Physiological pharmacokinetics of solutes in the isolated perfused rat hindlimb: Characterization of the physiology with changing perfusate flow,protein content,and temperature using statistical moment analysis

Distribution of Evans Blue (EB), sucrose, and water into the isolated perfused rat hindlimb was studied under various conditions using the multiple indicator dilution (MID) technique. Statistical moment analyses of the outflow profiles for the EB, sucrose, and water were used to define the vascular, extravascular, and total water spaces, respectively. The varied perfusion conditions included albumin content (2, 4.7, and 7%), temperature (25, 37, and 42 C), perfusate flow rate (2, 4, 8, and 12 ml/min) and the presence/absence of red blood cells. The range of studies undertaken were chosen to represent the variety of conditions used in the preparation of both isolated animal and human limbs, the latter being particularly important in cytotoxic therapy for recurrent malignant melanoma. The distribution volumes of EB, sucrose, and water were dependent on the flow rate and the albumin content of perfusate. The normalized variances (CV ² ) of the markers were of the following order: sucrose (2.18) > water (1.58) > EB (0.68), indicating that some disequilibrium occurs during the capillary exchange of water and sucrose. It is suggested that a Krebs-Henseleit buffer containing 2% BSA is a suitable perfusate for most studies of the isolated rat hindlimb perfusion. The effect of albumin concentration manifests itself only at higher flows.We acknowledge the support of the National Heart Foundation (Queensland) and the Mayne Bequest Foundation. This study was conducted while the investigator (Z.Y. Wu) was in receipt of a WHO Research Training Grant. Professor M. S. Roberts also acknowledges the support of the Queensland and Northern New South Wales Lions Kidney & Medical Research Foundation.     

HP 818: A centrally acting analgesic with neuroleptic properties

HP 818 (1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED₅₀ values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar > fentanyl > HP 818 > codeine > droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self-stimulation assays (ED₅₀ values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine- and apomorphine-induced stereotypy, indicative of D₂-dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting cardiorespiratory side effects.     

Ultra-fast velocity imaging in stenotically produced turbulent jets using RUFIS

A method for rapidly producing velocity images is presented. This sequence combines a modified bipolar gradient pulse to magnitude encode the velocity with the rotating ultra-fast imaging sequence (RUFIS) to image the encoded spins. Velocity encoding is done in 3 msec, and RUFIS acquires 32 projections in 8 msec. The method is applied to turbulent jets associated with a 75% stenosis in a 15-mm inner diameter glass pipe. Data is acquired upstream and downstream from the stenosis for Reynolds numbers from 560 to 3750. In addition, a robust method of reconstructing the unobserved short time region of a free induction decay is presented and incorporated into the image processing.     

Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain

The receptor mGluR5 is a metabotropic glutamate receptor with messenger RNA abundantly present throughout cortex, hippocampus, and caudate/putamen that is also coupled to phosphatidyl inositide hydrolysis and calcium mobilization. In this study, the distribution of mGluR5 was examined in rat brain by immunocytochemistry. The antibody utilized is highly specific and does not cross react with the most closely related other metabotropic glutamate receptor, as determined by Western blot analysis of nonneuronal cells transfected with metabotropic receptor coding sequences. The receptor mGluR5 is widely expressed with the highest density in olfactory bulb, caudate/putamen, lateral septum, cortex, and hippocampus, as confirmed with both immunocytochemistry and Western blot analysis. Electron microscopic studies in hippocampus and cortex indicate that the labeling is mostly on membranes of dendritic spines and shafts. Light and electron microscopic evidence indicates that some mGluR5 immunoreactivity is located in presynaptic axon terminals, suggesting that mGluR5 may function as a presynaptic receptor.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.     

Circadian esophageal motor function in patients with gastroesophageal reflux disease

Effective esophageal peristalsis is a major determinant of esophageal clearance function and may contribute to the development of complications in gastroesophageal reflux disease. Using 24-hour ambulatory esophageal manometry, we compared the circadian esophageal motor activity of normal volunteers to that of patients with increased esophageal exposure to gastric juice and various grades of mucosal injury (no mucosal injury, esophagitis, stricture, or Barrett's esophagus). The prevalence of a mechanically defective lower esophageal sphincter, esophageal acid exposure time, and the frequency of nonperistaltic esophageal contractions during the supine, upright, and meal periods increased with increasing severity of mucosal injury. The median amplitude of esophageal contractions was compromised only in patients with a mechanically defective sphincter. This was particularly so in patients with stricture or Barrett's esophagus and was associated with an increased frequency of ineffective contractions (less than 30 mm Hg). These data show that esophageal motor function deteriorates with increasing severity of mucosal injury. This appears to be caused by persistent reflux of gastric juice across a mechanically defective lower esophageal sphincter. The need for surgical correction of a mechanically defective sphincter before the loss of esophageal body function is implicated.