Phosphodiesterase-linked inhibition of nonmicturition activity in the isolated bladder

OBJECTIVE To explore the influence of intracellular cAMP on phasic activity in the isolated bladder (phasic rises in intravesical pressure associated with waves of contraction and local stretches that can be activated by muscarinic or nicotinic agonists), as it has been argued that this activity underlies nonmicturition contractions, and that it contributes to the generation and modulation of afferent nerve activity. MATERIALS AND METHODS Isolated whole bladders from female guinea pigs (270-300 g) were cannulated via the urethra and suspended in a chamber containing oxygenated Tyrode solution at 33-35 degreesC. Bladder pressure was recorded and pharmacological agents added to the solution bathing the abluminal surface of the bladder. RESULTS Forskolin (1-3 mumol/L), an activator of adenyl cyclase, reduced the frequency and amplitude of the phasic activity induced by the muscarinic agonist arecaidine (300 nmol/L). There were similar changes in frequency and amplitude in bladders exposed to the nonspecific phosphodiesterase (PDE) inhibitor iso-butyl-methyl-xanthene (IBMX). The actions of specific PDE inhibitors were explored to assess which isoenzymes might be responsible for regulating phasic activity. ENHA (PDE-2), zaprinast (PDE-5, -6, -8, -9 and -11) and siguazodan (PDE-3) had no effect. Zardavarine (PDE-3, -4) and Ro 20-1724 (PDE-4) reduced both the frequency and amplitude of the phasic activity. Nerve-mediated rises in intravesical pressure were also inhibited by Ro 20-1724, and the inhibition was more pronounced at 6.5 Hz than at 30 Hz stimulation. Ro 20-1724 inhibited nerve-mediated fluctuations induced by prolonged (200 s) stimulation at 6.5 Hz. CONCLUSION The mechanisms influencing the frequency of agonist-induced phasic activity in the isolated bladder are slowed by cAMP. Degradation of intracellular cAMP in the cells responsible for phasic activity appears to involve primarily PDE-4. The importance of these observations in relation to the overall physiological regulation of the bladder are discussed, and the possible importance of these findings in the development of pharmacological strategies to modulated bladder activity reviewed.