FAILURE OF THE NITRIC-OXIDE SYNTHASE INHIBITOR TO STIMULATE DUODENAL BICARBONATE SECRETION IN STREPTOZOTOCIN-DIABETIC RATS

We examined the HCO3- stimulatory effects of L-NAME (N-G-nitro-L-argin ine methyl ester) in the proximal duodenum of streptozotocin (STZ)-ind uced diabetic rats and compared with those of 16,16-dimethyl prostagla ndin E2 (dmPGE2) and vagal electrical stimulation. Male SD rats were g iven STZ (70 mg/kg) i.p., and the experiments were done using 1 simila r to 6 week STZ-diabetic rats with blood glucose levels of >300 mg/dl. Under urethane anesthesia the HCO3- secretion was measured in the pro ximal duodenal loop using a pH-stat method and by adding 10 mM HCl. Hy perglycemic conditions appeared 1 week after STZ treatment and remaine d during 6 week-test period. The duodenal HCO3- secretory response to L-NAME was significantly decreased in STZ-diabetic rats; the degree of reduction was dependent on the duration of diabetes, and the stimulat ory effect disappeared completely in rats after 5 similar to 6 weeks o f diabetes. Intravenous administration of L-NAME markedly increased ar terial blood pressure with significant decrease in heart rate in norma l rats, whereas in STZ-diabetic rats this agent caused only presser re sponse without any effect on heart rate. STZ-diabetic rats also secret ed significantly less amount of HCO3- from the duodenum in response to dmPGE2 and vagal electrical stimulation after 5 similar to 6 weeks of diabetes. These all changes observed in STZ-diabetic rats were signif icantly reversed by daily injection of insulin. These results suggest that 1) L-NAME failed to stimulate duodenal HCO3- secretion in STZ-dia betic rats, and 2) impairment of the duodenal HCO3- secretory ability in STZ-diabetic conditions is due to both vagal-dependent neuronal dys function and decreased sensitivity of the secreting cell.