Biomedical subjects

R D Bell

Publications and source records attributed to R D Bell.

At least 37 records · Page 2Linked to original sources

PubMed1987

Reevaluation of the effects of castration on naloxone-sensitive opiate receptors in the male rat brain.

There is a great deal of conflicting data regarding the issue of whether androgens influence opiate receptors in the whole male rat brain. Although Hahn and Fishman initially reported that long-term castration produced a large increase in the density of opiate-binding sites, relative to controls, no other independent group has been able to replicate these results. Recently, the former investigators reported that procedural differences could fully account for the discrepancies in the literature. Because of the importance of demonstrating a direct biochemical association between steroid- and endogenous opioid-containing neuronal elements in brain, we have reexamined the issue of whether long-term castration influences opiate receptors in whole male rat brain. To accomplish this goal, we incorporated all of the critical procedural variables which were identified by Hahn and Fishman as possible confounding variables in such studies. Our results clearly demonstrate that under identical conditions, we were unable to replicate the results of these investigators. In addition, we attempted to use other paradigms in an attempt to resolve this long-standing controversy in the literature, but these attempts were also unsuccessful. We are unable to explain our inability to replicate the results of Hahn and Fishman. However, it should be noted that at least 4 independent groups have now failed to reproduce their findings. Thus, it appears that the intrinsically attractive hypothesis that steroids influence opiate receptors cannot be addressed using whole brain analysis or relatively crude areas of brain and relatively nonspecific opiate ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗

PubMed1987

Vascular headache.

Vascular headache is an extremely common disorder. Current evidence points to an underlying neurogenic etiology, and the associated vascular changes are believed to be epiphenomena. Vascular headache tends to begin at a young age, is more common in women, and is frequently associated with a positive family history. Characteristics of the headache frequently suggest the diagnosis. The history and physical examination are keys to the diagnostic evaluation. A computed tomography scan when indicated is the single test with the highest yield of information. Non-narcotic analgesics, ergot compounds, and metoclopramide are the most commonly used agents for acute attacks. Beta blockers and amitriptyline are the most widely used prophylactic medications. Nonpharmacologic measures are occasionally of great benefit.

Adolescent↗

PubMed1986

Fluorocarbon emulsion as a potential contrast medium in the subarachnoid space and brain tissue. Experiments in cats.

Ventriculosubarachnoid perfusion with oxygenated fluorocarbon emulsion has been used in the treatment of severe cerebral ischemia in cats. The perfusion vehicle is prepared mimicking cerebrospinal fluid in terms of electrolyte content, osmolality, pH, glucose and amino acids. Fluorocarbon emulsion is prepared with the vehicle as the external phase and charged with high partial pressures of oxygen. This fluorocarbon emulsion has been well-tolerated by the central nervous system. In addition to delivering oxygen to the ischemic tissues via the ventriculosubarachnoid space, the fluorocarbon emulsion has an absorption coefficient higher than normal brain and cerebrospinal fluid. This property makes it easily detected on the CT scan. Determination of appearance, attenuation, distribution, and absorption of the fluorocarbon has been performed in cats after direct intraventricular injection of the substances and after perfusion of the emulsion. The results of these experiments stress the possibility of using a fluorocarbon emulsion as a potential contrast medium in the brain and subarachnoid space, particularly after brain anoxia.

Animals↗

PubMed1986

Ontogeny of the opioid-mediated control of reproductive endocrinology in the male and female rat.

