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T Akera

Publications and source records attributed to T Akera.

At least 91 records · Page 5Linked to original sources
PubMed1982

Enhancement of cardiac actions of ouabain and its binding to Na+, K+-adenosine triphosphatase by increased sodium influx in isolated guinea-pig heart.

The rate of development of the positive inotropic action of ouabain is enhanced when the heart is stimulated at higher frequencies. A hypothesis that this enhancement is due to a stimulation of the glycoside binding to sarcolemmal Na+,K+-adenosine triphosphatase (ATPase) caused by an increase in intracellular Na+ available to the sodium pump was tested in isolated left atrial muscle preparations of guinea-pig heart, incubated at 30 degrees C and electrically stimulated at 0.5, 1 or 2 Hz. The rate of development of the positive inotropic action of ouabain was dependent on the frequency of stimulation. Each preparation was homogenized at a predetermined time and the fractional occupancy of Na+,K+-ATPase by ouabain was estimated from the decrease in the initial velocity of ATP-dependent [3H]ouabain binding reaction. A parallel relationship was observed between effects of stimulation frequency of the positive inotropic action and those on the occupancy of Na+,K+-ATPase by ouabain. In quiescent preparations, a sodium ionophore, monensin, enhanced the development of contracture caused by a toxic concentration of ouabain and also the glycoside binding to Na+,K+-ATPase. Similar effects on the ouabain-induced contracture and on the glycoside binding were observed with either grayanotoxin I or batrachotoxin, agents known to increase sodium influx, when muscle preparations were exposed to these agents under 1.5 Hz stimulation and were subsequently tested for the actions of ouabain in quiescence. When the exposure to ouabain and either grayanotoxin I or batrachotoxin was restricted to quiescent period, the development of ouabain-induced contracture and glycoside binding to Na+,K+-ATPase were not significantly altered. Monensin, grayanotoxin I or batrachotoxin failed to significantly affect [3H]ouabain binding to muscle homogenates when added to the medium for the labeled glycoside binding assay. These results indicate that intracellular sodium ions promote the ouabain binding to Na+,K+-ATPase and thereby enhance the development of glycoside actions in the isolated atrial muscle of guinea-pig heart. The "beat-dependent" onset of the glycoside action is at least partially explained from the effect of membrane depolarization to increase Na+ available to the sodium pump and to enhance the glycoside binding.

Animals↗
PubMed1981

Inotropic effects of digitoxin in isolated guinea-pig heart under conditions which alter contraction.

In order to examine which calcium pool(s) might contribute to the therapeutic action of digitalis, the positive inotropic effect of digitoxin was quantified under conditions in which different calcium pools were either predominant or suppressed. Isolated left atrial muscle of guinea-pig heart was stimulated at 0.5 Hz at 30 degrees C. After a brief rest period, the first contraction (post-rest contraction) observed when electrical stimulation was resumed was markedly greater than the contraction observed under 0.5 Hz stimulation. Post-rest contraction was apparently dependent on the rest period and related to a ryanodine-sensitive, verapamil-insensitive calcium pool. Post-rest contraction was moderately enhanced by 0.2 microM digitoxin, either in the absence or presence of verapamil. A step-wise increase in the frequency of stimulation following the rest period caused a typical staircase phenomenon, which was markedly suppressed by verapamil but not by ryanodine. Digitoxin markedly augmented the staircase in the absence or presence of ryanodine. Paired-pulse stimulation markedly increased the developed tension, which was slightly reduced by verapamil but not by ryanodine. Digitoxin substantially increased the developed tension evoked by paired-pulse stimulation. In left atrial preparations of rat heart, an increase in stimulation frequency decreased the force of contraction; however, paired-pulse stimulation increased the force, indicating that the enhancement of developed tension by an increase in stimulation frequency and that by paired-pulse stimulation have different mechanisms. Thus, the positive inotropic action of digitoxin does not appear to be restricted to a specific calcium pool; however, the inotropic effect was greater under the conditions in which superficial calcium pool plays a predominant role.

