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T Akera

Publications and source records attributed to T Akera.

At least 19 recordsLinked to original sources
PubMed2001

Doxorubicin affects the cardiac muscarinic system in the rat.

During the study on the mechanism of doxorubicin-induced cardiotoxicity, we observed that a long incubation (4 hr) with doxorubicin reduced the maximal negative inotropic effects of a muscarinic receptor agonist, carbachol. The mechanism responsible for this doxorubicin-induced reduction of the efficacy of carbachol was examined in isolated guinea pig hearts. In isolated left atrial muscle preparations, 1 hr incubation with 100 microM doxorubicin caused a parallel right-ward shift of the concentration-response curves for carbachol, but a longer (4 hr) incubation with this agent (30, 100 or 200 microM), caused a significant reduction of the magnitude of the negative inotropic effect of carbachol in addition to the concentration-dependent parallel right-ward shift. The 4-hr incubation with these concentrations of doxorubicin also reduced the maximal negative inotropic effect of an adenosine A1 receptor agonist, R-phenylisopropyl adenosine (R-PIA), without affecting the potency of this agonist. Doxorubicin (1 to 100 microM) reduced [3H]quinuclidinyl benzilate (QNB) binding in a concentration dependent manner, but failed to alter [3HIR-PIA binding. The decrease in the magnitude of the maximal negative inotropic effect by doxorubicin was caused by changes in the muscarinic system at steps common to the transduction of muscarinic and adenosine A1 receptor mechanisms.

Adenosine↗
PubMed2000

Anti-muscarinic actions of mitoxantrone in isolated heart muscles of guinea pigs.

A hypotheses that mitoxantrone is a competitive antagonist at muscarinic cholinergic receptors was examined in guinea-pig hearts. In isolated left atrial muscle preparations, electrically paced at 2 Hz, the muscarinic agonist, carbachol, caused a concentration-dependent decrease in developed tension. Mitoxantrone caused a parallel right-ward shift of the concentration-response curve for carbachol. Schild plots for the effect of mitoxantrone on the carbachol concentration-response relationship were linear with a slope of 0.88 which was not significantly different from the unity. The right-ward shift of the carbachol concentration-response relationship by mitoxantrone significantly reversed after an additional incubation with a mitoxantrone-free solution, although the reversal was incomplete after a 2-h incubation in the mitoxantrone-free solution. Mitoxantrone caused a concentration-dependent displacement of specific [3H]quinuclidinyl benzilate binding to membrane preparations obtained from ventricular muscles of guinea-pig hearts. These results indicate that mitoxantrone acts as a competitive antagonist for the muscarinic receptors.

Analgesics↗
PubMed2000

Doxorubicin-induced late cardiotoxicity: delayed impairment of Ca2+-handling mechanisms in the sarcoplasmic reticulum in the rat.

Doxorubicin treatment causes delayed development of cardiotoxicity. Whether the doxorubicin-induced impairment of cardiac functions reverses or progresses with time after the cessation of the treatment was examined. The rats were injected with doxorubicin (2.5 mg/kg, i.v., once a week for 3 weeks) and sacrificed at 1 (1W), 13 (13W), or 18 (18W) weeks after the final doxorubicin administration. The time to peak of twitch contraction observed at 2-Hz stimulation was not altered in left atrial or ventricular muscle preparations isolated from 1W rats, but it was prolonged in those from 13W and 18W rats. The reduction of the magnitude of postrest contraction and the alteration of force-frequency relationships in left atrial muscle preparations in 1W rats were not significant, but were intensified in the 13W and 18W groups. Alterations in the postrest contraction and the force-frequency relationships in ventricular muscle preparations isolated from doxorubicin-treated rat hearts were weaker, but the pattern of alteration was similar to that observed in left atrial muscle preparations. Caffeine-induced contraction observed in skinned fibers that were isolated from the 1W rats was not altered, but it was reduced in the 18W rats. The Ca2+ sensitivity of contractile proteins was not altered in doxorubicin-treated rat hearts in any of the groups. The K(d) values estimated from a [3H]ryanodine binding study were not altered, but the B(max) values were significantly lower in the 13W and 18W groups than those observed in control rats. These results suggest that the dysfunction of the sarcoplasmic reticulum progresses after the completion of doxorubicin treatment and contributes to the doxorubicin-induced late cardiotoxicity.

Animals↗
PubMed1997

Ca2+ overloading causes the negative inotropic effect of doxorubicin in myocytes isolated from guinea-pig hearts.

