Although patients with lower urinary tract symptoms constitute a large and still growing population, understanding of bladder detrusor muscle physiology remains limited. Understanding the interactions between the detrusor smooth muscle cells and other bladder cell types (e.g. interstitial cells, IC) that may significantly contribute to coordinating and modulating detrusor contractions represents a considerable challenge. Computer modeling could help to elucidate some properties that are difficult to address experimentally; therefore, we developed in silico models of detrusor smooth muscle cell and interstitial cells, coupled through gap junctions. The models include all of the major ion conductances and transporters described in smooth muscle cell and interstitial cells in the literature. The model of normal detrusor muscle (smooth muscle cell and interstitial cells coupled through gap junctions) completely reproduced the experimental results obtained with detrusor strips in the presence of several pharmacological interventions (ryanodine, caffeine, nimodipine), whereas the model of smooth muscle cell alone (without interstitial cells) failed to reproduce the experimental results. Next, a model of overactive bladder, a highly prevalent clinical condition in both men and women with increasing incidence at older ages, was produced by modifying several processes as reported previously: a reduction of Ca(2+)-release through ryanodine receptors and a reduction of Ca(2+)-dependent K(+)-conductance with augmented gap junctional coupling. This model was also able to reproduce the pharmacological modulation of overactive bladder. In conclusion, a model of bladder detrusor muscle was developed that reproduced experimental results obtained in both normal and overactive bladder preparations. The results indicate that the non-smooth muscle cells of the detrusor (interstitial cells) contribute significantly to the contractile behavior of bladder detrusor muscle and should not be neglected. The model suggests that reduced Ca(2+)-release through ryanodine receptors and Ca(2+)-dependent K(+)-conductance together with augmented gap junctional coupling might play a major role in overactive bladder pathogenesis.
- MeSH
- Calcium-Transporting ATPases metabolism MeSH
- Endoplasmic Reticulum drug effects metabolism MeSH
- Urinary Bladder, Overactive physiopathology MeSH
- Humans MeSH
- Membrane Potentials drug effects physiology MeSH
- Urinary Bladder cytology physiology MeSH
- Myocytes, Smooth Muscle drug effects physiology MeSH
- Computer Simulation * MeSH
- Ryanodine pharmacology MeSH
- Sarcoplasmic Reticulum drug effects metabolism MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
The kinetics of the phasic synchronous and delayed asynchronous release of acetylcholine quanta was studied at the neuromuscular junctions of aging rats from infant to mature animals at various frequencies of rhythmic stimulation of the motor nerve. We found that in infants 6 (P6) and 10 (P10) days after birth a strongly asynchronous phase of quantal release was observed, along with a reduced number of quanta compared to the synapses of adults. The rise time and decay of uni-quantal end-plate currents were significantly longer in infant synapses. The presynaptic immunostaining revealed that the area of the synapses in infants was significantly (up to six times) smaller than in mature junctions. The intensity of delayed asynchronous release in infants increased with the frequency of stimulation more than in adults. A blockade of the ryanodine receptors, which can contribute to the formation of delayed asynchronous release, had no effect on the kinetics of delayed secretion in the infants unlike synapses of adults. Therefore, high degree of asynchrony of quantal release in infants is not associated with the activity of ryanodine receptors and with the liberation of calcium ions from intracellular calcium stores.
- MeSH
- Bungarotoxins pharmacokinetics MeSH
- Electric Stimulation MeSH
- Rats MeSH
- Gallic Acid analogs & derivatives pharmacokinetics MeSH
- Neuromuscular Junction drug effects growth & development metabolism MeSH
- Neurotransmitter Agents metabolism MeSH
- Receptors, Nicotinic metabolism MeSH
- Animals, Newborn MeSH
- Reaction Time physiology MeSH
- Ryanodine pharmacokinetics MeSH
- Synaptic Potentials physiology MeSH
- Synaptophysin metabolism MeSH
- Age Factors MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Financing, Organized MeSH
- Ventricular Function, Right drug effects MeSH
- Myocytes, Cardiac metabolism drug effects MeSH
- Myocardial Contraction drug effects MeSH
- Rabbits MeSH
- Ryanodine administration & dosage pharmacology MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Animals MeSH
- MeSH
- Dantrolene administration & dosage pharmacology MeSH
- Diastole physiology drug effects MeSH
- Ventricular Function, Right physiology drug effects MeSH
- Caffeine administration & dosage pharmacology MeSH
- Myocardial Contraction physiology drug effects MeSH
- Rabbits MeSH
- Ryanodine administration & dosage pharmacology MeSH
- Ryanodine Receptor Calcium Release Channel physiology drug effects MeSH
- Sarcoplasmic Reticulum drug effects MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Animals MeSH
- MeSH
- Rabbits MeSH
- Papillary Muscles physiology physiopathology growth & development MeSH
- Ryanodine administration & dosage MeSH
- Sarcoplasmic Reticulum physiology MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Animals MeSH
- Publication type
- Congress MeSH
65 s. : il., tab. ; 22 cm
- MeSH
- Malignant Hyperthermia MeSH
- Ryanodine MeSH
- Ryanodine Receptor Calcium Release Channel MeSH
- Publication type
- Academic Dissertation MeSH
- Conspectus
- Patologie. Klinická medicína
- NML Fields
- anesteziologie a intenzivní lékařství
