THE ROLE OF CAPSAICIN-SENSITIVE SENSORY NEURONS AND NITRIC-OXIDE IN REGULATION OF GASTRIC-MUCOSAL GROWTH

Capsaicin and nitric oxide (NO) cause potent vasorelaxation which is important in gastroprotective activity against damage but the mechanisms underlying these effects have not been elucidated. This study investigated the influence of capsaicin-induced functional ablation of afferent neurons and inhibition of NO production on the gastric mucosal growth in normal conditions, after 48 h fasting and subsequent refeeding. We found that ablation of sensory neurons by capsaicin pretreatment (100 mg/kg over 3 days) reduced by around 45% the mucosal blood flow (MBF), as measured by laser Doppler flowmetry, in normal fed and refed rats, while by 15% only in fasted animals. This last group of animals had significant decrease in the MBF even in control conditions as compared to that recorded in fed animals. This drop in MBF after capsaicin-induced denervation was accompanied by a significant decrease in DNA synthesis (by 40% in control group and 35% in refed rats) and was less pronounced in the group of fasted rats (23%). Ablation of sensory neurons resulted in the decrease in the stomach weight and RNA content in regular feed and refed but not in 48 h fasted group of animals. Treatment with N-G-nitro-L-arginine (L-NNA; 2 x 20 mg/kg daily s.c.), a selective blocker of NO synthase, significantly suppressed the MBF in all three groups of animals tested but this suppression was less pronounced when compared to capsaicin pretreatment. This inhibitory effect of L-NNA on MBF was fully antagonized by L-arginine (2 x 100 mg/kg daily s.c.). L-NNA injection s.c. reduced the DNA synthesis (36% control group, 38% refed animals, 18% fasted rats), stomach weight, RNA and DNA content in all tested groups of rats. This inhibition was reversed by the addition of L-arginine. The combination of capsaicin and L-NNA decreased the MBF significantly and the inhibition was stronger than the effect of each substance given alone. In normal fed and refed rats, the neurotoxic dose of capsaicin together with L-NNA significantly decreased the DNA synthesis, stomach weight, RNA and DNA content but these effects were smaller than the sum of the effects of each agent given alone. We conclude that both the capsaicin-induced denervation and the suppression of endogenous NO by L-NNA inhibit the growth of the gastric mucosa by the mechanism involving, at least in part, the suppression of gastric mucosal blood flow.