Animals↗
PubMed1981

Mechanism of grayanotoxin III-induced afterpotentials in feline cardiac Purkinje fibers.

Grayanotoxins are known to produce cardiac tachyarrhythmias. It is unknown, however, which of three mechanisms, i.e., reentry, induction of automatic activity or induction of triggered activity, accounts for grayanotoxin-induced arrhythmias. To distinguish between these possible mechanisms, effects of grayanotoxin III (GTX III) on the electrical activity of isolated feline cardiac Purkinje fibers were examined under control conditions in which reentry was not likely to occur (perfusion with an oxygenated physiological saline solution at 30 degrees C and pH 7.4) and under several other conditions known to either enhance or block triggered activity. GTX III alone (1 microM) produced either 1-2 low amplitude or repetitive, suprathreshold after potentials within 15 min of administration. At the onset of GTX III-induced afterpotentials, the configuration of electrically driven action potentials was only slightly altered. Increasing stimulation frequency, raising extracellular calcium concentration or lowering extracellular potassium concentration, each of which augment triggered activity, enhanced the production of GTX III-induced afterpotentials. Furthermore, verapamil, raising extracellular potassium concentration or phenytoin, each of which block triggered activity, suppressed afterpotentials elicited by GTX III. These results indicate that the mechanism underlying grayanotoxin-induced arrhythmias is the production of triggered activity in the form of oscillatory afterpotentials.

Animals↗
PubMed1981

Is ouabain-sensitive rubidium or potassium uptake a measure of sodium pump activity in isolated cardiac muscle?

(1) The significance of the specific (ouabain-sensitive) 86Rb+ or 42K+ uptake by cardiac muscle preparations which are not 'sodium-loaded' was studied. (2) In left atrial preparations of guinea-pig heart, resting 86Rb+ uptake was relatively low. It was markedly increased by electrical stimulation. This stimulated uptake was further enhanced by isoproterenol and inhibited by verapamil. (3) In rat atria, the resting 86Rb+ uptake was somewhat higher than in guinea-pig atria, and the increase in uptake caused by electrical stimulation was smaller. In guinea-pig right ventricular papillary muscle, the resting uptake was highest among those tissues studied, and the response to electrical stimulation was smallest. In the latter tissue, verapamil produced only a minimal inhibition of the specific 86Rb+ uptake. (4) The effect of the frequency of electrical stimulation of 86Rb+ uptake paralleled its influence on the force of contraction, suggesting the involvement of intracellular sodium in both events. (5) In both left atrial and right papillary muscle preparations of guinea-pig heart, specific 42K+ uptake observed with 5.8 mM K+ was relatively high, and was increased only slightly by electrical stimulation. This electrical stimulation, however, increased ouabain-induced inhibition of 42K+ uptake, suggesting that the stimulation increases the amount of Na+ available to the sodium pump. (6) When the K+ concentration was 1 mM, the resting 42K+ uptake was low, and could be enhanced by electrical stimulation. (7) Thus, in cardiac muscle preparations which are not sodium loaded, the specific 86Rb+ or 42K+ uptake can be used to estimate the rate of sodium influx, which is equivalent to the rate of sodium efflux under steady-state conditions, provided that neither Rb+ nor K+ is in excess compared to the Na+ available to the pump. If Rb+ or K+ is in excess, its specific uptake may not reflect changes in transmembrane Na+ movement.

Action Potentials↗
PubMed1981

Functional correlates of Na+,K+-ATPase in lean and obese (ob/ob) mice.

