Our previous work has shown that endotoxin triggers the release of calcitonin gene-related peptide (CGRP) from the mesenteric arterial bed, which is partially mediated by nitric oxide. In the present study, the changes of endotoxin-induced CGRP release from the isolated mesenteric arterial bed and the CGRP mRNA levels in dorsal root ganglia (DRG) of diabetic rats were studied in relation to the effect of nitric oxide. CGRP level in perfusate and the steady-state level of mRNA for CGRP in DRG were determined by RIA and semi-quantitatively by RT-PCR. The results showed that endotoxin (1-25 micrograms/ml) accumulated in perfusate caused concentration-dependent release of CGRP, which was significantly decreased in mesenteric arterial bed of diabetic rats. As compared with age-related control, the endotoxin (10 and 25 micrograms/ml) -induced CGRP release in diabetic rats was attenuated by 27% and 40%, respectively. L-NAME, an inhibitor of nitric oxide synthase, inhibited the effect of endotoxin in dose of 10 and 25 micrograms/ml by 23% and 46%, respectively against the control rats. However, there was no inhibitory effect of L-NAME on endotoxin-induced CGRP release in diabetic rats. The CGRP mRNA level in DRG showed no significant difference between the two groups. These results indicate that the response of the isolated mesenteric arterial bed to endotoxin-induced CGRP release in diabetic rats is significantly lower than that in control. The mechanism, at least in part, is due to a decrease of nitric oxide mediated release of CGRP, rather than a decrease of CGRP gene expression.