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At least 19 recordsLinked to original sources
PubMed1975

Irreversible inhibition of Na-+ +K-+ -ATPase by strophanthidin 3,5-bid-p-benzoyl benzoate, a photochemical analogue of strophanthidin.

A photoactivatible analogue of strophanthidin, strophanthidin 3,5-bis-p-benzoyl benzoate (SBB), was synthesized and tested as a photoaffinity label for the cardiotonic steroid binding site of Na-+ +K-+ -ATPase. SBB inhibited rat brain Na-+ +K-+ -ATPase with an I50 of approximately 1 times 10-minus 5 M and displaced (3-H) ouabain from its specific binding site on this enzyme while the photoaffinity group, methyl p-benzoyl benzoate (me-pBB), alone was not effective. Ultraviolet photoactivation of SBB which had been specifically bound at the cardiotonic steroid binding sites of this enzyme produced 35% irreversible inhibition of enzyme activity. However, only slightly less irreversible inhibition was observed in the absence of cardiotonic site directed binding of SBB and photoactivation of me-pBB itself produced marked inhibition of the enzyme. It was concluded that the bulk of the photoactivated inhibition occurring with SBB does not involve the cardiotonic steroid binding site and that a substantial reduction in the concentration of non-specifically bound SBB is required to expose any site directed labeling.

Adenosine Triphosphatases↗
PubMed1991

The effect of strophanthidin on action potential, calcium current and contraction in isolated guinea-pig ventricular myocytes.

1. A method is described for producing high yields of calcium-tolerant ventricular myocytes from guinea-pig hearts (73.4% rod-shaped cells, n = 19). Their action potential (AP) and membrane currents were recorded using conventional microelectrodes and cell shortening was measured optically using a linear photodiode array. 2. The sensitivity of the guinea-pig Na(+)-K+ pump to strophanthidin (a rapidly acting digitalis analogue) was determined by measuring the inhibition of outward pump current by different doses. The pump was found to have a dissociation constant (KD) for strophanthidin of 1.11 x 10(-5) M, and 5 x 10(-4) M-strophanthidin inhibited the pump maximally. 3. Exposure to strophanthidin resulted in an initial lengthening followed by a shortening of the AP, and an increased contraction. Initial AP lengthening was associated with a more positive AP plateau which became more negative as the AP shortened. 4. There was a reversible reduction of Ca2+ current (ICa) during exposure to strophanthidin. ICa changed reciprocally with contraction and with a similar time course. 5. Strophanthidin exposure caused a reduction of ICa at all activating voltages, suggesting that it resulted in a reduction of Ca2+ conductance with little change of its voltage dependence. 6. The role of an increase of intracellular calcium (Cai2+) was investigated by impaling myocytes with microelectrodes containing BAPTA 1,2-bis (2-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid, a calcium chelator) to increase Cai2+ buffering. Strophanthidin still shortened the AP when BAPTA was present, suggesting that a rise of Cai2+ is not a major cause of AP shortening. 7. Although AP shortening was little affected, the decline of ICa with strophanthidin was markedly reduced when BAPTA was present, suggesting that a rise of Cai2+ was the cause of the ICa decline with strophanthidin. 8. When barium ions carried the current through Ca2+ channels, strophanthidin did not reduce Ca2+ channel current, suggesting that this compound does not have a direct inhibitory effect on the channel. 9. The results suggest that strophanthidin causes a reduction of ICa by increasing Cai2+, via the mechanism of Cai(2+)-dependent inactivation of ICa. The reduction of ICa at least partially explains the AP shortening and more negative plateau with strophanthidin. 10. The shortening of the AP, more negative plateau and reduced ICa have negative inotropic effects which oppose the direct positive inotropic effect of strophanthidin.

Action Potentials↗
PubMed1988

Relation between Na+-K+ pump, Na+ activity and force in strophanthidin inotropy in sheep cardiac Purkinje fibres.

