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Biomedical subjects

R D Olson

Publications and source records attributed to R D Olson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Age-related pharmacokinetics of daunorubicin and daunorubicinol following intravenous bolus daunorubicin administration in the rat.

Age-related differences in pharmacokinetics may be important in determining altered anthracycline cardiotoxicity in the senescent rat and also in older humans. This study examined the effect of aging on daunorubicin pharmacokinetics in the Fischer 344 rat. Daunorubicin 7.5 mg/kg was administered i.v. to 6- and 24-month-old male Fischer 344 rats and plasma and tissue sampling was performed over 168 h for assay of daunorubicin and daunorubicinol concentrations by high-performance liquid chromatography. Systemic clearance of daunorubicin was decreased in older compared to younger animals (56 +/- 4 versus 202 +/- 17 ml min-1 kg-1; P < 0.05). In addition, the area under the plasma daunorubicinol concentration/time curve was significantly increased in older rats. In the heart, the area under the concentration/time curve was significantly increased in senescence both in the case of daunorubicin (201 +/- 12 versus 86 +/- 4 micrograms h g-1; P < 0.05) and daunorubicinol (1347 +/- 118 versus 182 +/- 4 micrograms h g-1; P < 0.05). Furthermore, the peak mean concentrations of daunorubicin were increased in older compared to younger rats both in plasma (1078 +/- 82 versus 663 +/- 66 ng ml-1; P < 0.05) and in heart (27 +/- 1 versus 10 +/- 1 micrograms g-1; P < 0.05). This also was true for daunorubicinol in plasma (284 +/- 39 versus 168 +/- 27 ng ml-1; P < 0.05) and in myocardium (8.6 +/- 0.6 versus 2.4 +/- 0.2 micrograms g-1; P < 0.05). Following daunorubicin injection, the ratio of daunorubicinol to daunorubicin concentrations in tissues increased with time, particularly in plasma and heart in senescent rats. Thus, there are significant age-related changes in daunorubicin and daunorubicinol kinetics in the rat that could alter susceptibility to acute systemic toxicity and to chronic cardiotoxicity.

Aging↗
PubMed1997

Endogenous opiates: 1996.

This paper is the nineteenth installment of our annual review of research concerning the opiate system. It summarizes papers published during 1996 reporting the behavioral effects of the opiate peptides and antagonists, excluding the purely analgesic effects, although stress-induced analgesia is included. The specific topics covered this year include stress, tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunological responses; and other behaviors.

Animals↗
PubMed1996

Endogenous opiates: 1995.

This article is the eighteenth installment of our annual review of research concerning the opiate system. It includes articles published during 1995 reporting the behavioral effects of the opiate peptides and antagonists, excluding the purely analgesic effects. The specific topics covered this year include stress: tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunological responses; and other behaviors.

Affect↗
PubMed1996

Age-related characterization of atrial adenosine A1 receptor activation: direct effects on chronotropic and inotropic function in the Fischer 344 rat.

Adenosine, an endogenously produced nucleoside, has direct negative chronotropic and inotropic effects on right and left atrial tissues, respectively. Age-related differences in the effects of A1 adenosine receptor activation on atrial rhythmic and contractile function were investigated in adult (6-8 months) and senescent (23-24 months) Fischer 344 (F344) rats. Senescent right atria (RA) were more sensitive to the negative chronotropic effects of R-phenylisopropyladenosine (R-PIA), a selective A1 receptor agonist, than adult RA (EC50: 4.8 +/- 0.7 vs 10.8 +/- 1.5 nM). However, senescent left atria (LA) were 15.4% less responsive to the maximal negative inotropic effects of R-PIA than adult LA. R-PIA did not significantly change resting force from basal values in either age group, but 90% relaxation time was prolonged threefold in senescent LA compared with adults. Radioligand binding experiments with 1,3-[3H]dipropyl-8-cyclopentylxanthine, a selective adenosine A1 receptor antagonist, showed a 56% greater density (Bmax) of adenosine A1 receptor in senescent than adult without differences in affinities (Kd). The increased sensitivity of senescent RA to the negative chronotropic effects of adenosine A1 receptor stimulation suggests a role for adenosine in abnormal sinus node function that occurs more frequently with age. Adenosine A1 receptor stimulation has more effect on relaxation than contraction in senescent LA compared with LA from adult F344 rats. However, the increase in density of adenosine A1 receptors suggests a functional dissociation between the availability of binding sites and receptor activation.

Adenosine↗
PubMed1996

Aging increases the cardiotoxicity of daunorubicin and daunorubicinol in the rat.

