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Department of Pharmacology, University of Lund, S-223 62 Lund, Sweden
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
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 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.
islets of Langerhans; L-arginine; L-homoarginine; nitric oxide synthase activity; insulin secretion; glucagon secretion; nitric oxide synthase inhibitors
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