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Biomedical subjects

M J Walker

Publications and source records attributed to M J Walker.

At least 19 recordsLinked to original sources
PubMed1992

Effects of naltrindole and nor-binaltorphimine treatment on antinociception induced by sub-acute selective mu opioid receptor blockade.

When administered repeatedly, in conjunction with hot plate testing, naloxone and naltrexone have the paradoxical effect of producing antinociception in rats and mice. Recently, we have found that the sub-acute selective blockade of mu opioid receptors leads to the development of antinociception and an augmentation of kappa receptor-mediated antinociception. In this study, acute delta/kappa antagonist treatment produced a significant decrease in paw lick latency in rats displaying antinociception induced by sub-acute mu blockade, however, the response level of these animals was still significantly above the baseline. In addition, rats receiving sub-acute combined mu and delta antagonist treatment took longer to develop an antinociceptive response than those treated with a mu antagonist alone. Sub-acute selective blockade of kappa or delta opioid receptors had no overall effect on paw lick latency during the course of 5 days of hot plate testing. The results indicate that delta receptor activity may play a role in the antinociception induced by sub-acute mu blockade. However, while delta antagonist treatment effected the expression, it did not completely attenuate the antinociception induced by sub-acute mu blockade suggesting that there is still a significant non-opioid component to this analgesic response. The results of a final experiment, in which acute delta antagonist treatment had no effect on antinociception induced by repeated systemic injections of naloxone, supported this hypothesis.

Animals↗
PubMed1992

Quinacainol, a new antiarrhythmic with class I antiarrhythmic actions in the rat.

The antiarrhythmic and electrophysiological actions of quinacainol, a new Class I antiarrhythmic, were assessed in rats. Electrophysiological actions of quinacainol were assessed in vivo in terms of drug-induced changes in ECG, responses to left ventricular electrical stimulation, and changes in epicardial intracellular potentials to precisely characterize the electrophysiological effects of this putative subclass Ic antiarrhythmic compound. Antiarrhythmic actions were assessed in conscious rats subjected to occlusion of the LAD coronary artery. Antiarrhythmic actions occurred with 2.0 and 4.0 mg/kg, whereas 8.0 mg/kg was pro-arrhythmic. At doses of 0.5 mg/kg and above quinacainol increased threshold currents for capture and for ventricular fibrillation. Doses of 2.0 mg/kg and above increased ventricular refractoriness. From 1.0 to 8.0 mg/kg, quinacainol reduced dV/dtmax of phase 0 of epicardial action potentials but only 8.0 mg/kg increased action potential duration. The Q-T interval was also increased with the highest dose. Quinacainol dose-relatedly increased P-R interval whereas QRS did not change. Thus the Class I electrophysiological properties of quinacainol over the dose range tested did not fit accurately into a single subclass of the various subclasses of Class I. However, the Class Ic actions seen with 2.0 and 4.0 mg/kg were associated with antiarrhythmic actions.

Action Potentials↗
PubMed1992

Antiarrhythmic effects of U-50,488H in rats subject to coronary artery occlusion.

The antiarrhythmic actions of low and high doses of U-50,488H, a selective kappa-receptor agonist, were examined in pentobarbitone-anaesthetized rats subjected to occlusion of the left anterior descending coronary artery. At a high dose (16 mumol/kg) U-50,488H reduced blood pressure, heart rate and prolonged the P-R and QRS intervals of the electrocardiogram. This dose reduced the incidence of ventricular arrhythmias produced by occlusion. The blood pressure, heart rate, ECG and antiarrhythmic actions of a high dose of U-50,488H were not antagonized by 8 mumol/kg naloxone, a dose which had no cardiovascular or ECG actions. Naloxone alone reduced arrhythmia incidence but to a lesser extent than U-50,488H. A low dose (0.2 mumol/kg) of U50,488H in the absence or presence of naloxone had no effect on arrhythmias. Thus, U-50,488H had antiarrhythmic actions at a high dose which were independent of opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Mexiletine's antifibrillatory actions are limited by the occurrence of convulsions in conscious animals.

The antiarrhythmic actions of the racemate and enantiomers of mexiletine were studied in conscious and anaesthetised rats. Racemate or enantiomers, at 20 mg/kg i.v., had little effect on ischaemia-induced ventricular fibrillation in conscious or anaesthetised rats. In conscious rats 20 mg/kg caused convulsions in 78-89% of rats when the plasma concentration of racemate was 20 +/- 2 microM. In anaesthetized animals a higher dose (40 mg/kg) of racemate could be given; this completely prevented ischaemia-induced fibrillation when the plasma concentration was 26 +/- 2 microM. Racemate and enantiomers accumulated in the heart and brain of conscious animals to give tissue: plasma ratios of 7.5 and 23, respectively. With electrical stimulation, both racemate and enantiomers dose dependently (4-32 mg/kg) increased threshold currents for induction of ventricular fibrillation, increased refractory period and minimally changed the ECG; findings expected with a Class Ib antiarrhythmic. The above studies failed to show major differences between racemate or enantiomers except for consistently lower (20-30%) plasma concentrations of R(-) at all dose levels. In conclusion, mexiletine prevented ischaemia-induced ventricular fibrillation in anaesthetised animals but only when given at doses producing convulsions in conscious animals.