This study examined effects of aging on the cardiac response in vitro to daunorubicin, a cancer chemotherapeutic agent that causes cardiotoxicity. Left ventricular trabeculae carneae from adult (aged 6-9 months) and old (aged 24-28 months) Fischer 344 rats were placed in oxygenated, physiological buffer. Preparations were treated with daunorubicin (175 microM) or saline (controls) over a 210-minute study period. Daunorubicin-induced decline in contractility (DS and dS/dt) was greater in old compared to adult myocardium (p < .02). Similarly, cardiac relaxation (90% relaxation time) was more impaired by daunorubicin in older preparations (p < 01). Although daunorubicin concentrations were unaffected by age, daunorubicinol concentrations in ventricular strips increased with time to a greater extent in the older group (p < .05). This study suggests that senescence increases the acute in vitro cardiotoxicity of daunorubicin and that the metabolite, daunorubicinol, may contribute to this toxicity.

Aging↗
PubMed1995

Daunorubicin and daunorubicinol pharmacokinetics in plasma and tissues in the rat.

Recent evidence suggests that 13-hydroxy metabolites of anthracyclines may contribute to cardiotoxicity. This study was designed to determine the pharmacokinetics of daunorubicin and the 13-hydroxy metabolite daunorubicinol in plasma and tissues, including the heart. Fisher 344 rats received 5 mg kg-1 daunorubicin i.v. by bolus injection. Rats were killed at selected intervals for up to 1 week after daunorubicin administration for determination of concentrations of daunorubicin and daunorubicinol in the plasma, heart, liver, kidney, lung, and skeletal muscle. Peak concentrations of daunorubicin were higher than those of daunorubicinol in the plasma (133 +/- 7 versus 36 +/- 2 ng ml-1; P < 0.05), heart (15.2 +/- 1.4 versus 3.4 +/- 0.4 micrograms g-1; P < 0.05), and other tissues. However, the apparent elimination half-life of daunorubicinol was longer than that of daunorubicin in most tissues, including the plasma (23.1 versus 14.5 h) and heart (38.5 versus 19.3 h). In addition, areas under the concentration/time curves (AUC infinity) obtained for daunorubicinol exceeded those found for daunorubicin in almost all tissues, with the ratios being 1.9 in plasma and 1.7 in the heart. The ratio of daunorubicinol to daunorubicin concentrations increased dramatically with time from < 1 at up to 1 h to 87 at 168 h in cardiac tissue. Thus, following daunorubicin injection, cumulative exposure (AUC infinity) to daunorubicinol was greater than that to daunorubicin in the plasma and heart. If daunorubicinol has equivalent or greater potency than daunorubicin in causing impairment of myocardial function, it may make an important contribution to the pathogenesis of cardiotoxicity.

Animals↗
PubMed1995

Endogenous opiates: 1994.

This article is the 17th installment of our annual review of research concerning the opiate system. It includes papers published during 1994 involving the behavioral, nonanalgesic, effects of the endogenous opiate peptides. The specific topics covered this year include stress; tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunological responses; and other behaviors.

Animals↗
PubMed1995

Quantification of the voltage-response relationship between punctate and field electrical stimulation and the function of isolated rat left atria and papillary muscles.

The effects of varying the electrical stimulation voltage on the noradrenergic tone and systolic and diastolic cardiac function of isolated rat cardiac preparations is unknown. If a wide range of voltages substantially alters the basal noradrerengic tone of isolated cardiac preparations, highly variable responses may complicate the interpretation of the cardiac effects of interventions, such as drugs or toxins. This study was designed to determine whether field or punctate electrode stimulation altered systolic and diastolic cardiac function of isolated rat atrial and ventricular muscle preparations through a beta-adrenergic receptor-mediated mechanism. Isolated left atria and right ventricular papillary muscles from adult Sprague-Dawley rats were stimulated to contract isometrically in Krebs bicarbonate buffer (30 degrees C, pH 7.4, 0.5 Hz). Cardiac muscle function was assessed by determining cardiac contractility (dF/dt), relaxation (80% relaxation time), and muscle stiffness (changes in resting force). Muscles were electrically stimulated to contract using either punctate or field electrodes. Basal values of cardiac function were determined at threshold voltages, and voltage was increased in stepwise fashion, over a wide range, to obtain a voltage response-relation to cardiac function. In left atrial preparations, both punctate and field electrical stimulation caused a 200% increase in cardiac contractility. The greatest changes in contractility occurred at near threshold voltages (less than 5 volts for punctate and 19 volts for field stimulation). The voltage-dependent increases in cardiac contractility were attenuated or abolished by pretreatment with atenolol (10 micromol/L; selective beta 1-antagonist) or reserpine (5 mg/kg i.p., 24 hr before euthanasia). In contrast to left atrial preparations, neither field or punctate electrical stimulation had any effect on the cardiac contractility of papillary muscle preparations. Neither field or punctate electrical stimulation had any effect on cardiac relaxation (80% relaxation time) or muscle stiffness (changes in resting force) of left atrial or papillary muscle preparations. This study demonstrates that punctate and field electrical stimulation can significantly increase cardiac contractility of rat left atrial preparations at near threshold voltages by increasing noradrenergic tone. Thus, control of the voltage range may be required to reduce variation in cardiac function of isolated rat left atrial preparations.

