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Biomedical subjects

R D Olson

Publications and source records attributed to R D Olson.

At least 55 records · Page 3Linked to original sources
PubMed1993

Picrotoxin-induced seizures modified by morphine and opiate antagonists.

The effects of naloxone, Tyr-MIF-1, and MIF-1 on morphine-mediated changes in susceptibility to picrotoxin-induced seizures were studied. Rats were pretreated with naloxone, MIF-1, Tyr-MIF-1, or saline. At 15-min intervals, they received a second pretreatment of morphine or saline and then were tested for seizures following a convulsant dose of picrotoxin. Several parameters of specific categories of seizures were scored. Morphine increased the number of focal seizure episodes, duration of postseizure akinesis, and incidence of generalized clonic seizures. Naloxone tended to block the morphine-mediated changes in susceptibility. Tyr-MIF-1 had effects similar to naloxone on duration of postseizure immobility but tended to potentiate the effects of morphine on focal seizure episodes. The effects of morphine and the opiate antagonists on focal seizure episodes and postseizure duration suggest the general involvement of several types of opiate receptors in these picrotoxin-induced behaviors. However, the observation of antagonistic effects for Tyr-MIF-1 on immobility but agonistic effects for focal seizures suggests that the type of effect exerted by opiate agents may depend upon other neuronal variables.

Animals↗
PubMed1993

Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function.

1. The present study evaluated the time-dependency of acute anthracycline cardiotoxicity by varying the duration of exposure of rabbit isolated atria to doxorubicin and determining changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C-13 hydroxy metabolite, doxorubicinol. 2. Following addition of doxorubicin (175 microM) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3. Doxorubicin (175 microM) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 microM), however, failed to produce time-related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4. During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5. To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration-response experiments with doxorubicinol (0.9-7.2 microM) were conducted. 6. Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin-treated than in doxorubicinol-treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function.7. Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2+ release from isolated SR vesicles, but 3 microM doxorubicinol promoted a 15 fold greater release rate than 3 microM doxorubicin.8. Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2+loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time-dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2+ homeostasis.

Animals↗
PubMed1993

Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model.

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [3H]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33 +/- 0.03 pmol/mg) compared with control rabbits (0.66 +/- 0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [3H]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. Bmax for [3H]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.

Animals↗
PubMed1992

Effect of a low-protein diet on doxorubicin pharmacokinetics in the rabbit.

Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enhanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low-protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8-12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1, n = 15; group 2, n = 14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48 +/- 3 vs 59 +/- 4 ml min-1 kg-1; P less than 0.05), prolonged the terminal elimination half-life (28 +/- 2 vs 22 +/- 2 h; P less than 0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722 +/- 122 vs 1405 +/- 71 ng h ml-1; P less than 0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-protein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52 +/- 5 vs 40 +/- 2 h; P less than 0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.

Animals↗
PubMed1992

Age- and sex-related changes in Tyr-MIF-1-like immunoreactivity in rat plasma.

The concentrations in plasma of the biologically active endogenous peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) have not been measured during development or in female rats. By radioimmunoassay, we found that Tyr-MIF-1-like immunoreactivity (Tyr-MIF-1-LI) was first consistently detectable in plasma when the rat was 5 days old, and then gradually increased to adult concentrations by day 15. In male rats, the levels remained relatively constant for the next 21 months. In female rats, plasma concentrations of Tyr-MIF-1-LI at day 15 were about the same as in male rats. At 6 months of age, however, the concentrations in females decreased by half and by 21 months of life were only about a third of the concentrations found at day 15 or in age-matched males. The differences with age were not due to the length of time of storage of the samples, because another group of rats 1 month old was killed on the same day as 5-day-old rats and still showed several times more Tyr-MIF-1-LI in the plasma; again, no differences were found between male and female rats at either 5 days or 1 month. A single injection of estradiol followed by progesterone lowered the concentrations in 1-month-old male rats. In female rats that were either ovariectomized or sham-ovariectomized, the expected similarity in their plasma concentrations of Tyr-MIF-1-LI was found at 1 month of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Distribution↗
PubMed1991

Aging alters the force-frequency relationship and toxicity of oxidative stress in rabbit heart.

