tetrodotoxin and Urinary-Bladder--Neurogenic

Focal injection of the sodium channel blocker tetrodotoxin (TTX) into the injury site at either 5 or 15 min after a standardized thoracic contusion spinal cord injury (SCI) reduces white matter pathology and loss of axons in the first 24 hr after injury. Focal injection of TTX at 15 min after SCI also reduces chronic white matter loss and hindlimb functional deficits. We have now tested the hypothesis that the reduction in chronic deficits with TTX treatment is associated with long-term preservation of axons after SCI and compared both acute (24 hr) and chronic (6 weeks) effects of TTX administered at 15 min prior to and 5 min or 4 hr after SCI. Our results indicate a significant reduction of acute white matter pathology in rats treated with TTX at 15 min before and 5 min after injury but no effect when treatment was delayed until 4 hr after contusion. Compared with injury controls, groups treated with TTX at 5 min and 4 hr after injury did not show a significant deficit reduction, nor was there a significant sparing of white matter at 6 weeks compared with injury controls. In contrast, the group treated with TTX at 15 min before SCI demonstrated significantly reduced hindlimb functional deficits beginning at 1 week after injury and throughout the 6 weeks of the study. This was associated with a significantly higher axon density in the ventromedial white matter at 6 weeks. The results demonstrate that blockade of sodium channels preserves axons from loss after SCI and points to the importance of time of administration of such drugs for therapeutic effectiveness.

Topics: Animals; Axons; Cell Count; Contusions; Convalescence; Drug Evaluation, Preclinical; Female; Ion Transport; Myelin Sheath; Neuroprotective Agents; Paraplegia; Rats; Rats, Sprague-Dawley; Sodium; Sodium Channels; Spinal Cord Injuries; Tetrodotoxin; Time Factors; Urinary Bladder, Neurogenic

The objective of the study was to quantify in vitro the magnitude of atropine-resistant contractions using human detrusor samples and to determine the cellular processes underlying these contractions.. Isometric contractile responses were measured in isolated strips of human detrusor muscle obtained from patients with i) stable, ii) unstable or iii) obstructed bladders. Preparations were electrically stimulated or exposed to carbachol and ATP in the superfusate.. Force-frequency curves were shifted to the right in samples from unstable and obstructed bladders. These same tissue groups also showed significant atropine-resistant contractions which were abolished by the neurotoxin TTX, or the non-hydrolysable ATP analog, alpha,beta-methylene ATP, suggesting that these contractions were mediated by neurally released ATP. Sub-division of the patient group with unstable bladders demonstrated that those with neuropathic instability did not show atropine-resistance, whereas those with idiopathic instability or secondary instability after obstruction did show atropine-resistant contractions. The potency of carbachol in generating a contracture was significantly greater than ATP (mean EC50 0.65 microM and 151 microM respectively) however, for each agonist there was no difference in potency between the three patient groups. Direct muscle excitability was similar in all three patient groups.. It is concluded that purinergic, atropine-resistant contractions are present in some types of dysfunctional bladder, and these are not caused by a differential sensitivity of the muscle to ATP and cholinergic agonists.

Topics: Adenosine Triphosphate; Atropine; Carbachol; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; In Vitro Techniques; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Tetrodotoxin; Urinary Bladder; Urinary Bladder Neck Obstruction; Urinary Bladder, Neurogenic

The effect of intramural nerve stimulation of isolated strips of human detrusor was investigated and compared with the response of isolated detrusor strips of control bladders. All patients with neurogenic bladder underwent ileocystoplasty in order to resolve intractable incontinence and/or vesicoureteric reflux due to low compliance or severe detrusor uninhibited contractions. The response of isolated strips of neurogenic bladder to field stimulation was significantly greater than the response of isolated strips of control bladders. Tetrodotoxin virtually eliminated the response to field stimulation for both groups. Atropine (10(-6)M) almost completely inhibited the response of control bladder strips to field stimulation (4% of the response remaining), whereas the responses of the strips from neurogenic bladders were inhibited by approximately 70%. Low dose KCl (5 and 10 mM) significantly enhanced the detrusor contractility of control bladders, whereas the response of neurogenic bladders was unchanged. The responses of both groups were significantly inhibited in the presence of 20 mM KCl. The dose response curves and the ED50 values for KCl were similar for both neurogenic and control bladders. The rate of reduction of the response to field stimulation in the presence of zero calcium medium was significantly smaller for the isolated strips of neurogenic bladders than for the control bladders.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Electric Stimulation; Female; Humans; Male; Muscle Contraction; Muscle, Smooth; Potassium Chloride; Tetrodotoxin; Urinary Bladder; Urinary Bladder, Neurogenic

The detrusor contraction induced by intramural nerve stimulation in human neurogenic bladders was investigated in comparison with control bladders. All the cases with the neurogenic bladder underwent ileocystoplasty in order to resolve intractable incontinence and/or vesicoureteral reflux due to low bladder compliance or severe detrusor uninhibited contraction. 1. The dose-response curve and ED50 value for KCl were not different between neurogenic and control bladders. 2. The response of neurogenic bladders induced by intramural stimulation was significantly stronger than that of control bladders. 3. After application of 10(-6) M atropine remaining contraction of neurogenic bladders was significantly greater than that of control bladders, i.e. 28.4% and 3.7% respectively. However, 10(-6) M tetrodotoxin almost completely inhibited the detrusor contraction in both groups. 4. The subthreshold KCl (5 mM or 10 mM) enhanced the detrusor contractility significantly in control bladders compared to neurogenic bladders. 5. After bathing medium was replaced into Ca-free Krebs' solution, the contractile response was decreased. The contraction of neurogenic bladders in Ca-free solution persisted longer than that of controls. In conclusion, though there was no intrinsic difference in detrusor contractility, contractile response to electrical field stimulation, atropine resistance, enhancement of response by potassium, and contractility in Ca-free solution were significantly different between neurogenic and control bladders.

Topics: Adolescent; Adult; Atropine; Child; Child, Preschool; Dose-Response Relationship, Drug; Electric Stimulation; Female; Humans; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Potassium Chloride; Tetrodotoxin; Urinary Bladder; Urinary Bladder, Neurogenic