The effect of neuropeptide Y (NPY) in neurotransmission of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves was investigated in rats. In perfused mesenteric vascular beds with active tone, perivascular nerve stimulation (PNS; 1-8 Hz) caused a frequency-dependent vasodilator response, which was abolished by 300 nM tetrodotoxin (TTX), 500 nM capsaicin, 1 microM human CGRP-(8-37), or cold storage denervation (4 degrees C for 72 h). NPY (5, 10, and 50 nM) concentration dependently inhibited the vasodilator response to PNS, whereas NPY had little effect on vasodilation induced by exogenous CGRP (10 and 100 pmol) or 1 nmol acetylcholine (ACh). NPY (10 nM) inhibited the neurogenic release of CGRP-like immunoreactivity induced by PNS (4 and 8 Hz), which was abolished by 300 nM TTX and the removal of Ca2+ from the medium. Combined perfusion with 5 nM NPY and 10 nM norepinephrine additively inhibited the vasodilator response to PNS but not to exogenous CGRP and ACh. Immunohistochemistry showed the distinct distribution of CGRP- and NPY-like immunoreactivity-containing fibers in rat mesenteric arteries. These results suggest that NPY modulates presynaptically the release of CGRP from CGRP-containing vasodilator nerves in rat mesenteric arteries.
ABSTRACT-Structure-activity relationship of the chicken calcitonin gene-related peptide (cCGRP) was investigated and compared with human-a-CGRP (hCGRP) and rat CGRP (rCGRP) in the perfused mesenteric vascular beds of rats. In precontracted mesenteric vascular beds, cCGRP, hCGRP and rCGRP produced a concentration-dependent vasodilation. The vasodilator activities of cCGRP and rCGRP were equipotent and more potent than that of hCGRP. (Ala2,')cCGRP and (Des-l-Ala)-a-deamino cCGRP were 100 and 10-fold less potent than cCGRP, respectively. However, cCGRP curves of rCGRP to the right, but both peptides did not affect the maximum response and vasodilator responses to isoproterenol, these peptides being equipotent an tagonists (pA2 values: 7.6 and 7.4). In rat brain membrane preparations, cCGRP and its fragments and analogues, except for cCGRP , competed for specific binding sites with [125I]-hCGRP. These results suggest that cCGRP has a potent vasodilator activity for which the disulfide bridge at position 2 and 7 of cCGRP is an important site and that position 37 is necessary for the binding of the peptide to the receptor. Also, cCGRP [8 37] is a competitive CGRP-receptor antagonist.
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