Henningsson R, Lundquist I
Department of Pharmacology, University of Lund, S-223 62 Lund, Sweden.
Am J Physiol. 1998 Sep;275(3):E500-6. doi: 10.1152/ajpendo.1998.275.3.E500.
Nitric oxide (NO) produced by islet constitutive NO synthase (cNOS) is a putative modulator of islet hormone secretion. We show here for the first time that the release of insulin induced by L-arginine or L-homoarginine is inhibited and that of glucagon stimulated in parallel with the rate of islet NO production. It was found that L-homoarginine was approximately 25-30% less potent than L-arginine as an insulin secretagogue but equally potent as a glucagon secretagogue. Biochemical determination of islet cNOS activity revealed that the NO production with L-homoarginine as substrate was only approximately 40% of that of L-arginine. Selective inhibition of islet cNOS potentiated insulin release during amino acid stimulation. Moreover, inhibition of cNOS suppressed glucagon release, more so with L-arginine than with L-homoarginine as secretagogue, reflecting the relative rates of their NO production. In K+-depolarized islets, inhibition of cNOS enhanced the insulin response to L-arginine by 50% and that to L-homoarginine by 23%, largely corresponding to their relative NO production. The intracellular NO donor hydroxylamine dose dependently inhibited insulin but increased glucagon secretion in K+-depolarized and amino acid-stimulated islets. We conclude that both amino acids have a dual action on insulin release, since their stimulatory effects are reduced in parallel with the rates of their NO production. Furthermore, the greater NO production induced by L-arginine relative to L-homoarginine corresponds to NO-mediated increases in glucagon release. These NO effects are mainly exerted independently of membrane depolarization events.
胰岛组成型一氧化氮合酶（cNOS）产生的一氧化氮（NO）是胰岛激素分泌的一种假定调节因子。我们首次在此表明，L-精氨酸或L-高精氨酸诱导的胰岛素释放受到抑制，而胰高血糖素的释放则与胰岛NO生成速率平行受到刺激。结果发现，作为胰岛素促分泌剂，L-高精氨酸的效力比L-精氨酸低约25 - 30%，但作为胰高血糖素促分泌剂的效力相同。胰岛cNOS活性的生化测定显示，以L-高精氨酸为底物时的NO生成量仅约为L-精氨酸的40%。选择性抑制胰岛cNOS可增强氨基酸刺激期间的胰岛素释放。此外，抑制cNOS可抑制胰高血糖素释放，以L-精氨酸作为促分泌剂时的抑制作用比L-高精氨酸更明显，这反映了它们的NO生成相对速率。在K⁺去极化的胰岛中，抑制cNOS可使对L-精氨酸的胰岛素反应增强50%，对L-高精氨酸的胰岛素反应增强23%，这在很大程度上与它们的相对NO生成量相对应。细胞内NO供体羟胺在K⁺去极化和氨基酸刺激的胰岛中剂量依赖性地抑制胰岛素分泌，但增加胰高血糖素分泌。我们得出结论，两种氨基酸对胰岛素释放都有双重作用，因为它们的刺激作用随着其NO生成速率的降低而减弱。此外，相对于L-高精氨酸，L-精氨酸诱导的更大NO生成量与NO介导的胰高血糖素释放增加相对应。这些NO效应主要独立于膜去极化事件发挥作用。