Endogenous opioids (EOP) appear to inhibit the release of luteinizing hormone-releasing hormone and, subsequently, luteinizing hormone (LH). These observations have led to the hypothesis that EOP-containing neuronal systems may be involved in the onset of puberty. To examine this possibility, rats were challenged with naloxone and morphine, as probes to decrease or exaggerate, respectively, the effects of EOP on luteinizing hormone releasing hormone/LH release at intervals from birth to adulthood. Morphine had no effect on serum LH up to 15 days of age in males, but thereafter was maximally effective. On the other hand, the onset of adult-appropriate responses to morphine occurred much later in females (30-35 days) and the depressions in LH were consistently less pronounced than in comparably aged males. Naloxone produced large increases in LH in 10- and 25-day-old females, but was ineffective at 15 or 20 days. After day 25, the response to naloxone declined gradually, but was still significantly greater than control values in adults. In contrast, naloxone failed to increase serum LH from 10 to 30 days after birth in males. Beginning at 30 to 35 days of age, however, a sudden onset in the sensitivity to naloxone occurred which increased exponentially until 60 days. At this time, serum LH levels were 5 times greater in naloxone-treated males than in controls, and were twice those found in similarly treated females. These age- and sex-related differences in response to the opiates were not related to pharmacokinetic variables and also could not be attributed to gross maturational alternations in the hypothalamic-pituitary-gonadal axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1985

A radiolabeled-ligand-binding technique for the characterization of opioid receptors in the intact mouse vas deferens.

The mouse vas deferens has served as a useful bioassay for examining the properties of opiate receptor subtypes. However, recent data indicate that the response of the vas deferens to opiates may be mediated by one or more of the several opiate receptors found in this preparation. Although a number of techniques can be utilized to assess the relative contribution of these receptors to the response of the mouse vas deferens to opiates (e.g., selective tolerance and naloxone antagonism studies), a radiolabeled-binding technique would provide an independent means of more completely characterizing the opiate receptor profiles in this preparation. Up to the present, however, there has been only limited success in developing a binding assay utilizing crude membrane fractions of the mouse vas deferens. To circumvent these problems, we have developed a binding technique utilizing the intact vas deferens. In contrast to results obtained with membrane fractions, we found highly specific (90-95%) and saturable binding of D-[2-3H]alanine, 5-D-leucine enkephalin, a ligand selective for delta opiate receptors, to the intact vas. Scatchard analyses indicated a single class of binding sites with an apparent Kd of 1.5 nM and a Bmax of approximately 12 pmol/2 vas. The selectivity of binding was also examined. Naltrexone was 40 times less potent than unlabeled 2-D-alanine, 5-D-leucine enkephalin in displacing binding, whereas morphine and ethylketocyclazocine were 300 and 500 times less effective, respectively. This technique, coupled with the mouse vas deferens bioassay, should provide a more complete characterization of opioid receptor populations than has heretofore been possible.

Animals↗

PubMed1985

Changes in postglomerular hemodynamics alters the composition of canine renal lymph.

Renal lymph was collected from either capsular or hilar lymphatic vessels in anesthetized dogs. Collections were made during control periods and during two levels of elevated renal vein pressure. Increases in renal vein pressure resulted in increased lymph flow and decreases in capsular lymph protein, creatinine and PAH concentrations relative to those of concurrently collected arterial blood plasma. Although hilar lymph flow increased in response to elevated renal vein pressure, only the lymph creatinine concentration was decreased. It was concluded that peritubular capillary filtration may not be a major factor in determining renal lymph composition. In addition, it appears that the steady-state protein and PAH concentrations in the interstitial fluid of the outer cortex are more sensitive to solute washout during increased renal vein pressure than those of the inner cortex and outer medulla.

Animals↗

PubMed1984

Exercise, age and the development of the myocardial vasculature.

Previous studies in experimental animals have indicated that physical activity can increase the extent of the myocardial vasculature but the optimal age, intensity, and duration of exercise that cause such modifications is not yet clear. The purpose of this study was to determine the effects of varying exercise intensity and duration on the myocardial vasculature of both prepubescent and postpubescent rats. Prepubescent animals were trained for 3 or 6 weeks at either a high or low exercise intensity beginning at 3 weeks of age. Postpubescent animals were trained in a similar manner beginning at 14 weeks of age. The high intensity exercise program administered prepubertally resulted in a significant increase in both the capillary density (25%) and the capillary to fibre ratio. The low intensity exercise program did not cause any modifications of the myocardial capillary density in the pre-pubescent animals. Postpubertally the high intensity 3 week exercise program caused a significant increase in the capillary density but no change in the capillary to fibre ratio. The low intensity exercise program did result in a significant degree of myocardial hypertrophy with a concomitant increase in capillary proliferation sufficient to maintain a constant capillary density. The results indicate that there may be a critical age related range of exercise intensity that is conducive to proliferation of the myocardial capillaries.

