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Biomedical subjects

T Akera

Publications and source records attributed to T Akera.

At least 55 records · Page 3Linked to original sources
PubMed1987

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on guinea pig heart muscle.

Cardiac effects of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) were examined using atrial muscle isolated from young or mature guinea pigs fed ad libitum, from young animals 10 or 20 days after a single ip injection of 1 microgram TCDD/kg body wt, and from control guinea pigs pair-fed to the TCDD-treated animals. Basal contraction force of left atrial muscle obtained from TCDD-treated and pair-fed control guinea pigs 10 days after treatment was significantly increased compared to atrial muscle obtained from ad libitum control animals. Atrial muscle from TCDD-treated animals 20 days after treatment had a significantly lower basal force of contraction while that from pair-fed animals was significantly higher relative to atrial muscle from ad libitum control animals. These results suggest that the TCDD-induced change in basal atrial contraction force is in part due to undernutrition and that prolonged exposure to TCDD inhibits this response observed in pair-fed animals. Furthermore, prolonged TCDD treatment shifted the dose-response curve for the positive inotropic effect of isoproterenol to the right with no statistically significant change in the maximal inotropic effect obtained with high concentrations of isoproterenol. The TCDD-induced changes in force of contraction and the dose-response curve for the positive inotropic effect of isoproterenol were similar in young TCDD-treated and mature control guinea pigs. TCDD did not alter the basal contraction frequency or the dose-response curve for the positive chronotropic effect of isoproterenol. There was no effect on cardiac lipoprotein lipase activity at 1 microgram/kg, but in animals administered 4 micrograms TCDD/kg activity was reduced. It was concluded that TCDD adversely affects atrial muscle of guinea pig heart.

Animals↗
PubMed1987

The effect of stimulation frequency and calcium concentration on maintenance of developed tension in isolated heart muscle preparations.

The ability of isolated cardiac muscle preparations to maintain force of contraction was assessed at different extracellular Ca2+ concentrations and at various stimulation frequencies. Preparations were incubated in Krebs-Henseleit buffer at 32 degrees C and electrically stimulated at frequencies between 0.25 and 3.0 Hz. Extra-cellular Ca2+ was maintained at given concentrations between 0.8 and 2.4 mM, a range that included the plasma-ionized Ca2+ levels determined for rat and guinea pig. Developed tension of atrial or papillary muscle preparations of guinea pig heart was more stable at higher stimulation frequencies. Rat atria and ventricular strips were more stable at 0.25 than at 0.5 or 1.0 Hz, and the stability increased at 2.0 and 3.0 Hz. Guinea pig atrial muscle was maintained for a longer time at higher media Ca2+ concentrations; however, no such effect was observed with rat atrial tissue. Thus, the decrementing at developed tension in isolated cardiac muscle preparations is dependent on stimulation frequency and Ca2+ concentrations and can be retarded by selection of appropriate incubation conditions.

Animals↗
PubMed1987

O2 free radicals: cause of ischemia-reperfusion injury to cardiac Na+-K+-ATPase.

The role of O2 free radicals in the reduction of sarcolemmal Na+-K+-ATPase, which occurs during reperfusion of ischemic heart, was examined in isolated guinea pig heart using exogenous scavengers of O2 radicals and an inhibitor of xanthine oxidase. Ischemia and reperfusion reduced Na+-K+-ATPase activity and specific [3H]ouabain binding to the enzyme in ventricular muscle homogenates and also markedly lowered sodium pump activity estimated from ouabain-sensitive 86Rb+ uptake by ventricular muscle slices. These effects of ischemia and reperfusion were prevented to various degrees by O2-radical scavengers, such as superoxide dismutase, catalase, dimethyl-sulfoxide, histidine, or vitamin E or by the xanthine oxidase inhibitor, allopurinol. The degree of protection afforded by these agents paralleled that of reduction in enhanced lipid peroxidation of myocardial tissue as estimated from malondialdehyde production. These results strongly suggest that O2 radicals play a crucial role in the injury to sarcolemmal Na+-K+-ATPase during reperfusion of ischemic heart.

