THE NEUROTRANSMITTER ROLE OF CALCITONIN GENE-RELATED PEPTIDE IN THE RAT AND GUINEA-PIG URETER - EFFECT OF A CALCITONIN GENE-RELATED PEPTIDE ANTAGONIST AND SPECIES-RELATED DIFFERENCES IN THE ACTION OF OMEGA CONOTOXIN ON CALCITONIN GENE-RELATED PEPTIDE RELEASE FROM PRIMARY AFFERENTS

In the rat and guinea-pig isolated ureter electrical field stimulation of intrinsic nerves (10 Hz for 10 s) produces transient inhibition of evoked (20 mM KCl or 0.1-1-mu-M neurokinin A) rhythmic contractions by releasing transmitter(s) from peripheral endings of capsaicin-sensitive primary afferents. The C-terminal fragment 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-evoked 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-mu-M) shown previously to inhibit sensory neuropeptide release in other guinea-pig tissues, 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.