Aging↗

PubMed1984

Renal lymph flow and composition during acetazolamide and furosemide diuresis.

Several lines of research suggest that renal lymph is formed totally, or in part, as a filtrate of postglomerular blood. Even so, renal interstitial fluid dynamics is necessarily dominated by the rapid transfer of large volumes of reabsorbate from tubular lumen to peritubular capillary. To determine the effects of tubular reabsorption on lymph formation, renal lymph flow and composition were studied before and during alterations in tubular reabsorption produced by diuresis. A 25% reduction in whole kidney fluid reabsorption rate did not alter renal lymph flow or lymph protein concentration. A concomitant decrease in plasma protein concentration, however, suggests that any deficit in lymph flow resulting from decreased reabsorbate content may have been obscured by an increase in vascular filtration. An increase in renal lymph PAH and creatinine concentrations relative to those of arterial and renal venous blood plasma supports this conclusion. It appears that renal lymph flow may be determined by both vascular filtration and tubular reabsorption.

Acetazolamide↗

PubMed1983

Role of nicotinamide adenine dinucleotide in ethanol-induced depressions in testicular steroidogenesis.

It is rapidly becoming accepted, without direct evidence, that a change in the NAD+/NADH ratio in the testes produced by the metabolism of ethanol is the principal mechanism involved in its now well-established effects on testicular steroidogenesis. The purposes of the present studies were 2-fold: (1) to examine whether, in fact, in vivo or in vitro ethanol exposure alters the NAD+/NADH ratio in the testes; and (2) to examine the validity of previous reports in which it was found that NAD+ prevented the effects of ethanol on testicular steroidogenesis under in vitro conditions. With regard to the first objective, we found that a large dose of ethanol (2.5 g/kg) markedly reduced gonadotropin-stimulated testicular steroidogenesis in vivo in the male rat, but it did not alter the NAD+ and NADH concentrations in the testes. Similarly, extremely high ethanol concentrations (200 mM) substantially suppressed hMG-stimulated testosterone biosynthesis in in vitro Leydig cell preparations but no change in NAD+ concentration occurred; NADH levels were very low in the Leydig cell preparations (less than 2% of NAD+ levels), but did not appear to change as a function of ethanol exposure. Finally, in contrast to previously published results, we found that NAD+ (1 mM) did not prevent the in vitro effects of ethanol on cAMP-stimulated testicular steroidogenesis. Consequently, our results fail to support the hypothesis that acute in vivo or in vitro ethanol administration inhibits the biosynthesis of testosterone by altering the NAD+/NADH ratio in the testes.

Acetaldehyde↗

PubMed1983

Methylphenidate decreases local glucose metabolism in the motor cortex.

The local cerebral metabolism on glucose (l-CMRg) was evaluated in animals given methylphenidate (15 mg/kg) in order to investigate possible mechanisms of action of the drug. Significant increases in l-CMRg (p greater than 0.05) were found in the globus pallidus, entopeduncular nucleus, substantia nigra, subthalamic nucleus, inferior olive, red nucleus, lateral cerebellar cortex, ventral lateral nucleus of the thalamus and the midbrain reticular formation. Significant decreases (p greater than 0.05) in l-CMRg were found in the motor cortex. These results suggest possible mechanisms for methylphenidate's action in attention deficit disorders.

Animals↗

PubMed1983

Comparative mammalian in vitro and in vivo studies on the mutagenic activity of rhodamine WT.

