Role of nitric oxide/cyclic GMP pathway in regulating spontaneous excitations in detrusor smooth muscle of the guinea-pig bladder.
OBJECTIVE
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.
Yanai
Yoshimasa
Y
Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. y_yanai@mac.com
Hashitani
Hikaru
H
Hayase
Masa
M
Sasaki
Shoichi
S
Suzuki
Hikaru
H
Kohri
Kenjiro
K
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000294:innervation / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D001743:Urinary Bladder / Q000294:innervation / Q000502:physiology*
D007211:Indoles; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009599:Nitroprusside; D009569:Nitric Oxide; C002385:linsidomine; D000068677:Sildenafil Citrate; D008981:Molsidomine; D006152:Cyclic GMP; D002118:Calcium; C000543:cyclopiazonic acid