1. The effects of different concentrations of strophanthidin on intracellular sodium activity (aiNa), membrane potential and contractile force have been studied in cardiac sheep Purkinje fibres under conditions (overdrive) that stimulate Na+-K+ pump activity. 2. In fibres driven at 1 Hz, a 5 min overdrive at 2 Hz in the steady state increased force by +74.2%, aiNa by +10.9% and the maximum diastolic potential (Emax) by 3.32 +/- 0.52 mV. 3. During the recovery from overdrive (the fibres being driven again at 1 Hz), both contractile force and aiNa transiently undershot the control value by -10.5 and -3.7%, respectively. When the fibres were quiescent during the recovery from overdrive, no aiNa undershoot was present. 4. During overdrive, force and aiNa were closely correlated when plotted either on linear (correlation coefficient, R = 0.98) or logarithmic (R = 0.98) co-ordinates. 5. A low concentration of strophanthidin (0.01 microM) decreased force (-31.7%) and aiNa (-7.2%): overdrive increased force and Emax more and aiNa less than in the absence of strophanthidin. During the recovery, the undershoot in force (-12.9%) and aiNa (-5.4%) was larger and longer than in the absence of strophanthidin. 6. An intermediate concentration of strophanthidin (0.05 microM) increased force (+43.5%) and aiNa (+6.4%): overdrive increased force and aiNa as usual, but during the recovery the force remained above the value prior to overdrive and there was no aiNa undershoot. 7. A high concentration of strophanthidin (0.1 microM) increased force (+91.4%) and aiNa (+11.7%): overdrive further increased force and aiNa more than in control but there was no increase in Emax. During the recovery, both force and aiNa remained well above the values prior to overdrive. 8. Force and aiNa were closely correlated whether aiNa decreased in 0.01 microM-strophanthidin (R = 0.99 both on linear and logarithmic co-ordinates) or increased in 0.05-microM- (R = 1.00 on both co-ordinates) and in 0.1 microM- (R = 0.98 and 0.99, respectively) strophanthidin. The two parameters were well correlated also during overdrive in the three strophanthidin solutions. However, the slope of the relation was less steep in the low- than in the higher-strophanthidin solutions. 9. For a 1 mM change in aiNa, force decreased less in the low- than it increased in the intermediate-strophanthidin solution. Also, in low-strophanthidin solution, at the end of overdrive the aNao/aNai ratio was similar to that in Tyrode solution but force was well above control (+73.2%).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Actions of the digitalis analogue strophanthidin on action potentials and L-type calcium current in single cells isolated from the rabbit atrioventricular node.

1. The atrioventricular node (AVN) of the heart is vital to normal cardiac function and is a major site of antiarrhythmic drug action. This study describes the effects of the cardiac glycoside analogue strophanthidin on spontaneous action potentials and L-type calcium current recorded from single AVN cells isolated from the rabbit heart. 2. With a standard KCl-based internal dialysis solution, exposure to 50 microM strophanthidin produced a progressive depolarization of the maximum diastolic potential and a reduction in action potential amplitude and upstroke velocity. Sustained application resulted in the loss of action potentials and occurrence of spontaneous 'bell-shaped' depolarizations. 3. Cells were whole-cell voltage clamped at -40 mV and depolarizing voltage clamps applied. With a standard KCl-based internal dialysis solution, exposure to 50 microM strophanthidin caused a large reduction of ICa,L at all potentials between -30 and +40 mV (n = 4). At + 10 mV, the mean ICa,L amplitude was reduced from -232 +/- 65 pA to -48 +/- 26 pA (P < 0.05; 1 test; n = 5 cells). 4. To record ICa,L more selectively, cells were dialysed with a Cs-based pipette solution. A short strophanthidin exposure reduced ICa,L amplitude from -250 +/- 31 pA to -88 +/- 19 pA (P < 0.001; n = 8 cells). For both KCl and CsCl-based solutions it was observed that sustained exposure to strophanthidin for several minutes caused spontaneous inward fluctuations in the membrane current record similar to the 'ITI' (arrhythmogenic oscillatory transient inward) current shown for other cardiac cells. 5. When the calcium chelator BAPTA was added to the pipette solution (10 mM), the reduction in ICa,L by strophanthidin was largely eliminated (P > 0.1), and no spontaneous inward current fluctuations were observed after sustained exposure to strophanthidin (n = 8 cells). 6. When external Ca in the perfusate was replaced with Ba, strophanthidin did not significantly reduce the Ba current through L-type calcium channels (n = 5 cells). 7. We conclude that strophanthidin reduces ICa,L by an indirect action, mediated by the rise in intracellular calcium (Cai) which follows inhibition of the Na/K pump caused by cardiac glycosides. The appearance of spontaneous ITI with strophanthidin would also seem to be mediated by a rise in Cai, and may contribute to the spontaneous oscillations in membrane potential observed after prolonged strophanthidin exposure.

Action Potentials↗
PubMed1982

Effect of strophanthidin on intracellular Na ion activity and twitch tension of constantly driven canine cardiac Purkinje fibers.