Animals↗
PubMed1987

Paradoxical positive inotropic effect of K+ in the rat heart.

In cardiac muscle isolated from most mammalian species, an elevation of extracellular K+ concentration decreases developed tension. This is explained from stimulation of the Na pump. In rat myocardium, however, developed tension increased when K+ concentration was raised from 3.5 to 9.5 mM, seemingly inconsistent with the above explanation. Activation of isolated Na+,K+-adenosinetriphosphatase by K+ was not different in rat and guinea pig heart. The K+-induced increase in developed tension observed in left atrial muscle preparations obtained from rat heart was not blocked by phentolamine and propranolol or by reserpine pretreatment but attenuated by stimulation at higher frequency, incubation at a lower temperature, or by veratridine, all of which have been shown to increase Na+ loading of myocardial cells. K+ slightly prolonged action potential duration and partially depolarized resting membrane potential; however, K+-induced changes in electrophysiological parameters or possible inactivation of early outward current observed in myocytes isolated from rat heart are unlikely to be the primary cause of the positive inotropic effect. Caffeine or Cd2+ eliminated the inotropic effect of K+ but ryanodine was ineffective. An increase in extracellular K+ from 1 to 3.5 mM decreased developed tension. These results indicate that K+ has dual effects on developed tension in rat myocardium: a negative inotropic effect resulting from Na pump stimulation and a positive inotropic effect. The latter effect is due to a process that is either unique or more strongly expressed in the rat myocardium and masks the former effect in the range of physiological K+ concentrations.

Action Potentials↗
PubMed1987

Two classes of ouabain binding sites in ferret heart and two forms of Na+-K+-ATPase.

In partially purified Na+-K+-adenosinetriphosphatase (ATPase) obtained from ferret heart, ouabain produced a monophasic inhibition curve; however, the curve spanned over 5 logarithmic units, indicating the presence of more than one classes of enzyme. [3H]ouabain binding studies revealed high-and low-affinity binding sites in approximately equal abundance, with apparent dissociation constants of 10 and 230 nM, respectively. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of phosphoenzyme formed from [gamma-32P]ATP showed two distinct K+-sensitive bands of approximately 100,000 molecular weight. Phosphoenzyme formation from the high-molecular-weight alpha(+) form was selectively inhibited by N-ethylmaleimide. Ouabain caused a 50% inhibition of phosphorylation of the alpha(+) form at 40 nM and the lower-molecular-weight alpha form at 300 nM. In papillary muscle preparations, 1-30 nM ouabain produced a modest positive inotropic effect that reached an apparent plateau at 30 nM. Further increases in ouabain concentrations, however, produced additional and prominent inotropic effects at 0.1-10 microM. These results indicate for the first time in cardiac muscle that the high- and low-affinity ouabain binding sites are associated with the alpha(+) and alpha forms of the Na+-K+-ATPase, respectively, and that binding of ouabain to either of these sites causes enzyme inhibition and the positive inotropic effect.

Animals↗
PubMed1987

Ligand effects on membrane lipids associated with sodium, potassium-activated adenosine triphosphatase: comparative spin probe studies with rat brain and heart enzyme preparations.

