Henningsson R, Alm P, Lundquist I
Department of Pharmacology, Institute of Physiological Sciences, University of Lund, S-223 62 Lund, Sweden.
Am J Physiol Cell Physiol. 2001 May;280(5):C1242-54. doi: 10.1152/ajpcell.2001.280.5.C1242.
We investigated, by a combined in vivo and in vitro approach, the temporal changes of islet nitric oxide synthase (NOS)-derived nitric oxide (NO) and heme oxygenase (HO)-derived carbon monoxide (CO) production in relation to insulin and glucagon secretion during acute endotoxemia induced by lipopolysaccharide (LPS) in mice. Basal plasma glucagon, islet cAMP and cGMP content after in vitro incubation, the insulin response to glucose in vivo and in vitro, and the insulin and glucagon responses to the adenylate cyclase activator forskolin were greatly increased after LPS. Immunoblots demonstrated expression of inducible NOS (iNOS), inducible HO (HO-1), and an increased expression of constitutive HO (HO-2) in islet tissue. Immunocytochemistry revealed a marked expression of iNOS in many beta-cells, but only in single alpha-cells after LPS. Moreover, biochemical analysis showed a time dependent and markedly increased production of NO and CO in these islets. Addition of a NOS inhibitor to such islets evoked a marked potentiation of glucose-stimulated insulin release. Finally, after incubation in vitro, a marked suppression of NO production by both exogenous CO and glucagon was observed in control islets. This effect occurred independently of a concomitant inhibition of guanylyl cyclase. We suggest that the impairing effect of increased production of islet NO on insulin secretion during acute endotoxemia is antagonized by increased activities of the islet cAMP and HO-CO systems, constituting important compensatory mechanisms against the noxious and diabetogenic actions of NO in endocrine pancreas.
我们采用体内和体外相结合的方法，研究了小鼠在脂多糖（LPS）诱导的急性内毒素血症期间，胰岛一氧化氮合酶（NOS）衍生的一氧化氮（NO）和血红素加氧酶（HO）衍生的一氧化碳（CO）产生的时间变化与胰岛素和胰高血糖素分泌的关系。LPS处理后，基础血浆胰高血糖素、体外孵育后的胰岛cAMP和cGMP含量、体内和体外对葡萄糖的胰岛素反应以及对腺苷酸环化酶激活剂福斯可林的胰岛素和胰高血糖素反应均显著增加。免疫印迹显示胰岛组织中诱导型NOS（iNOS）、诱导型HO（HO-1）表达，组成型HO（HO-2）表达增加。免疫细胞化学显示，LPS处理后，许多β细胞中有明显的iNOS表达，但仅在单个α细胞中有表达。此外，生化分析表明这些胰岛中NO和CO的产生呈时间依赖性且显著增加。向此类胰岛中添加NOS抑制剂可显著增强葡萄糖刺激的胰岛素释放。最后，体外孵育后，在对照胰岛中观察到外源性CO和胰高血糖素均显著抑制NO产生。这种作用独立于对鸟苷酸环化酶的同时抑制。我们认为，急性内毒素血症期间胰岛NO产生增加对胰岛素分泌的损害作用被胰岛cAMP和HO-CO系统活性增加所拮抗，这构成了对抗NO在胰腺内分泌中有害和致糖尿病作用的重要代偿机制。
