自由基的关系，以及3)氧自由基对血管收缩-松弛周期的影响。缓激肽通过B_2激肽受体操控的钙通道和Na~+-Ca~(2+)交换机制，刺激犬舌动脉环钙离子内流，产生非内皮依赖性收缩。氧自由基使B_2-激动素受体对激动素敏感。此外，内毒素可增加突触前α_2受体和M受体的敏感性；氧自由基是由内毒素本身产生的。因此，推测一旦氧自由基产生，牙周血管网络的功能就会受到干扰。氧自由基能抑制兔舌动脉环血管平滑肌细胞肌浆网钙离子的释放，并刺激钙离子通过电压依赖性钙通道内流。降钙素基因相关肽(CGRP)是犬舌动脉血管周围神经中的血管扩张物质。体外自由基生成系统(H_2O_2+FeSO_4)处理后，CGRP样免疫反应明显减弱。内毒素内毒素可通过产生氧自由基而直接刺激骨吸收，因此，上述结果推测，内毒素介导的氧自由基的产生可能导致牙周组织的循环衰竭。

In this research project, we wished to investigate 1) interaction between vasoactive substances include lipopolysaccharide (LPS) and oxygen-derived free radicals on the vascular reactivity in lingual artery, to characterize 2) intracellular Ca^<2+> transduction of the vascular smooth muscle in relation to oxygen-derived free radicals, and to define 3) the effect of oxygen-derived free radicals on the vascular contraction-relaxation cycle.1. Bradykinin produces endothelium-independent contraction of canine lingual artery ring preparations via stimulation of Ca^<2+> influx through B_2-kinin recaptor-operated Ca^<2+> channel and Na^+-Ca^<2+> exchange mechanism. Oxygen free radicals sensitize B_2-kinin receptors to kinins. Further, LPS increases prejunctional alpha_2- and muscarinic receptor sensitivity ; oxygen free radicals were produced from LPS itself. Therefore, it is hypothesized that once oxygen free radicals produced function of periodontal vascular network could be disturbed.2. Oxygen-derived free radicals produced inhibition of Ca^<2+> release from sarcoplasmic reticulum of vascular smooth muscle cells and stimulation of Ca^<2+> influx through voltage-dependent Ca^<2+> channel in rabbit lingual artery ring preparations in vitro.3. Calcitonin gene-related peptide (CGRP) was found to exist as the vasodilator substance in perivascular nerves in the canine lingual artery. The CGRP-like immunoreactivity was markedly diminished after treatment with in vitro free radical generating system (H_2O_2 plus FeSO_4).Endotoxin LPS may directly stimulate bone resorption due to its ability to generate oxygen free radicals ; therefore, the results stated above postulate that LPS-mediated generation of oxygen free radicals may produce circulatory failure in periodontal tissues.