Intracellular Na ion activity (aiNa) and twitch tension (T) of constantly driven (1 Hz) canine cardiac Purkinje fibers were measured simultaneously and continuously with neutral carrier Na+-selective microelectrodes and a force transducer. The aiNa of 8.9 +/- 1.4 mM (mean +/- SD, n = 52) was obtained in the driven fibers perfused with normal Tyrode solution. Temporary interruption of stimulation showed that aiNa of the driven fibers was approximately 1.5 mM greater than that of quiescent fibers. The constantly driven fibers were exposed to strophanthidin of 10(-8), 5 X 10(-8), 10(-7), 5 X 10(-7), and 10(-6) M for 5 min. No detectable changes in aiNa and T were observed in the fibers exposed to 10(-8) M strophanthidin, and the threshold concentration of the strophanthidin effect appeared to be approximately 5 X 10(-8) M. With concentrations greater than 5 X 10(-8) M, strophanthidin produced dose-dependent increases in aiNa and T. An increase in aiNa always accompanied an increase in T and after strophanthidin exposure both aiNa and T recovered completely. During onset and recovery periods of the strophanthidin effect the time course of change in aiNa was similar to that of change in T. A plot of T vs. aiNa during the onset and recovery periods showed a linear relationship between T and aiNa. These results indicate strongly that the positive inotropic effect of strophanthidin is closely associated with the increase in aiNa. Raising [K+]0 from 5.4 to 10.8 mM produced decreases in aiNa and T, and restoration of [K+]0 resulted in recoveries of aiNa and T. During the changes of [K+]0 the time course of change in aiNa was similar to that of the change in T. A steady-state sarcoplasmic Ca ion activity (aiCa) of 112 +/- 31 nM (mean +/- SD, n = 17) was obtained in the driven fibers with the use of neutral carrier Ca2+-selective microelectrodes. Temporary interruption produced 10-30% decreases in aiCa. No detectable changes in aiCa were observed in the fibers exposed to strophanthidin of 10(-7) M or less; 5 X 10(-7) and 10(-6) M strophanthidin produced 1.3-1.6 and 2-3-fold increases in aiCa, respectively. This result is consistent with the hypothesis that an increase in aiNa produces an increase in aiCa, which enhances Ca accumulation in the intracellular stores.

Animals↗
PubMed1984

The relationship among intracellular sodium activity, calcium, and strophanthidin inotropy in canine cardiac Purkinje fibers.

The role of sodium and calcium ions in strophanthidin inotropy was studied by measuring simultaneously the electrical, mechanical, and intracellular sodium ion activities in electrically driven cardiac Purkinje fibers under conditions that change the intracellular sodium or calcium level (tetrodotoxin, strophanthidin, high calcium, and norepinephrine). Tetrodotoxin (TTX; 1-5 X 10(-6)M) shifted the action potential plateau to more negative values, shortened the action potential duration, and decreased the contractile tension and the intracellular sodium ion activity (aiNa). The changes in tension and in aiNa caused by TTX appear to be related since they had similar time courses. Strophanthidin (2-5 X 10(-7)M) increased tension and aiNa less in the presence of TTX, and, for any given value of aiNa, tension was less than in the absence of TTX. Increasing extracellular calcium (from 1.8 to 3.3-3.6 mM) or adding norepinephrine (0.5-1 X 10(-6)M) increased tension and decreased aiNa less in the presence than in the absence of TTX. When two of the above procedures were combined, the results were different. Thus, during the increase in aiNa and tension caused by strophanthidin in the presence of TTX, increasing calcium or adding norepinephrine increased tension markedly but did not increase aiNa further. In a TTX-high calcium or TTX-norepinephrine solution, adding strophanthidin increased both tension and aiNa, and the increase in tension was far greater than in the presence of TTX alone. The results indicate that: (a) the contractile force in Purkinje fibers is affected by a change in aiNa; (b) a decrease in aiNa by TTX markedly reduces the inotropic effect of strophanthidin, possibly as a consequence of depletion of intracellular calcium; (c) increasing calcium influx with norepinephrine or high calcium in the TTX-strophanthidin solution produces a potentiation of tension development, even if aiNa does not increase further; and (d) when the calcium influx is already increased by high calcium or norepinephrine, strophanthidin has its usual inotropic effect even in the presence of TTX. In conclusion, the positive inotropic effect of strophanthidin requires that an increase in aiNa be associated with suitable calcium availability.

Action Potentials↗
PubMed1986

Strophanthidin inotropy in cardiac Purkinje fibers under conditions that vary cellular sodium or calcium.

