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Biomedical subjects

W Spinelli

Publications and source records attributed to W Spinelli.

28 records · Page 2Linked to original sources
PubMed1986

Developmental changes in the effects of beta-adrenergic blocking concentrations of propranolol on canine Purkinje fibers.

We used standard microelectrode techniques to investigate the developmental changes in the effects of the beta-blocker propranolol on canine Purkinje fibers. The effects of propranolol on the transmembrane action potential were similar in neonatal and adult Purkinje fibers. In automatic Purkinje fibers we obtained concentration-response (increase in rate) curves for isoproterenol alone and with an increasing concentration of propranolol. The curve for isoproterenol in neonatal Purkinje fibers had an EC50 of 1.0 X 10(-9) M, about 5-fold lower than in adult Purkinje fibers (EC50 = 5.03 X 10(-9) M, p less than 0.05). At both ages, propranolol caused a parallel, concentration-dependent shift of the response curves for isoproterenol, with no change in the maximum effect. Equiactive dose ratios in presence and absence of 3 concentrations of propranolol were compared by the Schild plot. The pA2 values for adult and neonate Purkinje fibers were 8.32 (8.14-8.46; 95% confidence level) and 8.86 (8.69-9.03; 95% confidence level), respectively. Our results indicate significant (p less than 0.05) developmental changes in the beta-blocking effects of propranolol in canine Purkinje fibers.

Action Potentials↗
PubMed1986

The effects of doxorubicin on ventricular tachycardia.

Doxorubicin, in concentrations that have no effect on fast or slow response action potentials, has been shown to suppress ouabain-induced delayed afterdepolarizations. In this study, we used standard microelectrode techniques to determine the effects of doxorubicin on isolated canine Purkinje fibers. We studied automaticity induced at normal and low membrane potentials, conduction in normal and K+-depolarized Purkinje fibers, and triggered activity induced by ouabain and by experimental myocardial infarction. Doxorubicin, 50 microM, suppressed the triggered activity and the delayed afterdepolarizations that induced it, but had no effect on the other variables. We then studied the effects of intravenous doxorubicin, 16 to 64 mg/m2 body surface area, on ouabain-induced ventricular tachycardia and the ventricular tachycardia that occurs 24 hr after ligation of the left anterior descending coronary artery in the intact dog. There was no effect on the infarct-induced arrhythmia, but concentrations of doxorubicin that had no other effect on the electrocardiogram suppressed those ouabain-induced arrhythmias that appeared to have been triggered. The automatic arrhythmias induced by ouabain were not affected. Both the latter mechanisms were verified in studies of isolated Purkinje fibers that were obtained on completion of the intact animal experiments. These results indicate that agents having high selectivity for specific arrhythmogenic mechanisms can be useful adjuncts in discriminating among the mechanisms responsible for arrhythmias in intact animals.

Animals↗
PubMed1986

Frequency-dependent actions of phenytoin in adult and young canine Purkinje fibers.

Phenytoin has been reported to be particularly effective in the treatment of postoperative ventricular arrhythmias in children. The authors used standard microelectrode techniques to examine the developmental changes in the action of phenytoin on the transmembrane action potential of neonatal and adult canine Purkinje fibers. Their goals were to test whether developmental differences in phenytoin action on the action potential might explain the clinical observations and to evaluate the contribution of use-dependent reduction of Vmax and effects on slow responses to the antiarrhythmic action of phenytoin. In Tyrode's solution with [K+]0 = 4 mM, phenytoin at 5 and 10 micrograms/ml (concentrations comparable to therapeutic plasma levels) had no major effects on action potential characteristics or use dependence at either age. At [K+]0 = 6 mM, on decreasing the drive cycle length from 1300 to 300 msec, phenytoin reduced Vmax significantly and in a concentration-dependent manner. The magnitude of this action was similar at both ages. Conduction times were also significantly prolonged. The time constants for onset of (tau o) and recovery from (tau r) use-dependent block were similar in neonates and adults. The effects of phenytoin on slow responses were significant, although modest, at both ages, but there was no significant effect on conduction. This study indicates that in K+-depolarized Purkinje fibers, use-dependent reduction of the fast Na+ current is a major determinant of the antiarrhythmic action of phenytoin. In contrast to lidocaine and quinidine, no age-related changes in phenytoin action were found, underscoring the different developmental effects of individual antiarrhythmic drugs.

Age Factors↗
PubMed1985

Modification of Vmax of canine cardiac Purkinje fibers and of the effects of lidocaine by SC-72-14.

We used standard microelectrode techniques to determine the effects of SC-72-14, a monoclonal antibody to the fast sodium channel, on the transmembrane potentials and Vmax of canine cardiac Purkinje fibers, and to study the interactions of the monoclonal antibody with lidocaine. SC-72-14 was prepared with receptor-rich membrane fragments of homogenized eel electroplax as the antigen. It reduced Vmax in a concentration-dependent fashion, and depressed membrane responsiveness, as well. These effects were attributable specifically to SC-72-14, and not to other substances in the vehicle. At slow rates of stimulation, the actions of SC-72-14 and lidocaine on Vmax equaled the sum of their effects, administered alone. These results are consistent with the interpretation that SC-72-14 and the local anesthetic did not compete for the same binding site. In contrast, at fast stimulation rates, the use-dependent blocking effects of lidocaine were suppressed by SC-72-14. The basis for the interference with the use-dependent action of lidocaine is not readily apparent, but may be the result of SC-72-14-induced changes in channel state, receptor affinity for drug, or the availability of ionized drug molecules. These possibilities all await further testing.