Adult (6 months) and senescent (greater than 5 years) rabbit atria were studied under conditions known to increase cytoplasmic calcium (increased frequency of contraction and oxidative stress). At a contraction frequency of 1/sec, cardiac relaxation (90% relaxation time) was similar in senescent and adult atria but at a frequency of 2 or 3/sec, relaxation was significantly slower in senescent preparations (P less than 0.05). Additional experiments indicated that H2O2 (500 microM), a powerful oxidant, increased resting force and decreased developed force (DF) much more rapidly in senescent than adult atria; the maximum decrease in DF, however, was less in senescent preparations (adult = 81 +/- 6% and senescent = 42 +/- 27% of pre-H2O2 values; P less than 0.05). Age-related differences in effects of H2O2 did not result simply from a decreased ability of senescent hearts to detoxify an oxidative stress by the glutathione pathway. Both basal glutathione (GSH) concentrations and the H2O2-mediated decreases in GSH were similar in adult and senescent ventricular preparations, as were activities of glutathione peroxidase and glutathione reductase. These observations suggest that interventions known to increase cytoplasmic calcium can amplify age-related impairments of cardiac relaxation through mechanisms that may be independent of the glutathione pathway.

Aging↗
PubMed1990

Taurine deficiency and doxorubicin: interaction with the cardiac sarcolemmal calcium pump.

An anticancer drug, doxorubicin, and a naturally occurring beta-amino acid, taurine, exert opposing actions on myocardial calcium content and lipid peroxidation. Thus, we tested the hypothesis that the two agents may interact to modify cardiac calcium metabolism and indices of lipid peroxidation. Cardiac taurine levels were reduced by half in rats given tap water containing a beta-amino transport inhibitor, beta-alanine. Taurine deficiency was associated with an increased susceptibility of the heart to doxorubicin-mediated calcium accumulation, a phenomenon commonly associated with doxorubicin cardiotoxicity. Taurine deficiency also predisposed the heart to enhanced formation of malondialdehyde caused by doxorubicin administration. While increases in malondialdehyde levels are often associated with lipid peroxidation, the failure of doxorubicin to cause changes in oxidized glutathione content makes peroxidative mechanisms a less likely explanation for the potentiation of doxorubicin-mediated myocardial calcium accumulation in taurine-deficient rats. A more likely possibility is the interaction between taurine deficiency and doxorubicin to inhibit the sarcolemmal calcium pump. The data also suggest that the interaction between doxorubicin and taurine deficiency does not involve alterations in the pharmacokinetics of doxorubicin or the cardiotoxic metabolite, doxorubicinol. It is concluded that reduction in sarcolemmal calcium pump activity by taurine deficiency may contribute to myocardial calcium accumulation in hearts whose calcium homeostasis has been compromised by doxorubicin.

Animals↗
PubMed1990

Doxorubicin cardiotoxicity: analysis of prevailing hypotheses.

Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents that produce a well-described but incompletely understood cardiac toxicity. According to a popular hypothesis, anthracyclines injure the heart by generating oxygen-centered free radicals. This free radical hypothesis, however, appears to be inconsistent with many observations, such as the frequent failure of anthracyclines at cardiotoxic doses to produce evidence of increased free radical generation. Other explanations of cardiotoxicity involve platelet-activating factor, prostaglandins, histamine, calcium, and C-13 hydroxy anthracycline metabolites. These C-13 hydroxy metabolites, on the basis of in vitro data, are considerably more potent than parent compounds as myocardial depressants and as inhibitors of ATPases of sarcoplasmic reticulum, mitochondria, and sarcolemma. Further studies will be required to determine whether metabolites or the other putative injurious agents discussed contribute substantially to the cardiomyopathy of anthracycline therapy. The hypotheses presented in this paper should provide a useful framework for subsequent investigations into the mechanisms of anthracycline cardiotoxicity.

Animals↗
PubMed1989

MIF-1 is active in a chronic stress animal model of depression.