The role of sodium and calcium on strophanthidin inotropy was studied in canine cardiac Purkinje fibers perfused in vitro under conditions that vary cellular sodium and calcium. With high concentrations of strophanthidin (greater than or equal to 10(-7) M), force increases more in the presence of low [Ca]0 or high [Na]0 and less in the presence of a low sodium-calcium concentration solution than in Tyrode solution. In a solution with a low concentration of sodium-calcium containing strophanthidin, restoring [Na]0 to normal decreases and then re-increases force: when [Na]0 is decreased again, the force transiently overshoots. These effects of strophanthidin are exaggerated by metabolic inhibitors. In a low [Ca] solution, low concentrations of strophanthidin (3 X 10(-8) or 5 X 10(-8) M) re-increase force a little or not at all. On recovery, the transient force increase is not exaggerated by low strophanthidin and is absent after manganese exposure. The inotropy of low concentrations of strophanthidin is potentiated by norepinephrine, high [Ca]0 (4 mM), or by lowering [Na]0. Thus, the present results suggest that the inotropic action of high strophanthidin concentrations depends primarily on sodium and secondarily on calcium, and that the inotropic action of low concentrations of strophanthidin involves a modification of the cell response to calcium.

Animals↗
PubMed1990

On the mechanism of the different sensitivity of Purkinje and myocardial fibers to strophanthidin.

The mechanism of the different sensitivity of Purkinje and myocardial fibers to strophanthidin was studied in these tissues isolated from the same hearts. Membrane potentials, force and, in some experiments, intracellular sodium activity were recorded under conditions that vary the sodium load in the absence and presence of strophanthidin. Strophanthidin (0.1-0.3 microM) increased force in percent terms more and at a faster rate in Purkinje than in myocardial fibers. Tetrodotoxin (TTX, 2 microM) markedly reduced whereas high [Na]o (176.6 mM) and veratridine (0.2 microM) potentiated strophanthidin inotropy in Purkinje but not in myocardial fibers. The rate of force development was augmented by high [Na]o and veratridine in Purkinje fibers but in myocardial fibers this effect was absent with high [Na]o and smaller with veratridine. Strophanthidin increased the action potential duration at plateau level in Purkinje and decreased it in myocardial fibers. The effects of TTX, high [Na]o and veratridine on the action potential were more pronounced in Purkinje than in myocardial fibers. TTX decreased far more and adding strophanthidin increased intracellular sodium activity (aiNa) less in Purkinje fibers. Strophanthidin increased aiNa to a similar extent in the presence of high [Na]o and veratridine in the two tissues. Thus, changes in Na influx modify the action potential duration, force and strophanthidin inotropy more in Purkinje than in myocardial fibers. This greater sensitivity of Purkinje fibers to strophanthidin does not appear to be related to a larger increase in aiNa, but rather to the changes in action potential (and consequent changes in calcium influx).

Action Potentials↗
PubMed1985

The role of intracellular sodium activity in the inotropy potentiation among high [Ca]o' norepinephrine and strophanthidin.

The mechanism by which high [Ca]o or norepinephrine potentiate the inotropic action of a low concentration of strophanthidin was investigated in cardiac Purkinje fibers perfused in vitro. The membrane potential, contractile force and intracellular sodium activity (aiNa) were recorded simultaneously and continuously. The following results were obtained. Increasing [Ca]o from 2.7 mM to 3.6 mM or administering norepinephrine (10(-7) M) increased the contractile force and decreased aiNa. Administration of a low concentration of strophanthidin (5 X 10(-8)M) increased the contractile force and aiNa. Occasionally, there was a transient small decrease in aiNa at the beginning of strophanthidin perfusion. When [Ca]o was increased in the presence of strophanthidin, aiNa decreased less and the contractile force increased more than in the absence of strophanthidin. Adding norepinephrine to the strophanthidin solution caused similar effects in that aiNa decreased less and contractile force more than in the absence of strophanthidin. The results suggest that the potentiation of the inotropic effect of strophanthidin by high [Ca]o or norepinephrine is due to the higher aiNa induced by strophanthidin and to the smaller decline in aiNa induced by high [Ca]o or norepinephrine.

Animals↗
PubMed1970

Fractionation of sodium effux in frog sartorius muscles by strophanthidin and removal of external sodium.

The influence of strophanthidin, ouabain, and the removal of external sodium on the sodium efflux from frog sartorius muscle was measured. In freshly dissected muscles strophanthidin and ouabain in maximally effective concentrations reduced the efflux of sodium by about 50%. Of the sodium efflux which is strophanthidin-insensitive about 75% is inhibited after complete replacement of external sodium by lithium. In the absence of strophanthidin replacement of external sodium by lithium, calcium, or magnesium produces an initial rise in the sodium efflux, followed by a fall in the efflux as the exposure of the muscles to sodium-free media is continued. When the muscles are exposed for prolonged periods in sodium-free media, the fraction of internal sodium lost per minute is higher when returned to normal Ringer fluid than it was initially. The activation of sodium efflux by external sodium after long periods in sodium-free solutions is partly strophanthidin-sensitive and partly strophanthidin-insensitive. The internal sodium concentration is an important factor in these effects. The effects of temperature on the sodium efflux were also measured. Above 7 degrees C the Q(10) of both the strophanthidin-sensitive and strophanthidin-insensitive sodium efflux is about 2.0. Below 7 degrees C the strophanthidin-insensitive sodium efflux has a Q(10) of about 7.4.

