RAPID NITRIC OXIDE-DEPENDENT AND PROSTAGLANDIN-DEPENDENT RELEASE OF CALCITONIN-GENE-RELATED PEPTIDE (CGRP) TRIGGERED BY ENDOTOXIN IN RAT MESENTERIC ARTERIAL BED

1 Our objective was to determine whether endotoxin (ETX) could directl y trigger the release of calcitonin gene-related peptide (CGRP) from p erivascular sensory nerves in the isolated mesenteric arterial bed (MA B) of the rat and to determine whether nitric oxide (NO) and prostagla ndins (PGs) are involved. 2 ETX caused time- and concentration-depende nt release of CGRP, and as much as a 17 fold increase in CGRP levels i n the perfusate at 10-15 min after the administration of ETX (50 mu g ml(-1)). 3 CGRP-like immunoreactivity in the perfusate was shown to co -elute with synthetic rat CGRP by reverse-phase h.p.l.c. 4 Pretreatmen t of MAB with capsaicin or ruthenium red inhibited ETX-induced CGRP re lease by 90% and 71%, respectively. ETX-evoked CGRP release was decrea sed by 84% during Ca2+-free perfusion. 5 The release of CGRP evoked by ETX was enhanced by L-arginine by 43% and inhibited by N-omega-nitro- L-arginine (L-NOARG) and methylene blue by 37% and 38%, respectively. L-Arginine reversed the effect of L-NOARG. 6 Indomethacin and ibuprofe n also inhibited the ETX-induced CGRP release by 34% and 44%, respecti vely. No additive inhibition could be found when L-NOARG and indometha cin were concomitantly incubated. 7 The data suggest that ETX triggers the release of CGRP from capsaicin-sensitive sensory nerves innervati ng blood vessels. The ETX-induced CGRP release is dependent on extrace llular Ca2+ influx and involves a ruthenium red-sensitive mechanism. B oth NO and PGs appear to be involved in the ETX-induced release of CGR P in the rat mesenteric arterial bed.