Inhibitory actions of calcitonin gene-related peptide and capsaicin: evidence for local axonal reflexes in the bladder wall.
OBJECTIVE
To explore the actions of capsaicin and the neurotransmitters released by capsaicin (substance P and calcitonin gene-related peptide, CGRP) on the phasic contractile activity generated in the whole isolated guinea pig bladder by muscarinic stimulation, and to examine the hypothesis that collateral fibres of sensory axons contribute to a local reflex in the bladder wall.


METHODS
All experiments used whole isolated bladders from female guinea pigs (270-300 g). Bladders were cannulated via the urethra to measure intravesical pressure and suspended in a heated chamber containing oxygenated Tyrode's solution at 33-35 degrees C. All drugs were added to the solution bathing the abluminal surface.


RESULTS
Application of capsaicin (10 micromol/L) to the whole isolated bladder resulted in complex changes in the frequency and amplitude of phasic activity generated by muscarinic stimulation; an initial burst of activity involving a rise in frequency, a second phase of reduced amplitude and frequency and a third phase where the amplitude of the transients recovered and the frequency increased. Capsaicin had no effect on the phasic activity generated by the nicotinic ligand lobeline (30 micromol/L). As capsaicin releases the neurotransmitter content of the sensory nerves, experiments explored the actions of CGRP and substance P on the muscarinic-induced activity. CGRP (3-30 nmol/L) reduced the amplitude and slowed the frequency of the phasic activity. On washing off CGRP the amplitude and frequency of the transient activity recovered and there was a transient increase in frequency above the levels before stimulation. There was also evidence of a desensitization to CGRP on repeated application. In contrast, substance P (100-300 nmol/L) increased the frequency of the transients, while on removing it there was an inhibition of both amplitude and frequency.


CONCLUSIONS
These results suggest that neurotransmitters released from sensory nerve endings in the guinea pig bladder wall affect phasic activity. The direct application of CGRP inhibited phasic activity while substance P was excitatory, indicating the specific contributions of these neurotransmitters. The excitation after stimulation with CGRP and inhibition with substance P may indicate that these neurotransmitters feed back on the sensory nerves to induce transmitter release. Taken together, these observations suggest the presence of a local reflex in the bladder wall, where axon collaterals of afferent sensory fibres innervate the pacemaker mechanism in the bladder wall responsible for generating phasic activity. The possible importance of this reflex in the physiology and pathophysiology of the bladder is discussed.
Gillespie
James I
JI
The Urophysiology Research Group, School of Surgical and Reproductive Sciences, The Medical School, The University, Newcastle upon Tyne NE2 4HH, UK. j.i.gillespie@ncl.ac.uk
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001369:Axons / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D012018:Reflex; D013373:Substance P / Q000187:drug effects / Q000378:metabolism*; D001743:Urinary Bladder / Q000294:innervation*
D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin