INTERLEUKIN-1-BETA EFFECTS ON CYCLIC-GMP AND CYCLIC-AMP IN CULTURED RAT ISLETS OF LANGERHANS ARGININE DEPENDENCE AND RELATIONSHIP TO INSULIN-SECRETION

When islets were cultured with interleukin-1beta (1 or 100 pmol/1) for 12 h in arginine-containing medium, cyclic GMP levels were increased 1.6- and 4.5-fold respectively. The arginine analogue, N-omega-nitro-L-arginine methyl ester, which blocks nitric oxide formation and partially reverses inhibition of insulin secretion by 100 pmol/I interleukin-1beta, largely, but not completely, blocked generation of cyclic GMP. Treatment of islets with 100 pmol/I interleukin-1beta for 12 h significantly decreased islet cyclic AMP generation in the absence of isobutylmethylxanthine (from 13.1 +/- 0.7 to 9.3 +/-0.8 fmol/mug islet protein), this fall was arginine-dependent and may have resulted from an effect on a cyclic AMP phosphodiesterase, since it was masked if isobutylmethylxanthine was present. Isobutylmethylxanthine (0.4 mmol/1) reduced the inhibitory potency of interleukin-1beta in 15 h slightly but significantly from 80.5 to 59.0%. The morpholinosydnonimine SIN-1, which is a nitric oxide donor, inhibited insulin secretion, raised islet cyclic GMP and lowered cyclic AMP; its effects were similar to those of interleukin-1beta. However, 6-anilinoquinoline-5,8-quinone, [LY83583 (1-10 mumol/1)], inhibited insulin secretion, and significantly decreased cyclic GMP while 8-bromocyclic GMP stimulated insulin secretion. Both low- and high-dose interleukin-1beta treatment give a large arginine-dependent and a small, yet significant, arginine-independent increase in cyclic GMP. The inhibitory effect of SIN-1 or interleukin-1beta on insulin secretion seems to depend to a small extent on decreased islet cyclic AMP, though sustained increases in nitric oxide or depleted islet GTP may directly affect the secretory process.