Combination of foot stimulation and tolterodine treatment eliminates bladder overactivity in cats.

AIMS: To determine whether transcutaneous foot stimulation combined with a lower dose tolterodine would inhibit bladder overactivity more effectively than either treatment alone. METHODS: Cystometrograms were performed on α-chloralose anesthetized cats (N = 6) by infusing 0.25% acetic acid (AA) to induce bladder overactivity. Foot stimulation (5 Hz) was applied at 2 and 4 times the threshold (T) intensity in volts (i.e., 2T or 4T) for inducing toe movement to inhibit bladder overactivity. Cumulative doses of tolterodine (0.003-0.3 mg/kg, i.v.) were also administered to determine the effect of combination treatment. RESULTS: AA irritation of the bladder significantly (P < 0.0001) reduced bladder capacity to 23.6 ± 7.1% of saline control capacity. Foot stimulation alone at 2T and 4T inhibited bladder overactivity and significantly (P < 0.0001) increased bladder capacity to 50.7 ± 6.8% and 79.0 ± 11.6% of saline control, respectively. Tolterodine alone at 0.3 mg/kg significantly (P < 0.05) increased bladder capacity to 65.6 ± 15.5% of saline control. However, when tolterodine at a threshold dose (0.3 mg/kg) was combined with foot stimulation, the bladder capacity was significantly (P < 0.05) increased to 86.2 ± 6.2% and 107.9 ± 10.6% by 2T and 4T stimulation, respectively. Complete inhibition of bladder overactivity could be achieved at a lower tolterodine dose (0.1 mg/kg) when combined with 4T stimulation (97.0 ± 11.2% of saline control). The amplitude of micturition contraction was not changed by tolterodine treatment. CONCLUSIONS: This study suggests a novel, efficacious, non-invasive therapy by combining foot stimulation with a lower dose tolterodine to treat bladder overactivity. It also provides the first objective evidence supporting an additive therapeutic benefit of neuromodulation and antimuscarinic combination treatment.

Future direction in pharmacotherapy for non-neurogenic male lower urinary tract symptoms.

BACKGROUND: The pathophysiology of male lower urinary tract symptoms (LUTS) is highly complex and multifactorial. The shift in perception that LUTS are not sex or organ specific has not been followed by significant innovations regarding the available drug classes. OBJECTIVE: To review pathophysiologic mechanisms and clinical and experimental data related to the development of new pharmacologic treatments for male LUTS. EVIDENCE ACQUISITION: The PubMed database was used to identify articles describing experimental and clinical studies of pathophysiologic mechanisms contributing to male LUTS and, supported by them, new pharmacotherapies with clinical or experimental evidence in the field. EVIDENCE SYNTHESIS: Several pathologic processes (eg, androgen signaling, inflammation, and metabolic factors) and targets (eg, the urothelium, prostate, interstitial cells, detrusor, neurotransmitters, neuromodulators, and receptors) have been implicated in male LUTS. Some newly introduced drugs, such as phosphodiesterase type 5 inhibitors and ß3-adrenergic agonists, have just started broad use in clinical practice. Drugs with potential benefit, such as vitamin D3 receptor analogs, gonadotropin-releasing hormone antagonists, cannabinoids, and drugs injected into the prostate, have been evaluated in experimental studies and have progressed to clinical trials. However, safety and efficacy data for these drugs are still scarce. Some compounds with interesting profiles have only been tested in experimental settings (eg, transient receptor potential channel blockers, Rho-kinase inhibitors, purinergic receptor blockers, and endothelin-converting enzyme inhibitors). CONCLUSIONS: New pathophysiologic mechanisms of male LUTS are described that lead to the continuous development of new pharmacotherapies. To date, few drugs have been added to the current armamentarium, and several are in various phases of clinical or experimental investigation.