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Title: The modulatory role of adenosine in detrusor smooth muscle
Author: Ikeda, Youko
ISNI:       0000 0001 3586 2397
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2006
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The contractile process of the mammalian detrusor smooth muscle is mediated through the co-release of acetylcholine (Ach) and adenosine triphosphate (ATP) from the embedded motor nerves. The transmitters are rapidly degraded in the synaptic cleft by extracellular enzymes and the breakdown products are taken back up into the synapse for re-synthesis. Adenosine is the final breakdown product of ATP, and can act through adenosine-specific PI-receptors to modulate the contractile process in detrusor smooth muscle. The nature of modulation by adenosine has not been fully investigated in human detrusor smooth muscle and the possible changes to this signalling system in disease states and the contribution to bladder overactivity. In this study, in vitro muscle strip experiments with guinea-pig and human detrusor showed that adenosine reduces the force of contraction, with both electric-field stimulation and direct-muscle stimulation by the muscarinic-agonist, carbachol. A greater effect of adenosine was found on stable human bladder samples as compared to overactive bladder samples in nerve-mediated contractions. PI-receptor specific agonists indicated that A1-receptors were involved in pre-synaptic modulation of the contractile process, with a possible A2-mediated action on the smooth muscle cell itself. There was also stimulation frequency-dependent differential release of Ach and ATP in guinea-pig detrusor samples, with PI-receptor activity having a preferential effect upon ATP- mediated contractions. Isolated cell experiments showed that Ca -transients evoked by carbachol were significantly reduced by adenosine and A2s-receptor activation in both human and guinea-pig detrusor cells. The use of an adenylate cyclase inhibitor, MDL-12230A, showed that agonist-induced Ca2+-release is influenced by cAMP. However, Pl- receptors do not appear to have a modulatory role in this process. The results from this investigation indicate that adenosine can have a modulatory action upon the contractile process in detrusor smooth muscle, with differential effects of adenosine in stable and overactive human bladders. The implications and further understanding of the modulatory role of adenosine in the neuromuscular transmission in detrusor smooth muscle will be discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available