Rhodamine WT, a xanthene dye used in the tracing of pollutants in water and in related studies, was tested for its mutagenicity in a battery of in vitro and in vivo mammalian assays. Using Chinese hamster ovary cells in the absence of metabolic activation mix, small dose-related increases in cytotoxicity, DNA damage (as detected by alkaline sucrose-gradient sedimentation) and sister-chromatid exchanges were detected, but an increase in the level of chromosomal damage was not seen. In the presence of metabolic activation a small, but statistically significant dose-related increase in sister-chromatid exchanges was evident, with no increase in cytotoxicity, DNA damage or chromosome aberrations. Furthermore, no increase in bone marrow micronuclei or sperm abnormalities was observed in male B6C3F1 mice. The data from all these mammalian assays, although involving different end-points, are in contrast to the mutagenic effects previously seen in Salmonella.

Animals↗

PubMed1983

Effect of erythromycin on carbamazepine kinetics.

Two recent reports of carbamazepine-induced intoxication during concurrent therapy with macrolide antibiotics prompted us to perform a carefully controlled two-way cross-over study in eight healthy male nonsmokers. Treatment A was 250 mg erythromycin every 6 hr for 5 days before and 3 days after 400 mg carbamazepine. Treatment B was 400 mg of carbamazepine alone. One half of the subjects received treatment A, then B, while the other half received treatment B, then A. There was a 4-wk washout period between treatments. Plasma samples obtained at various times up to 72 hr after the carbamazepine dose were assayed in duplicate by HPLC. The data were fit to a one-compartment open model with first-order absorption and elimination. Clearance of oral carbamazepine was lower in the presence of erythromycin (mean +/- SD, 0.290 +/- 0.074 and 0.360 +/- 0.072 1 X kg-1 X day-1). There were no differences in apparent volume of distribution (1.01 +/- 0.20 and 1.04 +/- 0.12 1 X kg-1), elimination rate constant (0.302 +/- 0.113 and 0.348 +/- 0.079 day-1), or absorption rate constant (14.5 +/- 8.7 and 15.5 +/- 16.6 day-1) between the two treatment groups. The decrease in clearance of oral carbamazepine secondary to erythromycin indicates that further clinical studies are warranted.

Adult↗

PubMed1983

Canine renal lymph formation during acute ECF expansion.

Renal lymph flow, composition and pressure were related to renal function and hemodynamics before and during acute extracellular fluid (ECF) expansion (Ringer's solution, 10% of body wt.) in anesthetized dogs. ECF expansion caused increases in renal lymph pressure and flow and a decrease in the plasma concentration and L/P ratio for protein without altering the transfer rate of protein from blood to lymph (lymph clearance). In contrast, the L/P ratios for creatinine and PAH were unchanged following ECF expansion while the lymph clearances of these substances increased roughly in proportion to the increase in lymph flow. These findings are consistent with two alternative hypotheses: a) renal lymph merely participates in the generalized increase in lymph formation that follows nononcotic ECF dilution, or b) some or all of the observed lymph flow increase was derived directly from an excess of tubular reabsorbate.

Animals↗

PubMed1983

Phenytoin cumulation profiles.

his study was performed to determine the potential utility of the cumulation profile of phenytoin during multiple oral dosing and to examine, under ideal conditions, the variability in apparent steady state concentrations. Six male subjects were administered oral phenytoin sodium 5-6 mg/kg/d in divided doses every 12h for six days. Predose serum phenytoin concentrations were measured every 12 hours by gas liquid chromatography. The resulting data were analyzed in order to estimate maintenance doses. Subjects were then placed on the estimated daily dose and pre-dose concentrations measured daily for at least two weeks. At the end of the study, all data were fit using non-linear regression analysis to obtain the best estimates of individual kinetic parameters. Parameter values, particularly the Km value, were dependent upon the input function used, either first- or zero-order. In two subjects there was evidence of modest auto-induction. At steady-state the average coefficient of variation of predose concentrations was 10.6% (Range: 5.2-16.2%).

Administration, Oral↗

PubMed1983

Effects of bradykinin on renal lymph flow and composition.