Animals↗
PubMed1995

Age-related effects in rabbit hearts of N6-R-phenylisopropyladenosine, an adenosine A1 receptor agonist.

Interventions known to increase cytoplasmic Ca2+ appear to amplify age-related impairment of cardiac function. In addition, increased release of interstitial adenosine, an endogenous nucleoside, has been suggested to mediate the diminished beta-adrenergic responsiveness in senescent heart. However, the direct effects of adenosine A1 receptor activation on senescent myocardium have not been investigated thoroughly. Therefore, the effects of N6-R-phenylisopropyladenosine (R-PIA), an A1 agonist, on atrial rate and contractility (+dF/dt) in adult (6-8 months) and senescent (5-7 years) New Zealand White rabbits were compared in spontaneously beating right atria and electrically stimulated isolated right papillary muscles. Although senescent right atria appeared to be more sensitive to the negative chronotropic-effects of R-PIA, the effective concentrations producing 50% of the maximum response (EC50 values) of R-PIA were not significantly different between adult (26 nM, 95% confidence limits: 12-52 nM) and senescent (13 nM; 95% confidence limits: 10-16 nM). However, senescent right ventricular papillary muscles were more sensitive to the negative inotropic effects of R-PIA. For example, at 90 contractions/min, 100 nM R-PIA decreased +dF/dt 25.3 +/- 7.4% and 61.9 +/- 4.8% in adult and senescent papillary muscles, respectively. To investigate whether R-PIA might alter sarcoplasmic reticulum (SR) function as a mechanism of decreased inotropy, we determined the inotropic effects of R-PIA on steady-state and 30-s postrest-potentiated contractions (PRP; an index of SR Ca2+ release) of left atria. R-PIA did not selectively decrease contractility of PRP compared to steady state in either adult or senescent left atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

Effects of Clostridium perfringens recombinant and crude phospholipase C and theta-toxin on rabbit hemodynamic parameters.

Clostridium perfringens exotoxins have been implicated as major virulence factors responsible for shock and organ failure in gas gangrene, yet the mechanism(s) by which they mediate cardiovascular dysfunction remain enigmatic. Recombinant (r) phospholipase C (PLC), r theta-toxin, culture supernatant (crude toxin), or 0.9% NaCl was infused intravenously into awake rabbits. Cardiac index (CI), mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), arterial blood gases, and hematocrit were measured 1 h before and for 3 h after toxin infusion. Crude toxin and rPLC decreased CI, MAP, and HR and increased CVP; mortality was 87.5% and 83%, respectively. r theta-toxin did not decrease CI or MAP and mortality was 25%. Further, crude toxin and rPLC but not r theta-toxin inhibited cardiac contractility (dF/dt) in isolated rabbit atrial muscles. These results suggest that PLC-induced myocardial dysfunction contributes to shock in C. perfringens infection.

Animals↗
PubMed1995

Effects of erythromycin on the rabbit pleura: its potential role as a pleural sclerosant.

Tetracycline (TCN) has been considered the agent of choice for pleurodesis in patients with symptomatic malignant pleural effusions and recurrent pneumothoraces. However, the intravenous form of TCN used for pleurodesis is no longer available. Erythromycin, like TCN, often produces irritation when administered intravenously. In view of these irritant properties, we tested the effect of erythromycin as a pleural sclerosant in rabbits as compared with TCN. Normal saline was used as a control. Adult rabbits weighing 2.5 to 3.0 kg underwent sterile placement of a silastic pleural tube in the right pleural space. Erythromycin (n = 17) or TCN (n = 6), each in doses of 35 mg/kg in 2 ml saline, was administered via the tube. Control animals (n = 6) received 2 ml saline. The chest tubes were left in place for removal of pleural fluid and to maintain lung expansion. Animals were killed 8 d after receiving the various treatments, and their pleural surfaces were examined grossly and histologically. Numerous adhesions were present between the visceral and parietal pleurae in all animals receiving erythromycin and TCN, but not in those receiving saline. On light microscopy, pleurae treated with erythromycin or TCN were histologically identical, showing inflammation, edema, and fibroblast proliferation in the submesothelial tissues. The saline-treated animals had a normal pleura. Because erythromycin produced pleural inflammation and adhesions within 8 d of treatment, we propose that it may have a potential role as a pleural sclerosant.