Concentrations of Na+,K+-ATPase enzyme units are lower in skeletal muscle and liver of adult obese (ob/ob) mice than in their lean counterparts. The present studies were designed to provide information on functional correlates of Na+,K+-ATPase in ob/ob mice. Obese mice had lower potassium (K+) content in muscle and liver and higher sodium (Na+) content in muscle and liver and higher sodium (Na+) content in muscle than lean counterparts. The calculated intracellular Na+/K+ ratio in muscle of obese mice was approximately twice as high as in muscle of lean mice. Oxygen consumption was measured in mice maintained at 14 degrees, 25 degrees, or 33 degrees for 40 min and injected with 0.3 or 0.9 microgram ouabain per g body weight. Ouabain, a specific inhibitor of Na+,K+-ATPase, decreased oxygen consumption less in obese mice (12%--25%) than in lean mice (19%--38%). These results suggest that Na+ pump activity may be reduced in obese mice.

Animals↗
PubMed1981

Effects of quinidine on the cardiac-glycoside sensitivity of guinea-pig and rat heart.

Quinidine causes a marked increase in plasma digoxin concentration in patients receiving the glycoside. Whether the sensitivity of the heart to digoxin is altered by quinidine was examined with rats and guinea pigs. In electrically stimulated rat atrial preparations, quinidine failed to affect digoxin-induced inhibition of ouabain-sensitive 42K+ uptake, an estimate of sodium pump activity. Effects of quinidine on digoxin binding to Na+, K+-adenosine triphosphatase (ATPase) in intact cells were examined by perfusion guinea-pig Langendorff preparations with digoxin and estimating the occupancy of the glycoside-binding sites on the enzyme from a reduction in the initial velocity of the ATP-dependent [3H]ouabain binding reaction. Quinidine did not alter the initial velocity of [3H]ouabain binding to ventricular homogenates obtained from digoxin-perfused preparations, indicating that digoxin binding to Na+, K+-AtPase during the perfusion was not altered. In isolated rat heart preparations, quinidine failed to affect the positive inotropic action of ouabain. Nor did quinidine modify the inotropic action of digoxin in Langendorff preparations of guinea-pig heart. Concurrent i.v. infusion of quinidine in anesthetized guinea pigs increased the digoxin concentration in plasma. Thus, quinidine does not modify digoxin-Na+, K+-ATPase interactions or the digoxin-sensitivity of the myocardium. Quinidine-induced alterations in apparent volume of digoxin distribution should quantitatively change the response of the animal to digoxin.

Animals↗
PubMed1981

Tissue binding sites involved in quinidine-cardiac glycoside interactions.

Quinidine has been shown to alter pharmacokinetics of digoxin by displacing the glycoside from mutual binding sites which are stereospecific with respect to quinidine. Characteristics of the binding site involved in quinidine-digoxin interaction were studied further in guinea pigs and rats. In the anesthetized rat quinidine significantly increased digoxin, but not digitoxin or ouabain, concentration in plasma during an i.v. infusion of a radiolabeled glycoside. In the anesthetized guinea pig, quinidine markedly increased plasma digoxin, but not digoxigenin or dihydrodigoxin, concentrations as estimated from a competitive binding assay using [3H]ouabain and a partially purified Na+, K+-adenosine triphosphatase preparation. Plasma sodium and potassium concentrations were not altered by quinidine either in control or digoxin-treated guinea pigs. In anesthetized guinea pigs, the quinidine concentrations in plasma was 6.4 +/- 1.1 muM after a 260-min fusion of quinidine at a rate of 26 mumol/kg/hr in control animals and 7.9 +/- 1.6 muM in those which were simultaneously infused with digoxin at a rate of 0.2 mumol/kg/hr. Antiarrhythmic agents, lidocaine, DL-propranolol or verapamil, did not cause a significant change in plasma digoxin concentration in the anesthetized guinea pigs. These results indicate that the binding site involved in quinidine-digoxin interaction has a strict structural requirement with respect ot the glycoside. Additionally, of the four antiarrhythmic drugs, quinidine appears to be the only agent which interacts with digoxin.