Physical properties of membrane lipids associated with rat or dog brain and heart Na+, K+-ATPase preparations were compared using an electron spin resonance probe, 5-doxyl stearate. The degree of acyl chain order of the membrane lipids was greater for brain enzyme than for heart enzyme preparations; membrane lipids in the rat heart enzyme preparations were the most disordered. In the absence of added ligands, membrane lipids did not appear to undergo a detectable temperature-dependent rearrangement or structural transition. An apparent transition was observed in the simultaneous presence of Na+, Mg2+, and ATP. These ligands increased lipid order at temperatures above the structural transition, but not below it. In the presence of the above ligands, K+ caused a marked decrease in the transition temperature in the rat brain enzyme preparations, but only a modest decrease in rat heart enzyme preparations. Arrhenius plots of rat brain and heart Na+, K+-ATPase activity revealed a break point roughly corresponding to respective membrane lipid transition temperatures observed in the presence of Na+, K+, Mg2+, and ATP. A low concentration of ouabain (1 microM) failed to affect either the lipid transition temperature estimated by the spin probe or the value of lipid order of the rat brain enzyme preparations observed in the presence of Na+, Mg2+, and ATP, but markedly reduced the effect of K+ to lower the transition temperature observed in the presence of the above ligands. A high concentration (100 microM) of ouabain which was needed to completely inhibit rat heart enzyme eliminated the thermally induced structural rearrangement observed in the presence of Na+, Mg2+, and ATP, apparently through a nonspecific lipid perturbation. These results indicate that differences in the physical properties of the membrane lipids per se are unlikely to account for the low affinity of rat heart Na+, K+-ATPase for ouabain and also suggest that the use of high concentrations of ouabain required to completely inhibit Na+, K+-ATPase activity may cause nonspecific changes in addition to inhibition of Na+, K+-ATPase or the sodium pump.

Animals↗
PubMed1987

Relative abundance of two molecular forms of Na+,K+-ATPase in the ferret heart: developmental changes and associated alterations of digitalis sensitivity.

We have previously reported that adult ferret hearts have high affinity and low affinity ouabain-binding sites in approximately equal abundance corresponding, respectively, to alpha(+) and alpha subunits of Na+,K+-ATPase. In the present study, possible changes in relative abundance of the two molecular forms of Na+,K+-ATPase during postnatal development were examined. In 5-day-old or 7- to 10-day-old ferret heart, there was a predominance of the alpha form of Na+,K+-ATPase, the alpha(+)/alpha ratio being approximately 1:7 and 1:4 at 5 and 7-10 days, respectively, in contrast to a 1:1 ratio observed previously in adult heart. Corresponding to the reduced number of high affinity ouabain-binding sites associated with the alpha(+) form of Na+,K+-ATPase, ouabain sensitivity of the Na+,K+-ATPase isolated from newborn ferret heart was lower than that of adult ferret heart. Furthermore, the low dose positive inotropic effect, which was apparent in the adult ferret heart, could not be observed in the newborn ferret heart. The present finding may represent a plausible explanation for low digitalis sensitivity of neonatal heart observed in several mammalian species.

Age Factors↗
PubMed1986

High affinity and low affinity ouabain binding sites in the rat heart.

Ventricular muscle of rat heart has two classes of receptors which are responsible for the positive inotropic effect of ouabain. Low affinity receptors are apparently related to Na+, K+-ATPase. To determine if high affinity receptors are also sarcolemmal Na+, K+-ATPase of muscle cells, their characteristics were examined. Binding of [3H]ouabain to the high affinity binding site required ATP in the presence of Mg2+ and Na+, was stimulated by Na+ in the presence of Mg2+ and ATP, and was inhibited by K+. Digoxin, digitoxin and cassaine all inhibited [3H]ouabain binding to the high affinity site. Cassaine was about an order of magnitude less potent than the glycosides. These results indicate similarities in high affinity ouabain binding sites in ventricular muscle of rat heart and Na+, K+-ATPase obtained from other sources. Destruction of sympathetic nerve terminals with 6-hydroxydopamine failed to affect the high affinity ouabain binding sites indicating that high affinity sites do not represent the Na+, K+-ATPase in sympathetic nerve terminals. Labeling of Na+, K+-ATPase from [gamma-32P]ATP indicates that high affinity ouabain binding sites account for 25% of the total enzyme molecules present in ventricular muscle of rat heart.

Animals↗
PubMed1986

13-Propylberberine reduces response of guinea-pig myocardium to inotropic interventions including changes in extracellular Ca2+.