We reported previously that conditions shown to increase Ca2+ loading augment the negative inotropic effect of doxorubicin: To examine if the negative inotropic effect is caused by Ca2+ overloading doxorubicin-induced changes in diastolic and systolic Ca2+ concentrations and twitch contractions were studied under altered Ca2+ loading. Intracellular Ca2+ concentrations ([Ca2+]i) were monitored in fura-2-loaded myocytes isolated from the ventricular muscle of guinea-pig hearts. Twitch contractions were estimated from the shortening of myocytes. In myocytes incubated at 34 degrees C a medium containing 1.2 mM CaCl2 (standard conditions), doxorubicin (100 microM) caused a significant decrease in diastolic length, and an increase in the amplitude of contraction. The positive inotropic effect of doxorubicin was followed by a negative effect. Concomitant with these changes in myocyte contractions, a monophasic increase in diastolic Ca2+ and an increase and a subsequent decrease in the amplitude of Ca2+ transients (peak [Ca2+]i minus diastolic [Ca2+]i) were observed. When the Ca2+ load of myocytes was increased by an incubation at a low temperature (25 degrees C) or in the presence of high Ca2+ in the incubation medium (2.4 mM CaCl2), diastolic [Ca2+]i was elevated. Doxorubicin further increased diastolic [Ca2+]i. Under these conditions, the doxorubicin-induced increase in the twitch contraction lasted a shorter period of time and the subsequent decrease in contraction was significantly enhanced. The peak [Ca2+]i initially increased slightly and then decreased. Thus, the decrease in the amplitude of Ca2+ transients, as well as myocyte contraction was greater compared to the corresponding values observed under the standard conditions. These changes in the contraction and Ca2+ transient developed with the same time course. The effects of the low temperature incubation were antagonized by verapamil. These results indicate that the negative inotropic effect of doxorubicin results from a decrease in the amplitude of Ca2+ transients caused by an increased diastolic [Ca2+]i and a decreased peak [Ca2+]i. These changes are likely to be caused by myocardial Ca2+ overload.

Animals↗
PubMed1994

Cellular Ca2+ loading and inotropic effects of doxorubicin in atrial muscle preparations isolated from rat or guinea-pig hearts.

The inotropic effects of doxorubicin were examined under conditions that alter the Ca2+ loading of myocardial cells. Atrial muscle preparations isolated from rat or guinea-pig hearts were used. Cellular Ca2+ loading was altered by changing the temperature, extracellular Ca2+ concentrations or the frequency of electrical stimulation. In guinea-pig heart muscle preparations stimulated at 2 Hz at 30 degrees C in the presence of 1.2 mM CaCl2, 30 microM doxorubicin caused biphasic (early and late phase) positive inotropic effects. A higher concentration (200 microM) of doxorubicin caused a transient positive inotropic effect followed by a gradual decrease in developed tension. An increase in CaCl2 concentration from 1.2 to 2.4 mM decreased the positive inotropic effect of 30 microM doxorubicin and changed the inotropic effect of 200 microM doxorubicin from positive to negative after a transient increase in developed tension. At 0.5-Hz stimulation or 36 degrees C incubation, 30 or 200 microM doxorubicin produced remarkable late phase positive inotropic effects. In rat heart muscle preparations, the patterns of the inotropic effects of doxorubicin were similar to those observed with guinea-pig hearts; however, the negative inotropic effect observed at 200 microM doxorubicin was greater. These results indicate that the early and the late phase positive inotropic effects of doxorubicin have different mechanisms. The pattern of inotropic effects of doxorubicin is affected by conditions that alter cellular Ca2+ loading or the concentration of doxorubicin.

Animals↗
PubMed1994

Dual effects of nicardipine: evidence from intracellular Ca2+ transients and twitch contractions observed in single myocytes obtained from rat heart.

Mechanisms responsible for dual actions of nicardipine were examined using myocytes isolated from ventricular muscle of rat heart. About 60% of isolated rat myocytes showed positive force-frequency relationships. These cells had lower intracellular Ca2+ concentrations at rest. In the remaining cells that had higher resting Ca(2+)-concentrations, an increase in frequency of stimulation from 1 Hz to 2 Hz produced either no change or reduction in the amplitude of Ca2+ transients and twitch contractions. In 13 of 34 myocytes that showed positive force-frequency relationships, nicardipine enhanced the Ca2+ transient and produced sustained positive inotropic effects. In 11 of 20 cells that showed negative force-frequency relationships, nicardipine produced negative inotropic effects. Inhibition was partly reversed by an increase in extracellular CaCl2 concentration from 1.2 to 3.6 mM. In the remaining cells, nicardipine failed to either increase or decrease the amplitude of Ca2+ transient or twitch contraction. Bay K-8644 produced positive inotropic effects in most cells. These results indicate that nicardipine either enhances or inhibits Ca2+ transients and twitch contractions depending on the Ca2+ loading state of myocytes. The present results are consistent with the hypothesis that nicardipine stabilizes the state of Ca2+ channels, either in the inactivated state in cells that are well loaded with Ca2+, or in the activated state when the degree of Ca2+ loading is relatively low.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Doxorubicin-induced changes in intracellular Ca2+ transients observed in cardiac myocytes isolated from guinea-pig heart.