Animals↗
PubMed1994

The Tyr-MIF-1 family of peptides.

A review of research on the Tyr-MIF-1 family of peptides is presented with emphasis on Tyr-MIF-1 and its structure, passage through the blood-brain barrier, and both opiate antagonist and agonist properties. Family members MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1 are also included.

Animals↗
PubMed1994

Endogenous opiates: 1993.

This paper is the sixteenth installment of our annual review of research concerning the opiate system. It is restricted to papers published during 1993 that concern the behavioral effects of the endogenous opiate peptides, and does not include papers dealing only with their analgesic properties. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; development; immunological responses; and other behaviors.

Affect↗
PubMed1993

Anthracycline-induced tension in permeabilized cardiac fibers: evidence for the activation of the calcium release channel of sarcoplasmic reticulum.

Anthracyclines, such as doxorubicin (DOX), are important cancer chemotherapeutic agents that are cardiotoxic. The mechanism for the cardiotoxicity is not well-defined. Recent studies have concluded that anthracyclines release calcium (Ca2+) from membrane fractions containing sarcoplasmic reticulum (SR). To determine whether anthracyclines release Ca2+ in situ from cardiac SR, the effects of DOX on Ca(2+)-activated contractions were analyzed in membrane-permeabilized and membrane-intact fibers from rabbit heart. DOX (10-120 microM) induced tension development in calcium-preloaded permeabilized fibers. DOX-induced tension required submicromolar Ca2+, and was blocked by ruthenium red (20 microM) and Triton X-100 treatment, characteristics shared by caffeine-induced tension referable to SR Ca(2+)-release. DOX (50 microM) did not alter the maximum Ca(2+)-activated tension or shift the Ca2+ concentration-tension relationship of permeabilized fibers, indicating no effect of DOX on the myofilaments. DOX (44-350 microM) depressed post-rest isometric contractility of membrane-intact fibers but did not inhibit steady-state contractility (at 1 Hz; 2.5 Mm Ca2+), similar to effects of caffeine and submicromolar ryanodine. The specific effects of DOX on post-rest contractility of membrane-intact fibers are consistent with DOX-induced Ca2+ release from the SR of membrane-permeabilized fibers. Thus, DOX alters SR Ca2+ release in situ which may contribute to the inotropic and lusitropic dysfunction observed with anthracyclines.

Animals↗
PubMed1993

Daunorubicin-induced cardiac injury in the rabbit: a role for daunorubicinol?

This study evaluated potential contributions of daunorubicin and its principle metabolite, daunorubicinol, to the cardiotoxicity of daunorubicin therapy. Daunorubicin (15 mg/kg) or placebo (normal saline) was administered by iv bolus to New Zealand white rabbits and 3 to 4 days later, hearts were removed to measure contractility (dF/dt), concentrations of daunorubicin and daunorubicinol, and evidence of oxidative stress on glutathione and glutathione peroxidase. Contractile function of isolated atria and papillary muscles was depressed (p < 0.05). Daunorubicinol exceeded daunorubicin concentration in the heart (p < 0.005) with a ratio of metabolite to parent drug of 26 in atrial and 32 in ventricular tissue. There was a significant correlation between peak plasma (r = -0.63; p < 0.05) or cardiac concentration (r = -0.78; p < 0.02) of daunorubicinol, but not daunorubicin, and depression of dF/dt in papillary muscles. In separate in vitro studies, daunorubicinol at a concentration (5.5 micrograms/g tissue or 10 microM) approximating that observed ex vivo in heart inhibited Ca2+ uptake into cardiac sarcoplasmic reticulum vesicles by 39 +/- 3%, whereas 10 microM daunorubicin (14-fold higher than actual ex vivo cardiac concentrations) did not demonstrate any detectable inhibition. Daunorubicin treatment failed to significantly alter concentrations of GSH or GSSG or activities of glutathione peroxidase in the heart. Thus, cardiac dysfunction observed 3 to 4 days after a single dose of daunorubicin did not clearly relate to oxidative stress, but was associated with a cardiac concentration of daunorubicinol that appeared sufficiently high to impair Ca2+ metabolism.

Animals↗
PubMed1993

Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit.

Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg.kg-1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739 +/- 265 vs 100 +/- 10 ng.ml-1) and doxorubicinol (78 +/- 3 vs 16 +/- 3 ng.ml-1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC infinity, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92 +/- 0.9 vs 3.59 +/- 0.72 micrograms.g-1 tissue; P < 0.001) and doxorubicinol (0.24 +/- 0.02 vs 0.09 +/- 0.01 micrograms.g-1 tissue; P < 0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol.

Animals↗