Berberine has been shown to increase developed tension in cardiac muscle but its derivatives have been reported to inhibit the catalytic subunit of adenylate cyclase. In the present study, the cardiac actions of the most potent derivative, 13-propylberberine, were examined. It produced a transient increase followed by a sustained decrease in developed tension in paced left atrial muscle preparations isolated from guinea-pig heart. In the presence of 13-propylberberine, isoproterenol caused only a transient increase in developed tension; marked desensitization to the positive inotropic effect of isoproterenol occurred within 20 min. After washout of isoproterenol and an additional 15-min incubation in the presence of 13-propylberberine, the muscle lost its sensitivity to isoproterenol. Moreover, the positive inotropic effect of ouabain or effects of decrease or increase in extracellular Ca2+ concentration on the force of muscle contraction were markedly attenuated. Isoproterenol-induced elevation of tissue cyclic AMP concentration was inhibited by 13-propylberberine; however, 13-propylberberine did not alter the basal cyclic AMP concentration and its effects on inotropic actions of ouabain or extracellular Ca2+ appear unrelated to tissue cyclic AMP concentration.

Animals↗
PubMed1986

Effects of BAY K-8644 on inotropic and arrhythmogenic actions of digoxin.

Myocardial intracellular 'Ca2+ overload' may be involved in the direct arrhythmogenic actions of cardiotonic steroids. This proposal was examined by determining if the sensitivity of guinea-pig atrial muscle to digoxin-induced arrhythmias was affected by BAY K-8644, a 1,4-dihydropyridine derivative which promotes Ca2+ influx via slow channels. BAY K-8644 significantly reduced both the time required for a given concentration of digoxin to produce arrhythmias and the amount of digoxin bound to atrial muscle at the onset of arrhythmias. In addition, BAY K-8644 increased the maximum developed tension observed in the presence of digoxin before the onset of arrhythmias. Similar results were obtained with increasing concentrations of buffer Ca2+. In contrast, A23187, a Ca2+ ionophore, enhanced the sensitivity to digoxin-induced arrhythmias without affecting maximum developed tension. These results suggest that increases in intracellular Ca2+ enhance cardiac sensitivity to digoxin-induced arrhythmias and that the arrhythmogenic action may involve Ca2+ overload at a pool other than that which activates contractile proteins.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Amiloride: effects on myocardial force of contraction, sodium pump and Na+/Ca2+ exchange.

The direct effects of amiloride on myocardial contractility were examined in electrically stimulated left atrial muscle of guinea-pig heart. Amiloride (0.3 to 1.5 mM) produced a positive inotropic effect which, at higher concentrations, was followed by a decline in developed tension. These effects were not accompanied by contracture or arrhythmia and were not affected by a combination of phentolamine, nadolol, cimetidine, tripelennamine and atropine. The above concentrations of amiloride prolonged the action potential duration during the development of the positive inotropic effect; however, no further change in the action potential duration was observed during the decline in developed tension caused by high concentrations of amiloride. Myocardial membrane Na,K-ATPase, ouabain-sensitive 86Rb+ uptake and Na+-dependent Ca2+ efflux from sarcolemmal membrane vesicles were all inhibited by amiloride. The positive inotropic effect of the agent is reduced and the negative inotropic action is enhanced in low Na+ solutions, i.e., under conditions likely to favor Ca2+ influx via Na+/Ca2+ exchange. These results suggest that amiloride, under the present conditions, has a complex interaction with cardiac muscle fibers. Amiloride may produce its inotropic effects in guinea-pig atrial muscle by several mechanisms including sodium pump inhibition, Na+/Ca2+ exchange inhibition, prolongation of the action potential duration, and/or actions such as Na+/H+ exchange inhibition which were not directly addressed in this study.

Action Potentials↗
PubMed1986

Effects of inotropic agents on isolated guinea pig heart under conditions that modify calcium pools involved in contractile activation.