Effects of doxorubicin on intracellular Ca2+ concentrations ([Ca2+]i) were examined using myocytes isolated from guinea-pig heart and loaded with fura 2. Changes in twitch contractions were assessed from the motion of myocytes. Ca2+ transients and contractions were triggered by electrical-field stimulation. Exposure of myocytes to doxorubicin depressed Ca2+ transients and contractions. The time to peak Ca2+ transient was prolonged, and Ca2+ sequestration was delayed. In myocytes treated with doxorubicin, an increase in external CaCl2 concentration from 1.2 to 3.6 mM increased the resting and peak [Ca2+]i and enhanced twitch contraction. In the presence of 3.6 mM CaCl2, isoproterenol failed to enhance Ca2+ transients or contractions of doxorubicin-treated myocytes. Effects of doxorubicin were compared with those of agents known to alter Ca2+ handling by myocytes. Caffeine enhanced the peak and resting [Ca2+]2 and contraction. Verapamil caused a rapid decrease in Ca2+ transients and twitch contractions. The effects of verapamil were reversed by isoproterenol in the presence of 3.6 mM CaCl2. Ryanodine alone and combined with doxorubicin depressed contractions and Ca2+ transients and elevated resting [Ca2+]i. Resting [Ca2+]i was further elevated by an increase in CaCl2 concentration and the addition of isoproterenol. The combination of verapamil and ryanodine inhibited Ca2+ transients and contractions. In the presence of verapamil and ryanodine, an increase in extracellular CaCl2 concentration increased resting and peak [Ca2+]i. Isoproterenol further elevated resting and peak [Ca2+]i and increased twitch contractions. These results indicate that doxorubicin alters cellular Ca2+ handling. The actions of doxorubicin are not mimicked by caffeine, verapamil, ryanodine, or the combination of verapamil and ryanodine. Among these agents, ryanodine produced effects that were closest to those observed with doxorubicin.

Animals↗
PubMed1993

Comparison of cardiac actions of doxorubicin, pirarubicin and aclarubicin in isolated guinea-pig heart.

The cardiac actions of doxorubicin were compared with those of pirarubicin and aclarubicin to understand the mechanisms responsible for differences in cardiotoxic effects of anthracycline agents. In left atrial muscle preparations obtained from guinea-pig heart and stimulated at 2 Hz, anthracyclines produced positive inotropic effects. The magnitude of the effect was pirarubicin > doxorubicin > aclarubicin. The order for depression of potentiated postrest contraction and prolongation of the time to peak twitch tension was doxorubicin > pirarubicin > aclarubicin. Drug washout following a 2-h incubation with 100 microM doxorubicin prevented a further increase in the time to peak twitch tension, caused a marked recovery of depressed potentiated postrest contractions, and augmented the positive inotropic effect. Pirarubicin and doxorubicin, but not aclarubicin, caused a parallel rightward shift of the dose-response curve for the negative inotropic effect of acetylcholine. The potency of inhibition of [3H]quinuclidinyl benzilate binding was pirarubicin > doxorubicin > aclarubicin. These results indicate that three anthracycline anticancer agents share similar effects on cardiac muscle contractility and on muscarinic acetylcholine receptors. The actions of aclarubicin were weak compared to those of doxorubicin or pirarubicin. Increases in the time to peak twitch tension and the depression of potentiated postrest contraction are apparently mediated by mechanisms different from those responsible for the positive inotropic effects or antagonism at muscarinic acetylcholine receptors.

Aclarubicin↗
PubMed1992

Doxorubicin: an antagonist of muscarinic receptors in guinea pig heart.