MIF-1 was tested in an animal model of depression that used unpredictable chronic stress. In this paradigm, rats received either no stressors or a daily protocol of a variety of stressors for 20 days, during which time daily, intraperitoneal injections of various compounds were given. The tricyclic antidepressant imipramine (5 mg/kg) and low doses (0.1 and 1.0 mg/kg) of MIF-1 significantly increased activity and decreased defecation in an open field on day 21. No dose of naloxone (0.01-10.0 mg/kg) acted as an antidepressant. A high dose (10.0 mg/kg) of MIF-1 significantly increased the effects of chronic stress and produced hyperalgesia. Chronically-stressed rats were significantly more analgesic than controls. The results indicate that MIF-1 can act as an antidepressant in this model.

Animals↗
PubMed1989

Differential effects of Tyr-MIF-1 and naloxone in two animal models involving benzodiazepine.

It has been shown previously that the endogenous brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) can act as an antiopiate and can also increase binding and function at the GABAA/benzodiazepine receptor complex. We now describe the effects of this tetrapeptide in two models in which the antiopiate naloxone has been reported to decrease the activity of benzodiazepines. Unlike naloxone, Tyr-MIF-1 and MIF-1 neither prevented chlordiazepoxide-induced locomotor hyperactivity in mice on a tilting floor nor suppressed chlordiazepoxide-induced eating in rats. Thus, in these two systems, Try-MIF-1 did not act as an antiopiate or alter the effects of a benzodiazepine, indicating a selectivity in the actions of Tyr-MIF-1.

Animals↗
PubMed1988

Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit.

Doxorubicin is metabolized extensively to doxorubicinol by the ubiquitous aldoketoreductase enzymes. The extent of conversion to this alcohol metabolite is important since doxorubicinol may be the major contributor to cardiotoxicity. Aldoketoreductases are inhibited in vitro by phenytoin. The present study was conducted to examine the effect of phenytoin on doxorubicin pharmacokinetics. Doxorubicin single-dose pharmacokinetic studies were performed in 10 New Zealand White rabbits after pretreatment with phenytoin or phenytoin vehicle (control) infusions in crossover fashion with 4-6 weeks between studies. Infusions were commenced 16 h before and during the course of the doxorubicin pharmacokinetic studies. Phenytoin infusion was guided by plasma phenytoin estimation to maintain total plasma concentrations between 20 and 30 micrograms/ml. Following doxorubicin 5 mg/kg by i.v. bolus, blood samples were obtained at intervals over 32 h. Plasma doxorubicin and doxorubicinol concentrations were measured by HPLC. The mean plasma phenytoin concentrations ranged from 17.4 to 33.9 micrograms/ml. Phenytoin infusion did not alter doxorubicin pharmacokinetics. The elimination half-life and volume of distribution were almost identical to control. Clearance of doxorubicin during phenytoin administration (60.9 +/- 5.8 ml/min per kg, mean +/- SE) was similar to that during vehicle infusion (67.5 +/- 5.4 ml/min per kg). Phenytoin administration was associated with a significant decrease in doxorubicinol elimination half-life from 41.0 +/- 4.8 to 25.6 +/- 2.8 h. The area under the plasma concentration/time curve (AUC) for doxorubicinol decreased significantly from 666.8 +/- 100.4 to 491.5 +/- 65.7 n.h.ml-1. These data suggest that phenytoin at clinically relevant concentrations does not alter the conversion of doxorubicin to doxorubicinol in the rabbit. The reduction in the AUC for doxorubicinol caused by phenytoin appears to be due to an increased rate of doxorubicinol elimination. Phenytoin or similar agents may have the effect of modifying doxorubicinol plasma concentrations by induction of doxorubicinol metabolism rather than by inhibition of aldoketoreductase enzymes.

Alcohol Dehydrogenase↗
PubMed1988

Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol.

Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.

Animals↗
PubMed1988

Lethal effects and cardiovascular effects of purified alpha- and theta-toxins from Clostridium perfringens.