Positive inotropic effects of strophanthidin were compared with those of isoproterenol, BAY K 8644, grayanotoxin, veratridine, and monensin in electrically stimulated left atrial muscle preparations of guinea pig heart under conditions in which the calcium pool, playing a primary role in contractile activation, was altered. In concentrations that caused similar degrees of increase in developed tension under 1 Hz stimulation, grayanotoxin and strophanthidin caused a relatively large increase in potentiated postrest contraction compared with that caused by isoproterenol, whereas the effect of BAY K 8644 on the postrest contraction was the smallest. The effect of high concentrations of grayanotoxin or strophanthidin, however, resembled that of isoproterenol. The sensitivity of the isolated heart muscle to these agents was compared under conditions in which utilization of various calcium pools contributing to contractile activation was suppressed. Mn2+, which reduces contribution of very superficial Ca2+, reduced sensitivity of heart muscle to the positive inotropic effect of isoproterenol and enhanced the inotropic effect of monensin or veratridine. Verapamil, nifedipine, diltiazem, or ryanodine did not have marked effects on the positive inotropic action of Ca2+, monensin, veratridine, or strophanthidin. These results suggest that the positive inotropic actions of veratridine, grayanotoxin, and strophanthidin share a common mechanism and that low concentrations of strophanthidin may increase loading of Ca2+ pool, which plays an important role in potentiated postrest contraction.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Concealed positive force-frequency relationships in rat and mouse cardiac muscle revealed by ryanodine.

Increases in stimulation frequency between 0.3 and 2 Hz decrease developed tension in rat, seemingly inconsistent with the explanation that an elevation of intracellular Na+-ion concentration is responsible for the positive force-frequency relationships observed in most species. Thus the force-frequency relationships were reevaluated in isolated atrial muscle of rat and mouse heart that show negative relationships, comparing them with ferret and guinea pig that show positive relationships. Ryanodine (2 nM, 45-min exposure) markedly reduced potentiated postrest contractions in all four species and caused a marked negative inotropic effect especially at low stimulation frequencies in rat and mouse, a moderate effect in ferret, but only a modest effect in guinea pig. In the presence of ryanodine, all four species showed positive force-frequency relationships. These results indicate that activator calcium in rat, mouse, and ferret cardiac muscle has a large ryanodine-sensitive component that shows a negative force-frequency relationship, masking a component for positive force-frequency relationships that exists in all species.

Alkaloids↗
PubMed1986

Lack of pharmacodynamic interactions between quinidine and digoxin in isolated atrial muscle of guinea pig heart.

Quinidine has been reported to have no effect on the positive inotropic action of digoxin observed in isolated cardiac muscle preparations. This is surprising because quinidine has been shown to reduce Na+ influx in cardiac muscle. The conditions which increase Na+ influx stimulate the glycoside binding to Na+- and K+-activated Mg++-dependent ATP phosphohydrolase (Na+,K+-ATPase), and therefore quinidine may be expected to have an opposite effect. Thus, the effects of quinidine on cardiac muscle and its possible interactions with digoxin were re-evaluated using electrically paced left atrial muscle preparations of guinea pig heart. Quinidine caused a frequency- and concentration-dependent decrease in maximal upstroke velocity and amplitude of the action potential without altering resting membrane potential. In addition, quinidine prolonged action potential duration markedly in a frequency-dependent manner. Despite action potential prolongation, the alkaloid reduced net Na+ influx as determined by a decrease in steady-state ouabain-sensitive 86Rb+ uptake. Under these conditions, however, quinidine failed to reduce the rate of onset or the maximal positive inotropic effect of digoxin; or did it reduce digoxin binding to Na+,K+- ATPase in beating atrial muscle preparations. Benzocaine, which reduced net Na+ influx without increasing the action potential duration, also failed to affect the peak inotropic effect of digoxin or the glycoside binding. Quinidine had no direct effects on glycoside binding to isolated cardiac Na+,K+-ATPase. Moreover, [3H]ouabain binding to isolated enzyme was relatively insensitive to changes in Na+ concentrations between 1 and 8 mM although binding was stimulated clearly by Na+ above 8 mM. These results indicate that quinidine, at therapeutic concentrations, does not interact pharmacodynamically with digoxin in isolated cardiac muscle.

