Abstract
In the rat and guinea-pig isolated ureter electrical field stimulation of intrinsic nerves (10 Hz for 10 s) produced transient inhibition of evoked (20 mM KCl or 0.1–1 μM neurokinin A) rhtyhmic contractions by releasing transmitter(s) from peripheral endings of capsaicin-sensitive primary afferents. The C-terminal fragments of human calcitonin gene-related peptide (8–37) blocked the inhibitory effect of electrical field stimulation as well as that produced by exogenous calcitonin gene-related peptide, while leaving unaffected the inhibitory response to isoprenaline. Human calcitonin gene-related peptide (8–37) was devoid of any inhibitory activity of its own but enhanced the amplitude and frequency of KCl-evokded rhythmic contractions in the rat ureter, probably by antagonizing the inhibitory effect of endogenous calcitonin gene-related peptide released by KCl. Omega conotoxin fraction GVIA, a peptide which possesses a potent blocking activity of N-type voltage-sensitive calcium channels, prevented the inhibitory response to electrical stimulation in the guinea-pig ureter, while leaving the response unaffected in the rat ureter. Conotoxin had no effect toward the inhibition produced by exogenous calcitonin gene-related peptide indicating its prejunctional site of action, demonstrated previously in the guinea-pig ureter [Maggi et al. (1990) Neurosci. Lett. 114, 203–206]. Dermorphin, an amphibian peptide with potent agonist activity on mu-type opioid receptors, inhibited the response to electrical stimulation in the guinea-pig ureter but had no effect in the rat ureter. Neuropeptide Y and galanin, at a concentration (0.1 μM) shown previously to inhibit sensory neuropeptide release in other guinea-pig tissue, had no effect in either the rat or guinea-pig ureter. These findings provide direct pharmacological evidence for a role of calcitonin gene-related peptide as an inhibitory transmitter in the ureter of both rats and guinea-pigs. A species difference emerges in the mechanisms of release of calcitonin gene-related peptide, conotoxin-sensitive calcium channels being important for electrically-evoked calcitonin gene-related peptide release in the guinea-pig but not in the rat ureter. Furthermore, organ-related differences in mechanisms of prejunctional modulation of sensory neuropeptide release may exist in guinea-pigs.
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