Pascual D W, Pascual V H, Bost K L, McGhee J R, Oparil S
Department of Oral Biology, Baptist Medical Centers, Birmingham, Ala.
Hypertension. 1993 Feb;21(2):185-94. doi: 10.1161/01.hyp.21.2.185.
The immune system of the spontaneously hypertensive rat is dysfunctional compared with that of normotensive control strains. Previous studies from our laboratory have shown that immunodepression in the spontaneously hypertensive rat was mediated by macrophages. The current study examines the mechanism for the depressed proliferative responses to concanavalin A typically observed by splenic mononuclear cells of spontaneously hypertensive rats. We tested various inhibitors of known macrophage products responsible for suppressing lymphoid function. The nitric oxide synthetase inhibitor NG-monomethyl L-arginine produced dose-dependent derepression of the proliferative responses of splenic mononuclear cells to concanavalin A. In contrast, indomethacin and catalase exhibited only weak derepression of the proliferative responses. Subsequent analysis showed that splenic mononuclear cells from spontaneously hypertensive rats generated greater nitric oxide levels than cells from Wistar-Kyoto rats, and nitric oxide levels were reduced when the inhibitor was added to splenic mononuclear cell cultures from spontaneously hypertensive rats. We further demonstrated that L-arginine is required for the development of the depressed mitogen-induced proliferative responses in these cells. Addition of L-arginine in excess of 10 microM to cultures diminished cell proliferation and increased nitric oxide. Polyclonal antibodies to murine interferon gamma reduced nitric oxide accumulation by approximately 50%, suggesting that interferon gamma is partially responsible for enhancing nitric oxide production in mitogen-stimulated splenic mononuclear cell cultures from spontaneously hypertensive rats. Thus, this study provides evidence that the immune depression observed in the spontaneously hypertensive rat is nitric oxide dependent.
与正常血压对照品系相比，自发性高血压大鼠的免疫系统功能失调。我们实验室之前的研究表明，自发性高血压大鼠的免疫抑制是由巨噬细胞介导的。本研究探讨了自发性高血压大鼠脾单核细胞对伴刀豆球蛋白A增殖反应降低的机制。我们测试了多种已知的负责抑制淋巴细胞功能的巨噬细胞产物抑制剂。一氧化氮合酶抑制剂NG-单甲基-L-精氨酸剂量依赖性地解除了脾单核细胞对伴刀豆球蛋白A增殖反应的抑制。相比之下，吲哚美辛和过氧化氢酶仅表现出对增殖反应的微弱解除抑制作用。后续分析表明，自发性高血压大鼠的脾单核细胞产生的一氧化氮水平高于Wistar-Kyoto大鼠的细胞，并且当将抑制剂添加到自发性高血压大鼠的脾单核细胞培养物中时，一氧化氮水平降低。我们进一步证明，L-精氨酸是这些细胞中丝裂原诱导的增殖反应抑制发展所必需的。向培养物中添加超过10 microM的L-精氨酸会减少细胞增殖并增加一氧化氮。抗小鼠干扰素γ的多克隆抗体使一氧化氮积累减少约50%，表明干扰素γ部分负责增强自发性高血压大鼠丝裂原刺激的脾单核细胞培养物中的一氧化氮产生。因此，本研究提供了证据表明自发性高血压大鼠中观察到的免疫抑制是一氧化氮依赖性的。