Animals↗
PubMed1992

Ischemic but not reperfusion arrhythmias depend upon serum potassium concentration.

The effects of variations in serum concentrations of potassium on the occurrence and severity of ischemia- and reperfusion-induced arrhythmias have been studied in conscious rats. Serum potassium concentrations were modified by maintaining rats on diets which varied in potassium concentration, by treatment with hydrochlorothiazide, amiloride, spironolactone or infusions of potassium chloride. An inverse linear relationship was demonstrated between ischemia-induced arrhythmias and log(e) serum potassium concentration such that a 50% reduction in arrhythmias occur with a 3.8-fold increase in serum potassium concentration. On the other hand, the incidence of reperfusion-induced arrhythmias after 7 min of regional ischemia prior to reperfusion in previously untreated rats were not influenced by elevation of serum potassium concentrations prior to and after reperfusion. Effects on ischemia-induced arrhythmias could not be explained by changes in blood pressure or heart rate. It is speculated that modification of potassium concentration in non-ischemic or border zone ventricular tissue may directly modify arrhythmogenesis due to ischemia but not that due to reperfusion.

Animals↗
PubMed1992

Expression of Bordetella pertussis filamentous hemagglutinin in Escherichia coli using a two cistron system.

Expression of Bordetella pertussis filamentous hemagglutinin (FHA) has been achieved in Escherichia coli K-12. This involved the construction of a two cistron system where the first cistron was provided by the NH2-terminus (first 98 amino acids) of MS2 polymerase. When the FHA gene sequences were fused to the first cistron, higher levels of expression were obtained and the fusion protein aggregated in inclusion bodies. FHA expressed by the two cistron system, however, appeared to be diffusely dispersed in the cytoplasm.

Adhesins, Bacterial↗
PubMed1992

A new ECG measure (RSh) for detecting possible sodium channel blockade in vivo in rats.

A new electrocardiographic (ECG) measure for detecting possible sodium channel blocking actions of drugs in anaesthetized rats is described. The conventional measures for sodium channel blockers are increased QRS width and/or P-R prolongation, however, these are limited in their sensitivity. This new measure, RSh, is the height from the peak of the R wave to the bottom of the S wave; it is more sensitive to known sodium channel blocking agents than conventional measures. This was shown by comparing the ECG effects of sodium channel blocking class I antiarrhythmic drugs from the three subclasses lidocaine (Ia), quinidine (Ib), and flecainide (Ic). In each case, RSh increased before changes could be detected in QRS or P-R. With tetrodotoxin and quinacainol, a new class I agent, changes in RSh correlated directly with previously reported changes in dV/dtmax of intracellular potentials recorded in vivo from epicardial cells. Representatives from antiarrhythmic classes II, III, and IV were also tested and only changed RSh when they had known sodium channel blocking properties at high doses. Other physiological maneuvers for altering heart rate, such as changing vagal activity, administration of catecholamines, or direct right atrial pacing, did not alter RSh. Thus RSh is a useful in vivo measure for the detection of possible class I antiarrhythmic actions. It has the advantages of being sensitive, selective, easy to measure, and involving minimal preparation.

Animals↗
PubMed1992

Late effects following central nervous system radiation in a pediatric population.

Between 1970 and 1986, 120 children with central nervous system malignancy were treated with radiation therapy. These included 44 low-grade astrocytomas, 11 high grade astrocytomas, 32 medulloblastomas, 15 ependymomas/ependymoblastomas, 3 primitive neuroectodermal tumors and 8 pineal tumors. Seven children were treated without biopsy. Fifty-one treated children were evaluated for the effects of therapy on growth, endocrine function, IQ and hair regrowth. Mean height was 1.5 standard deviations below the mean height for the patient's age at study (range 0-5.7). Height was significantly less in patients receiving radiation to the pituitary and those with somatomedin-C deficiency. Height was also decreased with whole CNS radiation and spine dose > 20 Gy but not to a significant degree. Pituitary radiation in any dose increased the chance of endocrine deficiency (p = 0.004) and 21 of 51 patients had somatomedin-C deficiency. Mean IQ was 92.7 (+/- 18.8), with a slight trend toward decreased IQ with increasing whole brain dose of radiation. Hair regrowth was complete in 20 of 46 evaluated patients, diminished regrowth occurring with increasing volume and dose of radiation. No difference in the measured late effects could be detected with respect to age at treatment, sex, histology or location of tumor.