Animals↗
PubMed1980

Possible mechanisms for inotropic actions of vanadate in isolated guinea pig and rat heart preparations.

The mechanism of inotropic actions of vanadate studied in isolated, electrically stimulated atrial and ventricular muscle preparations of rat or guinea-pig heart. Vanadate produced a negative inotropic effect in guinea-pig left atrial preparations associated with a marked shortening of the action potential plateau. In guinea-pig papillary muscle, or rat atrial or ventricular muscle preparations, vanadate produced a positive inotropic effect, which was not affected by either propranolol, phentolamine or metiamide. The positive inotropic effect was observed when action potential duration was either increased or decreased. Inotropic concentrations of vanadate failed to significantly alter the ouabain-sensitive 86Rb+-uptake, an estimate of sodium pump activity, or tissue concentration of cyclic AMP in electrically stimulated preparations. In partially depolarized rat atrial preparations in which fast sodium channels were inactivated in the presence of a high concentration of K+ (22 mmol/l), vanadate restored electrical activity (calcium-dependent action potentials) and the contraction, similar to isoproterenol. This action of vanadate was abolished by Mn2+, a slow channel inhibitor, but not by tetrodotoxin. The characteristic of vanadate- and isoproterenol-restored preparations, however, were substantially different. Moreover, vanadate failed to restore the contraction or action potential in partially depolarized guinea pig atrial preparations unlike isoproterenol. These results indicate that vanadate may either enhance or inhibit slow channels in cardiac muscle.

Action Potentials↗
PubMed1980

Positive inotropic action of digoxigenin and sodium pump inhibition: effects of enhanced sodium influx.

A possibility that intracellular Na+ ions available to Na+,K+-adenosine triphosphatase influence the action of digoxigenin to cause sodium-pump inhibition and a positive inotropic effect was examined with isolated left atria of guinea-pig hearts. The positive inotropic action of digoxigenin developed more rapidly when atria were stimulated at 3 Hz than at 1.5 Hz. The rate of development of the positive inotropic action was dependent on the frequency of membrane depolarizations rather than on contractions. Monensin, a known Na+ ionophore, enhanced the rate of development of the positive inotropic action of digoxigenin. Sodium pump activity, as estimated from ouabain-sensitive 86Rb uptake, was inhibited by digoxigenin in a concentration-dependent manner in quiescent atria. The inhibition was enhanced by electrical stimulation which shifted the concentration-inhibition curves to the left. The sensitivity of the sodium pump for digoxigenin was also affected by membrane depolarizations, suggesting a role for intracellular Na+. These data indicate that similar to the cardiac glycosides, the interaction of the aglycone with Na+,K+-adenosine triphosphatase is essential for the development of the positive inotropic action of this agent.

Action Potentials↗
PubMed1979

Sodium ions and the development of the inotropic action of ouabain in guinea-pig heart.

Factors that determine the interaction of ouabain with the positive inotropic receptor were examined in isolated perfused guinea-pig hearts. The hearts were exposed to ouabain during a perfusion with a modified Krebs-Henseleit solution. The interaction of ouabain with the inotropic receptors under those conditions was estimated by subsequently perfusing the heart with a regular Krebs-Henseleit solution and monitoring the resting and developed tension. Ouabain failed to cause an increase in the force of contraction when the cardiac tissue was exposed to this agent in the absence of Na+ and Ca2+ either in the presence of a low or high concentration of K+. The absence of Ca2+ or the lack of contraction was not responsible for the failure of ouabain to interact with the inotropic receptor, since the exposure of cardiac tissue to ouabain in a Ca,+-free medium containing Na+ resulted in a development of the positive inotropic effect. Thus, ouabain does not interact with its inotropic receptor in the absence of Na+. The properties of the ouabain-receptor interaction resemble those of ouabain binding to Na+, K+-ATPase. In addition, ouabain increases the mobility of superficially bound Ca2+.

Animals↗