Animals↗
PubMed1981

Interactions of norepinephrine and strophanthidin in cardiac Purkinje fibers.

The actions and interactions between strophanthidin and norepinephrine on electrical and mechanical events were studied in cardiac canine Purkinje fibers perfused in vitro. The results obtained show that norepinephrine (but not strophanthidin) shifts phase 1 and the beginning of the plateau to a more positive potential, an effect reduced by beta-receptor blockade. Norepinephrine increases the contractile force to the maximal value sooner than strophanthidin. In low Ca solution, the inotropic action of strophanthidin far exceeds that of norepinephrine. Norepinephrine does not cause spontaneous discharge in the driven fibers, whereas strophanthidin eventually induces fast spontaneous rhythms. When norepinephrine is given in the presence of strophanthidin (or vice versa) spontaneous activity is induced which consists either of a slow rhythm (characterized by large action potentials) or of a fast rhythm (characterized by small action potentials). The latter is typically induced by strophanthidin alone but occurs sooner in the presence of both agents. Propranolol prevents the onset of the slow rhythm but not that of the fast rhythm. It is concluded that norepinephrine and strophanthidin increase force by different mechanisms and that the potentiation between these agents in causing spontaneous discharge may involve an enhancement of diastolic depolarization(slow rhythm) or of the oscillatory potential (fast rhythm).

Action Potentials↗
PubMed1986

Dissociation between force and intracellular sodium activity with strophanthidin in isolated sheep Purkinje fibres.

1. We have recorded membrane potential, intracellular Na activity (aiNa) and force of contraction in sheep Purkinje fibres. Force and aiNa were recorded continuously and simultaneously during exposure to strophanthidin and its subsequent washing off. 2. Exposure to strophanthidin in concentrations of 1.5 X 10(-7), 5 X 10(-7) and 10(-5) M caused an increase in force of contraction which was temporally dissociated from the increase of aiNa. 3. There was hysteresis in the relationship between force and aiNa when the period of increasing force was compared to the period of decreasing force. When force increased on exposure to strophanthidin, the same aiNa was always associated with a higher force than when force was decreasing while washing off the drug. 4. For the same rise of aiNa higher doses of strophanthidin produced larger rises of force than lower doses. 5. When diphenylhydantoin was present in the bathing solution at concentrations of 10(-5) and 10(-4) M, the relation between force and aiNa with 10(-5) M-strophanthidin had a less steep slope, but still displayed hysteresis. 6. The relationship between force and aiNa during changes of the bathing K concentration also displayed a hysteresis, which was in the same direction as that found with strophanthidin. 7. These results are discussed in relation to proposed mechanisms of action of strophanthidin and more generally in relation to the factors linking force of contraction and aiNa. We conclude that in sheep Purkinje fibres the increase of force caused by strophanthidin is not solely due to an increase of aiNa, and that other interventions can also result in hysteresis between force and aiNa.

Action Potentials↗
PubMed1991

On the mechanism of the positive inotropy of low concentrations of strophanthidin.

The hypothesis that low concentrations of strophanthidin may decrease contractile force (and intracellular sodium activity, aiNa) under normal conditions but might increase force (while still decreasing aiNa) under conditions of increased Ca load was tested in sheep cardiac Purkinje fibers perfused in vitro. Strophanthidin was used at concentrations (7.5-25 nM, "low strophanthidin") that decreased both force and aiNa in different preparations. A marked reduction in flow rate of Tyrode solution ("ischemia") increases aiNa and increases and eventually decreases force: during ischemia, low strophanthidin decreases aiNa but increases force. High [Ca]o (16.2 mM) and norepinephrine (10 nM) increase force and decrease aiNa: in their presence, low strophanthidin decreases aiNa further but increases force. Caffeine (4 mM) decreases force and increases aiNa, and low strophanthidin increases force while having little effect on the increase of aiNa. In ventricular trabeculae, strophanthidin decreases force under basal conditions but increases force during ischemia or Ca overload. Thus, strophanthidin decreases force by lowering aiNa under normal conditions, but it increases force in spite (and perhaps because) of the decrease in aina under conditions of increased calcium load.

Action Potentials↗