Body Height↗
PubMed1992

Cardiovascular actions of the kappa-agonist, U-50,488H, in the absence and presence of opioid receptor blockade.

1. The cardiovascular actions of U-50,488H, a kappa-receptor agonist, were studied in rat isolated perfused hearts, and in anaesthetized rats, over concentrations or doses generally above those required to produce kappa-receptor-mediated effects. 2. U-50,488H dose-dependently decreased left-ventricular peak systolic pressure and beating rate in vitro and reduced blood pressure and heart rate in vivo. 3. Over the concentration range of 1-30 microM in vitro, and the dose-range of 0.5-32 mumol kg-1 in vivo, U-50,488H prolonged the P-R, QRS and Q-T intervals of the ECG. 4. The effects of U-50,488H were not antagonized by an opioid receptor antagonist, naloxone (1 microM or 8 mumol kg-1). Similarly, the opioid receptor antagonist, MR 2266, at 8 mumol kg-1 did not significantly reduce the cardiovascular actions of U-50,488H in vivo. 5. The actions of U-50,488H on responses to electrical stimulation were also studied. Over the dose range of 0.5-32 mumol kg-1, U-50,488H altered thresholds and effective refractory period. It had a biphasic action on thresholds for induction of ventricular fibrillation. Thresholds were decreased at lower doses (0.5-4 mumol kg-1) but increased at higher doses (8-32 mumol kg-1). The effects of lower doses were blocked by naloxone. Effective refractory period and threshold pulse width only increased with dose. 6. In conclusion, U-50,488H at high concentration, had direct depressant actions on cardiac contractility, electrical excitability and the ECG. These depressant effects were not antagonized by the opioid receptor antagonists, naloxone and MR 2266, and probably do not involve opioid receptors. Furthermore, some of the observed effects were those expected to result from sodium channel blockade.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Specific lung mucosal and systemic immune responses after oral immunization of mice with Salmonella typhimurium aroA, Salmonella typhi Ty21a, and invasive Escherichia coli expressing recombinant pertussis toxin S1 subunit.

Pertussis toxin (PT) is considered an essential protective component for incorporation into new generation vaccines against Bordetella pertussis, the causative agent of whooping cough. Traditionally, antipertussis vaccination has employed an intramuscular route. An alternative to this approach is to stimulate mucosal and systemic immune responses by oral immunization with live vaccine carrier strains of Salmonella spp. or Escherichia coli. Recombinant S1 subunit of pertussis toxin was expressed in the attenuated aroA mutant of Salmonella typhimurium, SL3261, in the human typhoid vaccine strain Salmonella typhi Ty21a, and in E. coli CAG629 containing the Shigella flexneri plasmid pWR110, which encodes bacterial invasiveness of epithelial cells. Expression of recombinant PT S1 subunit (rPT-S1) did not affect in vitro invasiveness of the tested strains, which retained the ability to adhere to and invade the embryonic human intestinal cell line HI-407. Following oral immunization of mice with the live vaccine strains expressing rPT-S1, immunoglobulin G (IgG), IgA, and IgM responses were monitored. IgG specific to PT was detected in serum samples of mice, while IgG and IgA specific to PT were detected in lung washes after oral immunization with living Salmonella spp. or E. coli (pWR110) expressing rPT-S1. Utilization of live oral vaccines expressing B. pertussis antigens, which stimulate both a systemic and lung mucosal response, may provide an attractive alternative to purified component vaccines against whooping cough.

Administration, Oral↗
PubMed1991

A redox reaction between MPP+ and MPDP+ to produce superoxide radicals does not impair mitochondrial function.

Rat brain mitochondria were incubated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its two metabolites (1-methyl-4-phenyl-2,3-dihydropyridium (MPDP+) and 1-methyl-4-phenylpyridinium (MPP+), and O2 uptake was assessed. MPP+ (500 and 1000 microM) inhibited state 3 and state 4 respiration with a reduction in the respiratory control ratio (RCR). In the presence of MPTP or MPDP+ (100-1000 microM) no inhibition of mitochondrial function occurred. Incubation with MPP+ (100-1000 microM) in combination with equimolar concentrations of MPDP+ or MPTP (100-1000 microM) did not increase the inhibition of mitochondrial function produced by MPP+ alone. Inhibition of mitochondrial function produced by MPP+ (500 microM) was not reduced by incorporation of superoxide dismutase (SOD) (50-1000 units/mL). However, the RCR in the presence of 500 microM MPP+ and 1000 units/mL SOD was not different from control values. SOD did not prevent the inhibition of state 3 and state 4 respiration produced by the combination of MPP+ and MPDP+. The results suggest that a redox reaction between MPP+ and MPDP+ to generate superoxide radicals does not contribute to the impairment of mitochondrial function produced by MPTP administration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Interrelationship between histopathologic characteristics of melanoma and estrogen receptor status.

