ARGININE-INDUCED INSULIN RELEASE IS DECREASED AND GLUCAGON INCREASED IN PARALLEL WITH ISLET NO PRODUCTION

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-hom oarginine is inhibited and that of glucagon stimulated in parallel wit h the rate of islet NO production. It was found that L-homoarginine wa s approximate to 25-30% less potent than L-arginine as an insulin secr etagogue but equally potent as a glucagon secretagogue. Biochemical de termination of islet cNOS activity revealed that the NO production wit h L-homoarginine as substrate was only approximate to 40% of that of L -arginine. Selective inhibition of islet cNOS potentiated insulin rele ase during amino acid stimulation. Moreover, inhibition of cNOS suppre ssed glucagon release, more so with L-arginine than with L-homoarginin e as secretagogue, reflecting the relative rates of their NO productio n. In K+-depolarized islets, inhibition of cNOS enhanced the insulin r esponse to L-arginine by 50% and that to L-homoarginine by 23%, largel y corresponding to their relative NO production. The intracellular NO donor hydroxylamine dose dependently inhibited insulin but increased g lucagon secretion in K+-depolarized and amino acid-stimulated islets. We conclude that both amino acids have a dual action on insulin releas e, since their stimulatory effects are reduced in parallel with the ra tes of their NO production. Furthermore, the greater NO production ind uced by L-arginine relative to L-homoarginine corresponds to NO-mediat ed increases in glucagon release. These NO effects are mainly exerted independently of membrane depolarization events.