While studying the mechanisms of doxorubicin-induced cardiotoxicity, we observed that doxorubicin inhibited the negative inotropic effect of acetylcholine in isolated heart muscle preparations. We therefore examined the effects of doxorubicin on muscarinic acetylcholine receptors. In left atrial muscle preparations isolated from guinea pig heart and stimulated at 2 Hz at 30 degrees C, doxorubicin caused a parallel right-ward shift of the dose-response curves for the negative inotropic effects of acetylcholine. The inhibitory action was reversed by an additional incubation in the absence of doxorubicin. Doxorubicin reversed the carbachol-induced inhibition of developed tension: a high concentration of doxorubicin brought the force back to its original strength. Doxorubicin inhibited specific [3H]quinuclidinyl benzilate (QNB) binding to membrane preparations obtained from ventricular muscle of guinea pig hearts. The pA2 value for doxorubicin obtained in the inotropic study corresponded to the IC50 value for doxorubicin observed in the [3H]QNB binding assay. These results indicate that doxorubicin acts as a weak competitive antagonist on muscarinic acetylcholine receptors.

Animals↗
PubMed1991

Na+,K(+)-ATPase inhibition by an endogenous peptide, SPAI-1, isolated from porcine duodenum.

SPAI-1, a peptide isolated from porcine duodenum, has been shown to inhibit Na+,K(+)-ATPase in vitro (Araki et al. (1989) Biochem. Biophys. Res. Commun. 164, 496-502). The characteristics of ATPase inhibition by this novel peptide were examined. SPAI-1 inhibited Na+,K(+)-ATPase preparations isolated from various organs of dog or rat or from sheep kidney with similar potency. Three isoforms of rat Na+,K(+)-ATPase had similar sensitivity to inhibition by SPAI-1 although these isoforms had remarkable differences in their sensitivity to the inhibitory effect of ouabain. Ca(2+)-ATPase isolated from the sarcoplasmic reticulum of rabbit skeletal muscle was insensitive to inhibition by SPAI-1. Ouabain-insensitive Mg(2+)-ATPase activity was unaffected by low concentrations of SPAI-1, but was stimulated at high concentrations. SPAI-1 inhibited H+,K(+)-ATPase from hog stomach in concentrations similar to that required for Na+,K(+)-ATPase inhibition. These results indicate that SPAI-1 is a specific inhibitor for monovalent cation transporting ATPases.

Adenosine Triphosphatases↗
PubMed1991

Aging: stimulation rate on cardiac intracellular Na+ activity and developed tension.

Previous reports suggested that Na,K-ATPase activity and Na(+)-pump capacity decrease with senescence in left atrial myocardium of F344 rats. Current experiments were designed to determine if this reduction in the Na(+)-pump affects free intracellular Na+ levels. Mean intracellular Na+ ion activity (aiNa) was measured with Na-selective microelectrodes in left atrial muscle isolated from hearts of 4-, 14- and 25-month-old F344 rats. Preparations were stimulated randomly at frequencies between 0 and 12 h. There were no age-associated differences in aiNa measured at any frequency or in the decay of Na+ activity following discontinuation of electrical stimulation. These data indicate that the aging-related decline in Na,K-ATPase does not result in elevated aiNa even at extremely high stimulation frequencies, thus suggesting that other routes of Na+ influx and efflux are also altered in atrial muscle.

Aging↗
PubMed1991

Purification and characterization of the recombinant human aldose reductase expressed in baculovirus system.

Large quantities of recombinant human aldose reductase were produced using Spodoptera frugiperda cells and properties of the enzyme were characterized. Direct purification of the recombinant aldose reductase by affinity column chromatography using Matrex gel orange A yielded a single 36 kDa band, similar in size to the purified human muscle aldose reductase, on a sodium dodecyl sulfate-polyacrylamide gel after silver staining. The isoelectric point of the recombinant enzyme was 5.85 which is identical to the human muscle aldose reductase. Following the treatment with an acylamino-acid releasing enzyme, the blocked NH2-terminal amino acid was identified to be acetylalanine. The successive NH2-terminal sequence and that of the COOH-terminal peptide concurred with the expected translated sequence. Kinetic analyses of the recombinant enzyme activity for various substrates and the cofactor, NADPH, demonstrated a good agreement with the previously reported kinetic data on the purified human aldose reductase. A high concentration of (NH4)2SO4 elicited a significant increase in both Km and Kcat for DL-glyceraldehyde as well as D-glucose. Although IC50 values for most of the aldose reductase inhibitors with recombinant enzyme were found to fall within the comparable range of those obtained with nonhuman mammalian enzymes, the IC50 value for epalrestat was more than 10-fold higher in the recombinant enzyme. These results indicate that the recombinant human aldose reductase expressed in the baculovirus system possesses structurally and enzymatically similar properties as those reported for the native human enzyme and should serve as a superior enzyme preparation to nonhuman mammalian enzymes for the screening of the efficacy and potency of newly developed aldose reductase inhibitors.

Aldehyde Reductase↗
PubMed1991

Digitalis sensitivity of Na+,K(+)-ATPase, myocytes and the heart.