Action Potentials↗
PubMed1985

Suppression of positive inotropic and toxic effects of cardiac glycosides by amiloride.

Effects of amiloride on the inotropic and toxic actions of cardiac glycosides were examined using left atrial muscle isolated from guinea pig heart. Preincubation of atrial muscle with amiloride significantly decreased the maximum positive inotropic effect of dihydrodigoxin but failed to reduce that of isoproterenol. Amiloride prevented the contracture and significantly reduced the incidence of arrhythmias induced by 2 microM digoxin. Similar experiments examining 5 microM digoxin-induced arrhythmias showed that amiloride increased both the time required to produce arrhythmias and the fractional occupancy of sarcolemmal Na,K-ATPase by digoxin at the onset of arrhythmias. The antagonism of cardiac glycoside actions was best observed during the decline in developed tension elicited by amiloride subsequent to its initial positive inotropic effect. Amiloride had no effect on binding site concentration for ATP-dependent [3H]ouabain binding but decreased affinity of the binding sites for ouabain in membrane preparations obtained from guinea pig heart. Furthermore, amiloride inhibited Na,K-ATPase activity and increased the IC50 value for ouabain inhibition of the enzyme. These results indicate that amiloride antagonizes the positive inotropic and toxic effects of cardiac glycosides. Possible mechanisms for the antagonism include inhibition of sarcolemmal Na+/Ca2+ or Na+/H+ exchange.

Amiloride↗
PubMed1985

In ability of Na+,K+-ATPase inhibitor to cause hypertension in sodium-loaded or deoxycorticosterone-treated one kidney rats.

The role of an endogenous inhibitor of Na+,K+-ATPase in hypertension observed in one-kidney NaCl-loaded rats treated with deoxycorticosterone (DOC) was examined. Ouabain or digitoxin, an exogenous inhibitor of Na+,K+-ATPase, failed to cause hypertension in one-kidney NaCl-loaded rats without DOC treatment or one-kidney DOC-treated rats without NaCl loading. Moreover, neither ouabain nor digitoxin acted additively with a putative endogenous inhibitor of Na+,K+-ATPase to augment hypertension observed in one-kidney NaCl-loaded rats treated with DOC. The results do not support the hypothesis that an endogenous inhibitor of Na+,K+-ATPase plays an important role in the development or maintenance of hypertension in this animal model.

Animals↗
PubMed1985

Aging and digitalis sensitivity of cardiac muscle in rats.

The cause of the reduced tolerance of aged rats to the arrhythmogenic effect of ouabain was studied in left atrial and left ventricular muscle preparations obtained from 3-, 8- or 26-month old Fischer 344 rats. Under 1.5-Hz stimulation, the concentration-response curves for the positive inotropic effect of ouabain showed a tendency to shift to the left with age. The toxic effects occurred at lower ouabain or digoxin concentrations in the ventricular muscle obtained from senescent rats especially when the muscle was stimulated at a higher frequency (4 Hz), although differences in tolerance to the toxic effect of ouabain were not apparent in atrial muscle preparations stimulated at 1.5 Hz. No age-related difference in intracellular sodium or potassium concentration was observed in perfused ventricular muscle preparations paced at 1.5 Hz. There was no significant age effect on Na+-induced activation of Na+,K+-ATPase. In aged myocardium, however, the upstroke velocity of the action potential was reduced especially under high frequency stimulations, and the ability to follow high frequency stimulation was compromised. These results suggest that reserve capacity of the sodium pump is reduced in aged ventricular muscle, thereby elevating its sensitivity to the cardiac glycoside.

Aging↗