Shock, a common and frequently fatal manifestation of gas gangrene caused by Clostridium perfringens, is probably mediated by extracellular toxins. Previous studies implicating alpha-toxin as the major lethal factor were frequently done with preparations contaminated with a second lethal factor, theta-toxin. We purified alpha- and theta-toxins from C. perfringens and demonstrated that both were lethal to mice. We investigated the effects of these purified toxins on cardiovascular function in intact rabbits; both toxins caused profound hypotension and bradycardia within 40 min. Reduced cardiac output preceded the development of hypotension and bradycardia. Purified alpha-toxin produced a dose-dependent reduction in myocardial function in isolated rabbit atrial preparations. Purified theta-toxin did not directly inhibit myocardial function. Shock induced by alpha-toxin may be partly mediated by direct depression of myocardial function. theta-Toxin reduced cardiac output in intact animals but had no direct effects on isolated heart preparations at concentrations that induced shock in intact animals. These data suggest that theta-toxin-induced shock could be mediated by an endogenous myocardial depressant factor.

Animals↗
PubMed1988

Effects of amperozide and azaperone on aggression and productivity of growing-finishing pigs.

Levels of aggression, activity and performance were determined in 270 pigs (initial wt 29.8 kg) injected with amperozide (1.0 mg/kg i.m.), azaperone (2.2 mg/kg i.m.) or saline (.1 ml/kg i.m.) immediately prior to mixing. Pigs had ad libitum access to feed in pens of 15, and six pens were allotted to each treatment. Each pen was video-taped for 48 h after injection. Aggression was determined by continuous observation and summarized for each 2-h period. Injuries on the ears and shoulders of each pig were scored prior to injection and 1, 2, 3 and 7 d after treatment. Eating, drinking and lying were determined by scan sampling at 2-min intervals and summarized for each 2-h period. Weight gain, feed consumption and efficiency were determined for periods ending on d 3, 7, 14, 28, 42, 56, 70 and 84. Both drugs reduced total fighting from 309.8 min for saline to 190.7 and 189.6 min for amperozide- and azaperone-treated pens, respectively (P less than .01). Treatment differences in aggression and lying were evident during the initial 6 h only. Amperozide resulted in fewer fights involving two pigs (197.3/pen) than did azaperone (260.2/pen) or saline (298.3/pen) (P less than .05). Injuries to the ears (P less than .01) and total injuries (P less than .05) were less severe in amperozide-treated pigs than in pigs on the other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1987

The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions.

Doxorubicin (adriamycin) is a highly effective cancer chemotherapeutic drug but its clinical utility is limited by its cardiotoxicity. Doxorubicinol, the major metabolite of doxorubicin, is up to 10 times more potent than doxorubicin at inhibiting isometric contraction of the papillary muscle isolated from the right ventricle of rabbit heart. Doxorubicinol also increases resting tension of isolated cardiac muscle indicative of incomplete relaxation between contractions, a characteristic of doxorubicinol but not of doxorubicin. This study assesses the effect(s) of doxorubicinol on a variety of ion pumps which may explain, in part, the action of the metabolite in the intact muscle. We find the doxorubicinol is a potent inhibitor (IC50 less than 5 micrograms/ml) of calcium-stimulated ATPase activity of sarcoplasmic reticulum from canine heart and rabbit skeletal muscle. At comparable levels, doxorubicinol is also a potent inhibitor of (Na + K)-ATPase of cardiac sarcolemma and the Mg-dependent ATPase activity referable to the F0F1 proton pump of mitochondria. For each of these ion pumps, doxorubicinol is at least 80 times more potent an inhibitor than doxorubicin. Doxorubicinol, between 10 and 50 micrograms/ml, increases resting tension up to 4-fold in isolated papillary muscles cyclically contracting at 30 times/min. Resting stress is relatively insensitive to doxorubicin. Thus, doxorubicinol is a potent inhibitor of several key cationic pumps that directly or indirectly regulate cell calcium and inhibits relaxation in the isolated fiber preparation. These observations add a new dimension to understanding the cardiotoxicity of doxorubicin.

5'-Nucleotidase↗
PubMed1987

Phenytoin pharmacokinetics in the rabbit: evidence of rapid autoinduction.

Phenytoin pharmacokinetics were studied during continuous intravenous infusion in 12 New Zealand white rabbits. The mean clearance at 40 hours (5.1 +/- 1.1 ml/min per kg; mean +/- SE) was significantly greater than that at 16 hours (3.1 +/- 0.5 ml/min per kg; p less than 0.05). These data suggest that with chronic administration, autoinduction of metabolism results in an increase in the rate of phenytoin clearance in the rabbit.

Animals↗