Cardiac Na+,K(+)-ATPase, the receptor molecule for digitalis glycosides, have isoforms with different intrinsic affinities for the glycosides. Expression of these isoforms are under developmental and hormonal regulation. Switching in isoforms to those with lower intrinsic affinity may decrease digitalis sensitivity of the heart. In addition to the intrinsic affinity of the cardiac Na+,K(+)-ATPase for the glycoside, increases in the rate of Na+ influx and decreases in extracellular K+ concentrations increase glycoside sensitivity of the heart and also reduces the margin of safety by reducing reserve capacity of the sodium pump. Reserve capacity of the sodium pump is also reduced by pathological conditions or aging, resulting in reduced margin of safety for the glycoside. Events that follow sodium pump inhibition also affect sensitivity of the heart to digitalis toxicity. These are hypercalcemia and magnesium depletion. It is now feasible to predict digitalis sensitivity of the heart, not empirically but based on the understanding of the mechanisms responsible for the positive inotropic and toxic actions of the glycoside.

Child↗
PubMed1991

Developmental changes in inotropic actions of neurotoxins observed in ventricular muscle of rat heart.

Developmental changes in functions of myocardial sodium channels were examined from inotropic effects of several neurotoxins in ventricular muscle preparations obtained from prenatal (20-22 day gestation) or adult (3-4 months old) rat hearts. Tetrodotoxin caused a negative inotropic effect in low concentrations and a loss of muscle responsiveness to electrical stimulation in high concentrations in preparations obtained from either prenatal or adult rat heart. The tetrodotoxin concentration that caused a 50% decrease in developed tension was higher in prenatal rats. Anemonia sulcata toxin, Androctonus australis toxin, veratridine, and Centruroides sculpturatus toxin all produced positive inotropic effects in adult rat heart. The effects were largest with A. sulcata and A. australis toxins, intermediate with veratridine, and smallest with C. sculpturatus toxin. Prenatal heart required higher concentrations of either veratridine, or A. sulcata or A. australis toxins to produce comparable positive inotropic effects. With C. sculpturatus toxin, no significant positive inotropic effect was observed in prenatal heart muscle preparations. These results indicate that cardiac sodium channels undergo significant functional changes during development and that negative and positive inotropic effects of neurotoxins resulting from inhibition and enhancement of fast Na+ channels reflect developmental changes in the cardiac sodium channels.

Animals↗
PubMed1991

Reperfusion-induced contracture develops with a decreasing [Ca2+]i in single heart cells.

The causal relationship between intracellular Ca2+ overloading and reperfusion-induced contracture was examined from changes in intracellular Ca2+ concentration ([Ca2+]i) at rest, changes in the magnitude and time course of intracellular Ca2+ transients, and the development of contracture. Single myocytes isolated from guinea pig hearts were subjected to the conditions mimicking ischemia and reperfusion. Ischemic condition was produced by superfusing myocytes with hypoxic substrate-free solutions containing elevated concentrations of K+, H+, and lactate as described by Ferrier et al. (Circ. Res. 56: 184-194, 1985). Changes in [Ca2+]i were estimated using fura-2 as the Ca2+ indicator. Under these conditions, twitch contractions were suppressed during simulated ischemia associated with an early and gradual rise of [Ca2+]i. The development of contracture, however, was not observed. Upon "reperfusion" of myocytes that had been subjected to 20 min of the above "ischemic" condition, the elevated [Ca2+]i declined rapidly. With the recovery of twitch contractions, contracture developed despite a substantial decrease in [Ca2+]i. These results indicate that reperfusion-induced contracture is not associated with a concomitant increase in [Ca2+]i in isolated myocytes.

Animals↗
PubMed1991

Use of drugs during pregnancy in Japanese women.

The use of drugs during pregnancy was studied in 890 women, who were delivered of their babies in 11 obstetric departments of general hospitals in Japan, during the one month period of November 1989. Of these women, 889 (99.9%) took one or more drugs during the whole period of pregnancy and the number of drugs taken averaged 9.6. During pregnancy 172 women (19.3%) did not take drugs, and the remaining 718 (80.7%) took a total of 1766 medications. The most commonly used drugs were anti-anemic, anti-abortion medications, digestives, and antimicrobials. Bronchodilators, psychotropic agents, anticonvulsants, and steroids were each prescribed during pregnancy for about 1% of the women. Malformations were found at birth in 12 infants (1.3%). No significant relations were found between these anomalies and ingestion of particular drugs. During pregnancy, 9.3% of the women continued to smoke, and 1.9% continued to consume moderate amounts or more of alcohol. (Tab. 8, Ref. 7.)

Abnormalities, Drug-Induced↗