Role of nitric oxide/cyclic GMP pathway in regulating spontaneous excitations in detrusor smooth muscle of the guinea-pig bladder

• Published in: Neurourology and urodynamics 2008-06, Vol.27 (5), p.446-453
• Main Authors: Yanai, Yoshimasa, Hashitani, Hikaru, Hayase, Masa, Sasaki, Shoichi, Suzuki, Hikaru, Kohri, Kenjiro
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Calcium - metabolism; cyclic GMP; Cyclic GMP - physiology; detrusor smooth muscle; Electrophysiology; Female; Guinea Pigs; In Vitro Techniques; Indoles - pharmacology; interstitial cell; Isometric Contraction - drug effects; Male; Molsidomine - analogs & derivatives; Molsidomine - pharmacology; Muscle Contraction - physiology; Muscle, Smooth - innervation; Muscle, Smooth - physiology; nitric oxide; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; Nitroprusside - pharmacology; Phosphodiesterase Inhibitors - pharmacology; Piperazines - pharmacology; Purines - pharmacology; Signal Transduction - physiology; Sildenafil Citrate; Sulfones - pharmacology; Urinary Bladder - innervation; Urinary Bladder - physiology
• ISSN: 0733-2467; 1520-6777
• DOI: 10.1002/nau.20517

Aims The role of nitric oxide (NO)/cyclic GMP (cGMP) pathway in regulating detrusor smooth muscle (DSM) function is still to be elucidated. We have investigated the effects of NO donors and phosphodiesterase‐5 (PDE5) inhibition on spontaneous excitations in DSM. Methods Multibundle DSM of the guinea‐pig bladder generated spontaneous phasic contractions. The effects of sodium nitroprusside (SNP) and 3‐morpholinosydnonimine (SIN‐1), NO donors, 8‐bromo‐cyclicGMP (8‐Br‐cGMP), a cell‐permeable cGMP analog and sildenafil, a PDE5 inhibitor on these contractions were examined. The effects of these agents on spontaneous action potentials were also studied using intracellular recording technique in single‐bundle DSM. Results SNP and SIN‐1 enhanced spontaneous contractions in multibundle DSM and increased the frequency of spontaneous action potentials in single‐bundle DSM. These excitatory effects were not antagonized by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ), an inhibitor for guanylate cyclase, but were attenuated by cyclopiazonic acid (CPA), an inhibitor of sarco‐ and endoplasmic Ca ATPase (SERCA). 8‐Br‐cGMP invariably suppressed spontaneous contractility. Sildenafil inhibited spontaneous contractions in about 65% of multibundle DSM but had no effects on the remainder. In single‐bundle DSM, sildenafil had no effect on spontaneous action potentials. Conclusions These results suggested that NO caused an enhancement of spontaneous contractions in DSM by accelerating spontaneous action potentials through cGMP‐independent mechanisms, which may involve the Ca release from intracellular stores, whilst cGMP itself has inhibitory effects on DSM contractility. Sildenafil may indirectly suppress DSM contractility by diminishing synchronicity between functional units of DSM bundles without inhibiting excitability of DSM themselves. Neurourol. Urodynam. 27:446–453, 2008. © 2007 Wiley‐Liss, Inc.