Reduced genioglossus muscle activity caused by fluid overload in anesthetized rats.

INTRODUCTION: Although the precise cause of obstructive sleep apnea (OSA) remains unknown, various anatomical or structural factors are thought to influence upper airway patency. Recent clinical studies show that OSA is frequently observed among patients with fluid-retaining states, such as heart/renal failure and postsurgery. It is important to note that a cause-effect relationship is not yet established, and our understanding of the effects of fluid overload is limited. The goal of this study was to investigate an animal model that can characterize the physiological changes that occur in response to fluid overload. METHOD: Acute nonsurvival experiments were conducted in 16 Sprague-Dawley rats. Rats were initially anesthetized by inhaled isoflurane, while the femoral vein was cannulated and urethane (1.2-1.5 g/Kg body weight) was gradually delivered intravenously to induce anesthesia. Additional doses of urethane were delivered as necessary to maintain a surgical plane of anesthesia. A surgical incision was made on the cervical area to catheterize carotid artery to measure blood pressure. A pair of stainless-steel wires was injected into the tongue to measure genioglossus muscle activity (GGEMG). All physiological measurements were recorded as intravenous infusion of saline was provided to the rat (infusion rate = 22 ml/kg over 30 min). RESULTS: Acute saline overloading resulted in a 33% decrease in GGEMG, when compared to baseline. There was also a gradual drop in the respiratory rate (13% decrease) that reached statistical significance at 10 min after infusion was stopped. The blood pressure exhibited a 14% increase which subsequently returned to baseline within 40 min stopping infusion. There were no significant changes in the heart rate. CONCLUSION: The results of this study indicate that systemic fluid overload can affect significant changes in different physiological systems including reduction in genioglossus muscle activity, increase in blood pressure, and change autonomic nervous system function.

Recruitment of unmyelinated C-fibers mediates the bladder-inhibitory effects of tibial nerve stimulation in a continuous-fill anesthetized rat model.

Although percutaneous tibial nerve stimulation is considered a clinically effective therapy for treating overactive bladder, the mechanism by which overactive bladder symptoms are suppressed remains unclear. The goal of the present study was to better understand the role of specific neural inputs (i.e., fiber types) on the bladder-inhibitory effects of tibial nerve stimulation (TNS). In 24 urethane-anesthetized rats, a continuous suprapubic saline infusion model was used to achieve repeated filling and emptying of the bladder. A total of 4 TNS trials (pulse frequency: 5 Hz) were applied in randomized order, where each trial used different amplitude settings: 1) no stimulation (control), 2) Aß-fiber activation, 3) Aδ-fiber activation, and 4) C-fiber activation. Each stimulation trial was 30 min in duration, with an intertrial washout period of 60-90 min. Our findings showed that TNS evoked statistically significant changes in bladder function (e.g., bladder capacity, residual volume, voiding efficiency, and basal pressure) only at stimulation amplitudes that electrically recruited unmyelinated C-fibers. In a subset of experiments, TNS also resulted in transient episodes of overflow incontinence. It is noted that changes in bladder function occurred only during the poststimulation period. The bladder-inhibitory effects of TNS in a continuous bladder filling model suggests that electrical recruitment of unmyelinated C-fibers has important functional significance. The implications of these findings in percutaneous tibial nerve stimulation therapy should be further investigated.

Conditional and continuous electrical stimulation increase cystometric capacity in persons with spinal cord injury.

AIMS: Individuals with spinal cord injury (SCI) exhibit neurogenic detrusor overactivity (NDO) causing high intravesicle pressures and incontinence. The first aim was to measure changes in maximum cystometric capacity (MCC) evoked by electrical stimulation of the dorsal genital nerve (DGN) delivered either continuously or conditionally (only during bladder contractions) in persons with SCI. The second aim was to use the external anal sphincter electromyogram (EMG(EAS)) for real-time control of conditional stimulation. METHODS: Serial filling cystometries were performed in nine volunteers with complete or incomplete supra-sacral SCI. Conditional stimulation was delivered automatically when detrusor pressure increased to 8-12 cmH(2)O above baseline. MCCs were measured for each treatment (continuous, conditional, and no stimulation) and compared using post-ANOVA Tukey HSD paired comparisons. Additional treatments in two subjects used the EMG(EAS) for automatic control of conditional stimulation. RESULTS: Continuous and conditional stimulation increased MCC by 63 +/- 73 ml (36 +/- 24%) and 74 +/- 71 ml (51 +/- 37%), respectively (P < 0.05), compared to no stimulation. There was no significant difference between MCCs for conditional and continuous stimulation, but conditional stimulation significantly reduced stimulation time (174 +/- 154 sec, or 27 +/- 17% of total time) as compared to continuous stimulation (469 +/- 269 sec, 100% of total time, P < 0.001). The EMG(EAS) algorithm provided reliable detection of bladder contractions (six of six contractions over four trials) and reduced stimulation time (21 +/- 8% of total time). CONCLUSIONS: Conditional stimulation generates increases in bladder capacity while substantially reducing stimulation time. Furthermore, EMG(EAS) was successfully used as a real-time feedback signal to control conditional electrical stimulation in a laboratory setting.

Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats.

Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[(18)F]FU (PET/5-[(18)F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[(18)F]FU in vivo. This study explored the combined use of PET/5-[(18)F]FU and eniluracil (5-ethynyluracil), a potent inhibitor of 5-FU catabolism, to measure the pharmacokinetics of 5-FU uptake and metabolism in tumors. Rats bearing a s.c. implanted rat colon tumor were given eniluracil and injected i.v. with 5-[(18)F]FU. Dynamic PET and arterial blood sampling were performed 0-2 h. Tumors (n = 5) were then rapidly excised, frozen, and analyzed for labeled metabolites by high performance liquid chromatography. Tumor TACs were analyzed by compartmental modeling. Compartments were identified with molecular species by comparison with ex vivo assays. Tumor extracellular fluid volume was determined in a separate group of rats. Kinetic analysis indicated partial trapping of (18)F within tumors 0-2 h after injection. Tumor time-activity curves conformed closely to a catenary 3-compartment, 5-parameter model. The model yielded values for 5-FU clearance from plasma into the trap that agreed closely with those reported previously for gastrointestinal tumors from a PET/5-[(18)F]FU + eniluracil study in humans. Tumor extracellular fluid volume as measured with (99m)Tc DTPA [(3.1 +/- 0.2) x 10(-1) ml/g; n = 5] agreed well with the distribution volume for compartment 1 of the 3-compartment, 5-parameter model [(3.7 +/- 0.3) x 10(-1) ml/g; n = 5], thus indicating that compartment 1 corresponds to tumor extracellular space. Compartment 3 closely matched the combined magnitudes of (18)F fluoronucleoside (FN) triphosphates and macromolecules in all of the cases, and compartment 2 was quantitatively consistent with the sum of intracellular 5-FU, FNs, and FN mono- and diphosphates. These observations show that PET/5-[(18)F]FU combined with an inhibitor of 5-FU catabolism and compartmental modeling is capable of quantifying the following for 5-FU in tumors: distribution volume in the extracellular space, cell transport, size and turnover rate of an intermediate intracellular pool, and formation of a long-lived intracellular pool comprising FN triphosphates + macromolecules. Such information could be useful in predicting tumor response to 5-FU, formulating protocols that increase delivery of 5-FU into tumor cells, and modulating 5-FU kinetics to overcome tumor resistance.