To evaluate whether the increase in disease-free survival and survival previously reported for women with melanomas with estrogen receptors (ER) was a reflection of the histopathology of the primary melanoma, the interrelationship of histopathologic characteristics of 143 patients with such tumors was examined. The ER was assayed in the primary tumor from 44 patients and in 99 metastatic deposits from the other patients. Tumor thickness, level of invasion, prognostic index, mitoses/mm2, ulceration, vascular invasion, necrosis, histologic grade, preexisting nevus, and predominant malignant cell type were examined. There was no relationship between ER presence and any histopathologic characteristic examined, irrespective of the tumor source (primary or metastatic). Examination of histopathologic characteristics as a function of sex and receptor status showed a slight but insignificant predominance of more well-differentiated, thinner tumors in women whose lesions were positive for the ER. These results suggest that the increased disease-free survival in patients with ER-positive lesions is not attributable to the pathologic characteristics of the primary tumor examined during this study.

Female↗
PubMed1991

Chronic selective blockade of mu opioid receptors produces analgesia and augmentation of the effects of a kappa agonist.

We have previously demonstrated that, when administered chronically, naloxone and naltrexone have the paradoxical effect of producing analgesia in rats. In this study, rats treated chronically with intracerebroventricular (i.c.v.) microinjections, and mice treated chronically with subcutaneous (s.c.) injections of naloxone or beta-funaltrexamine (beta-FNA) developed analgesia on daily hot plate tests. There was not drug effect on the first day of hot plate testing, but significant increases in paw lick latency developed over subsequent acquisition sessions for animals treated with beta-FNA or naloxone. An augmented analgesic response to a 5 mg/kg s.c. injection of the kappa opioid agonist, U50-488H, was observed in mice previously treated with naloxone or beta-FNA. The primary findings of the present study were: (1) chronic blockade of mu opioid receptors is sufficient to produce analgesia on repeated hot plate tests in both rats and mice; (2) chronic blockade of mu receptors in the presence of stressful stimuli results in augmentation of kappa agonist-induced analgesia; and (3) the phenomenon of opioid blockade-induced analgesia (OBA) occurs in mice as well as rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Role of central versus peripheral opioid receptors in analgesia induced by repeated administration of opioid antagonists.

Although analgesia induced by blockade of opioid receptors has been well established, it is still unknown whether its development is mediated by the blockade of centrally located opioid receptors. Therefore, rats were treated with either systemically or ICV applied naloxone or quaternary naltrexone (QN), an opioid antagonist that does not easily penetrate the blood-brain barrier. Following antagonist administration, each animal was tested for paw lick latency on a 51 degrees C hot plate. Hot plate testing and drug injections were carried out for 4 consecutive days. Rats treated with ICV microinjections of QN or naloxone displayed paw lick latencies that were significantly longer than those observed in control animals. In contrast, rats treated with SC injections of QN did not show any increase in paw lick latency, whereas rats treated with SC injections of naloxone displayed paw lick latencies that were significantly longer than those of control rats. These results are consistent with the hypothesis that the blockade of central opioid receptors underlies the development of an analgesic response.

Analgesia↗
PubMed1991

Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker.

1. Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion-induced arrhythmias in conscious animals. 2. The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo. 3. Tedisamil (1-4 mg kg-1, i.v.) caused bradycardia, elevated blood pressure and dose-dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia-associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil-induced bradycardia was prevented by electrically-pacing the left ventricle. 4. Tedisamil dose-dependently lengthened the effective refractory period and prevented electrically-induced VF. In vivo, tedisamil (0.5-4 mg kg-1, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%. 5. Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.

Action Potentials↗
PubMed1991

Direct expression of Bordetella pertussis filamentous hemagglutinin in Escherichia coli and Salmonella typhimurium aroA.

Nonfused (i.e., nonhybrid) filamentous hemagglutinin (FHA) of Bordetella pertussis was efficiently expressed in Escherichia coli K-12 and Salmonella typhimurium aroA at levels higher than those found in wild-type B. pertussis when the upstream signals of the gene were replaced and the translation initiation region was engineered to optimize translational efficiency. Inclusion of part of the C-terminal FHA open reading frame, whose translation product does not appear to be part of the major secreted species of FHA, was shown to be important in achieving protein expression in both E. coli and S. typhimurium aroA; removal of the downstream gene sequence abolished recombinant FHA production. The levels of expression observed varied widely according to the construct and host bacterium used.

Adhesins, Bacterial↗