It has been reported that bradykinin causes permeability changes with increased vascular leakage in many peripheral tissues, but not in the renal parenchyma. In the present experiments, the effects of bradykinin on renal hilar lymph flow and concentrations of protein and PAH were studied. The results of these experiments show that the protein permeability of the intrarenal vessels from which lymph is derived is not altered by bradykinin. The data presented does, however, suggest that renal lymph may contain tubular reabsorbate, a component from the glomerulus, or both. In addition, data is presented which suggests that a significant amount of lymph may be formed in the renal medulla during renal vasodilation.

Animals↗

PubMed1982

Ethanol inhibits the naloxone-induced release of luteinizing hormone-releasing hormone from the hypothalamus of the male rat.

It has been inferred that ethanol suppresses the secretion of luteinizing hormone (LH) in the male by depressing the release of LH-releasing hormone (LH-RH) from the hypothalamus. Direct support for this inference has been difficult to obtain, however, because of significant technical difficulties in measuring LH-RH release under in vivo conditions. To circumvent these problems, we made use of the opiate antagonist naloxone, as a neuroendocrine probe, to elicit the release of LH-RH under in vivo conditions. We found that ethanol was a potent suppressor of the increase in serum LH levels evoked by naloxone at extremely low blood ethanol concentrations ( less than 60 mg/dl). Furthermore, we observed that the antagonism between ethanol and naloxone appeared to be competitive in nature since a fixed dose of ethanol (1 g/kg, blood ethanol concentration 60 mg/dl) shifted the naloxone dose-response curve significantly to the right and high doses of the antagonist overcame ethanol's effects. Finally, we found that the interaction between ethanol and naloxone took place at the level of the hypothalamus. Our results, therefore, seem to provide the first in vivo evidence supporting the widely-held hypothesis that ethanol reduces serum LH levels by depressing the hypothalamically-medicated release of LH-RH. The mechanisms underlying ethanol's depression of naloxone-induced increases in the release of LH-RH are not fully understood at this time, but one prominent possibility is that ethanol enhances the synthesis or release of endogenous opioids which in turn override naloxone's effects.

Animals↗

PubMed1982

Ethanol-induced reductions in testicular steroidogenesis: major differences between in vitro and in vitro approaches.

Although it is well established that ethanol suppresses gonadotropin- and cAMP-stimulated testicular steroidogenesis, there is not good agreement on two issues: which is the step in testosterone's biosynthetic pathway affected by ethanol; and the role of alterations in the NAD+/NADH ratio in ethanol's effects. In these studies, we have identified major differences between in vivo and in vitro approaches, which have previously been considered as totally equivalent experimental paradigms, which could explain these discrepancies. Under in vitro conditions, we observed that ethanol selectively inhibited the conversion of androstenedione to testosterone, but that it had a much more general effect under in vivo conditions. In addition, in agreement with other studies, NAD+ overcame ethanol's effects on testicular steroidogenesis in vitro, but only when labeled or unlabeled pregnenolone was added. In the absence of added pregnenolone, NAD+ was not effective in preventing ethanol's effects. Our results, thus, indicate that the differences which currently exist in the literature may be explained by the indiscriminate usage of in vivo and in vitro techniques.

Androgens↗

PubMed1982

The methylphenidate-induced stereotypy in the awake rat: local cerebral metabolism.

The local cerebral metabolic rate for glucose (1=CMRg) was computed in rats with methylphenidate-induced stereotypy using the quantitative 14C-2-deoxyglucose (2-DG) technique. Four rats received methylphenidate 15 mg per kilogram IP. Compared to five control animals, treated rats showed statistically significant (p less than or equal to 0.05) increases in 1-CMRg in globus pallidus, ventral lateral nucleus of the thalamus, subthalamic nucleus, red nucleus, substantia nigra, entopeduncular nucleus, inferior olivary nucleus, and the lateral cerebellar cortex. Significantly, 1-CMRg decreased in area 4 of the motor cortex. The auditory system showed no change in 1-CMRg, demonstrating the specific action of methylphenidate in the rat brain. This technique allows evaluation of the functional anatomy of the entire central nervous system and may be helpful in understanding the mechanisms of methylphenidate-induced stereotypy.

Animals↗