Pruritus ani: is anal sphincter dysfunction important in aetiology?

Forty-three patients whose principal symptom was pruritus ani were studied. Twenty-eight had anal disease, while in 15 no such disease could be shown. Maximum resting pressures and transient and sustained pressures of the anal canal in response to rectal distension were measured by manometry. Although the maximum resting pressure in the patients with no disease was about the same as that in the group with disease, the pressures recorded in response to rectal distension were significantly lower. These results show that the anal sphincter relaxes in response to rectal distension more readily in patients with no anal disease. Hence soiling may occur, which may be a factor in the genesis of pruritus ani.     

Relaxation by β3-adrenoceptor agonists of the isolated human internal anal sphincter

AimsIn this study, responses of β₃-adrenoceptor agonists were examined on human isolated internal anal sphincter (IAS) in order to explore their relaxant effects on hypertonicity of IAS.Main methodsThe relaxant efficacy (E_max) and potency (? logIC₅₀) of BRL37344 and SR58611A, β₃-adrenoceptor agonists, were examined in contracted IAS muscle strips. The presence of β₃-adrenoceptors, and changes in intracellular calcium and cyclic nucleotide levels in IAS muscle were tested by Western blotting, epifluorescence microscopy and enzyme immunoassay, respectively.Key findingsBRL37344 and SR58611A relaxed contracted IAS muscle (E_max = 27 ± 3% and 35 ± 3%; -logIC₅₀ = 6.26 ± 0.24 and 4.87 ± 0.13; respectively). These relaxant responses were blocked by SR59230A, a selective β₃-antagonist but not by β₁/β₂-selective antagonists, neuronal inhibitor or inhibition of nitric oxide synthase. The E_max of β₃-agonists was similar to that of β₂-selective agonists but smaller than that of isoprenaline (nonselective agonist) or β₁-selective agonists. BRL37344 (100 μM) increased cAMP (1.5-fold) without cGMP change, and depressed intracellular calcium signal. β₃-Adrenoceptor expression was smaller than that of β₁- and β₂-adrenoceptors.SignificanceThis is the first study demonstrating the presence of β₃-adrenoceptor in human IAS muscle and β₃-mediated relaxation of augmented sphincter tone. However, direct β₃-relaxation appears smaller than that obtained for nonselective agonists which may limit their potential use in the treatment of anorectal hypertonicity disorders.     

Sphincter incontinence: Is regenerative medicine the best alternative to restore urinary or anal sphincter function?

Incontinence is a major public health concern in aging societies. It is caused by age-dependent spontaneous apoptosis of muscle cells in the urinary and fecal sphincters, and is aggravated in women due to birth trauma. Compared to other currently employed invasive surgical management techniques associated with morbidity and recurrence, replacement or regeneration of dysfunctional sphincter through stem cell therapy and tissue engineering techniques hold great promise. This review focuses on the pathophysiological analysis of urinary incontinence and the possible application of muscle-derived-stem cells, satellite cells, chondrocytes and adipose-derived-stem cells in restoring sphincter functions.     

nNOS in canine lower esophageal sphincter: colocalized with Cav-1 and Ca2+-handling proteins?

Immunochemical studies with light microscopy, confocal microscopy, and electron microscopy were used to examine proteins associated with caveolin (Cav) in canine lower esophageal sphincter. The main Cav was Cav-1. It appeared to be colocalized at the cell periphery, in punctate sites, with immunoreactivity to antibodies against different COOH- and NH2-terminal epitopes of neuronal nitric oxide (NO) synthase (nNOS). One COOH-terminal-directed antibody, made in guinea pig, was used to colocalize other immunoreactivities. Those that apparently colocalized with nNOS were L-Ca2+ channels, the PM Ca2+ pump, and, in part, calreticulin and calsequestrin. The large-conductance Ca2+-activated K+ (BK(Ca)) channels were located in discrete peripheral sites, some with Cav. Immunoreactivities not fully colocalized with nNOS were to the sarcoplasmic reticulum Ca2+ pump, connexins 43, 40, and 45, and vinculin. In patch-clamp studies, NO-driven outward currents, mainly through BK(Ca) channels, were inhibited by antibodies to Cav-1 and not by calmodulin and were restored by an NO donor. Several Ca2+-handling molecules are localized at the PM with and/or near Cav. This may allow intracellular calcium concentration levels to be controlled differently than those in the cytosol near caveolae.     

Sacral anterior root stimulation and cryotechnique: A new option for selective urethral sphincter block and reversible deafferentation in the future?

A possible application of cryotechnique might be a selective block of nerve fiber activity during sacral anterior root stimulation to achieve selective block of urethral sphincter and reversible deafferentation. In 13 foxhounds, electrical stimulation of sacral anterior roots S2 was performed while the accompanying spinal nerves were simultaneously cooled down from +25 degrees C in a stepwise fashion until a block of urethral sphincter activity was observed. The effects of cold block on the urethral sphincter and bladder were monitored by urodynamic investigation. In 2 additional dogs sacral posterior roots S2 were cooled down to +3 degrees C while accompanying anterior and posterior roots were stimulated distal to the cryothermode. Compound action potentials (APs) were registered proximal to the cryothermode before, during and after cooling and recovery time of cold blocked nerves was evaluated. Complete cold block of the urethral sphincter during spinal nerve cooling was achieved in all cases. Block temperature averaged +12 degrees C. Detrusor pressure was a mean 5,2 cm water. Recovery time was on average 5 min. The cold block was always reversible. In both dogs of the second series the compound action potentials disappeared nearly completely at +3 degrees C. Three min after the end of the cooling period the appearance of the compound action potentials was back to normal. In this study, cryotechnique proved to be effective for selective and reversible block of nerve fibers during sacral anterior root stimulation. In functional electrical stimulation this technique may lead to an improvement of quality of life in para- or tetraplegic patients resulting in optimization of voiding, standing, walking and grasping and does so without the necessity of surgical dorsal root rhizotomy.