Animals↗
PubMed1985

Neurite formation modulated by nerve growth factor, insulin, and tumor promoter receptors.

Until recently, nerve growth factor could be considered the only neurotrophic factor with an established physiological role. We discuss the emerging evidence indicating that the insulinlike factors may constitute a family of related neurotrophic proteins, and the observations suggesting that the receptor for the phorbol ester tumor promoters is closely associated with neuronal differentiation. The emphasis of the discussion is placed on neurite formation under multiple modulation by insulinlike factors, nerve growth factor, and tumor promoter receptors in sensory, sympathetic and human neuroblastoma cells.

Animals↗
PubMed1985

Gentamicin kinetics in the neonate.

Gentamicin serum levels were measured and elimination half-life was calculated in a group of neonates with postconceptual ages ranging between 25-42 weeks. Infants were receiving intravenous gentamicin (2.5 mg/Kg/dose) at various dosage intervals and t 1/2e was calculated using a one-compartment open model. Evidence of gentamicin accumulation was present in 82% of infants 34 weeks. T 1/2e was 8.8 +/- .7 hours in infants 30 weeks, 7.8 +/- 1.1 hour in infants between 30-34 weeks and 6.2 +/- .5 in infants greater than 34 weeks. The results of the study suggest that gentamicin elimination is related to postconceptual age and that infants treated with recommended dosage regimens may have possible gentamicin tissue accumulation and nephrotoxicity. Therefore, the dosage interval may have to be lengthened to 18 hours in infants less than 34 weeks with close gentamicin plasma level monitoring.

Bacterial Infections↗
PubMed1984

Gentamicin absorption during prophylactic use for necrotizing enterocolitis.

Gentamicin absorption was measured after oral administration in 18 neonates treated prophylactically in an attempt to decrease the incidence of necrotizing enterocolitis. Patients were given 10 mg/kg/day in four divided doses via nasogastric tube for a total of 10 days. Levels were assayed using the Emit system. Serum levels ranged between 0 and 2.2 micrograms/ml. Mean levels over 10 days were 0.42 +/- (SD) 0.47 micrograms/ml and did not vary significantly from day to day. From these data we conclude that enterally administered gentamicin is not absorbed to a degree that would result in toxic or even therapeutic serum concentrations.

Birth Weight↗
PubMed1983

Tumor promoter receptors regulating neurite formation in cultured human neuroblastoma cells.

The mouse skin tumor promoter phorbol-12,13-dibutyrate (PDBU) reversibly enhanced neurite outgrowth in SH-SY5Y human neuroblastoma cells, whether serum was present or absent. The half-maximum response in serum occurred at 10 nM. The binding of [20-3H]phorbol-12,13-dibutyrate [( 3H]PDBU) was studied. Five mouse skin tumor promoters, which included teleocidin, mezerein, and three structural congeners of phorbol, enhanced neurite outgrowth and inhibited binding of [3H]PDBU, but two nonpromoting phorbol congeners did neither. Saccharin and cyclamate, promoters in rat bladder, did not inhibit [3H]PDBU binding. Binding of 10 nM [3H]PDBU at 37 degrees was maximal within 5 min and stable for at least 5 hr. Down modulation of binding was not detected. Following binding at 37 degrees, the dissociation rate in excess PDBU was biphasic, whether measured at 37 degrees or at 4 degrees. The Scatchard curve was also consistent with two types of sites, about 2.5 X 10(5) sites/cell with Kd = 8.5 nM and 1.2 X 10(6) sites with Kd = 125 nM. Negative cooperativity was not observed. In short-term assays, nerve growth factor (NGF) did not alter [3H]PDBU binding, and phorbol ester promoters did not alter 125I-NGF binding. Furthermore, [3H]PDBU binding was unaltered following growth of cells for 1 week in PDBU or NGF, conditions under which neurite outgrowth was continuously enhanced, and other phenotypic expressions of differentiation are known to be increased. Specific [3H]PDBU binding sites were present in five neuroblastoma cell lines, two of which are responsive and three unresponsive by neurite outgrowth to promoters and NGF, suggesting the possibility of a common lesion in distal steps in the unresponsive lines.

Axons↗
PubMed1982

Effects of phorbol ester tumor promoters and nerve growth factor on neurite outgrowth in cultured human neuroblastoma cells.

The effect of phorbol ester tumor promoters on neurite outgrowth was studied in cultured human neuroblastoma cell lines and in cultured embryonic chick and neonatal rat sympathetic ganglia. Promoters inhibited nerve growth factor (NGF)-stimulated neurite outgrowth in sympathetic ganglia while nonpromoting structural congeners did not, in keeping with previous results in embryonic sensory ganglia. In contradistinction, promoters reversibly enhanced neurite outgrowth in malignant SH-SY5Y neuroblastoma cells, whereas nonpromoting congeners were inactive. The potent promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) reversibly increased the proportion of SH-SY5Y cells with neurites and the average length of neurites; the effects of the combination of TPA and NGF were greater than that of either compound alone. The half-maximum response to TPA was at about 2 ng/ml (3 nM). The neurites were thinner, straighter, and less branched and showed more swellings resembling beads or varicosities in comparison with NGF-induced neurites. TPA transiently inhibited the cellular growth rate between Days 2 and 4. Thereafter, the rate was the same as in untreated cultures. The transient inhibition was due to causes other than degradation of TPA since fresh TPA was added. The effect of TPA on neurite outgrowth was not transient and was independent of effects on growth. TPA also enhanced neurite outgrowth in another NGF responsive line, LA-N-5, but not in two unresponsive lines, CHP-100 and CHP-134.

Animals↗