Acetyl Strophanthidin Research Articles

Effects of Cardiac Glycosides on Atrial Contractile Dysfunction After Short-term Atrial Fibrillation

Despite a long history of use in the treatment of paroxysmal atrial fibrillation (AF), the efficacy of cardiac glycosides has not been established. If such drugs are beneficial in this condition, the general view is that the benefit must be related to their inotropic actions. To assess the effects of the rapid-acting cardiac glycoside, acetylstrophanthidin (AS), on AF and AF-induced right atrial (RA) "stunning," RA wall motion (with ultrasonic crystals), RA pressure, and peak first derivative of pressure (dp/dt) (with microtip transducers) were measured before and after 5 min of high-intensity rapid atrial stimulation (10 Hz; 10 mA; 1 ms) and after the cessation of poststimulation AF. Measurements were made in neurally intact and autonomically blockaded dogs both before and after the administration of AS (0.01 mg/kg IV bolus and 0.015 mg/kg/h IV infusion). AS prevented the post-AF reduction in RA peak dp/dt under neurally intact and autonomically blockaded conditions, and it prevented the post-AF increase in the RA end-systolic dimension and the decrease in the percentage of RA systolic shortening with autonomic blockade. AS was beneficial whether or not baseline inotropy was enhanced by AS. The duration of AF following atrial stimulation was the same before and after AS, but when compared to controls, AS treatment appeared to prolong AF. Cardiac glycosides exert a favorable effect on AF-induced RA stunning, but this action is unrelated to its effects on the duration of AF.

Enhancement of delayed afterdepolarizations and triggered activity by class III antiarrhythmic drugs: Multiple effects of E-4031 and dofetilide

The effects of class III antiarrhythmic agents E-4031 and dofetilide were studied on action potentials and subthreshold delayed afterdepolarizations (DADs) induced by the cardiac glycoside acetylstrophanthidin (AS) in isolated cardiac Purkinje fibers. Action potentials were recorded from cardiac Purkinje fibers using microelectrode techniques. E-4031 and dofetilide consistently increased DAD amplitude, occasionally caused triggered action potentials and shortened action potential duration. The application of E-4031 without prior AS exposure, resulted in the typical class III antiarrhythmic effects of action potential lengthening and the induction of early afterdepolarizations. These findings suggest that under our conditions of AS-induced cell Ca2+ overload, the effects of the "pure" class III antiarrhythmic drugs, E-4031 and dofetilide, are markedly different from those found in non-Ca2+ loaded cells. This may represent an additional electrophysiological mechanism for class III antiarrhythmic drug toxicity.

P-463 - Effects of phenylglyoxal (PGO) and acetyl-strophanthidin(AS) on contractile responses in single fibers from frog ventricle

P-463 - Effects of phenylglyoxal (PGO) and acetyl-strophanthidin(AS) on contractile responses in single fibers from frog ventricle

Myocardial inositol and sodium in diabetes

Although inhibition of Na +K + ATPase has been described in the diabetic heart, K + loss from myocardium has not been observed in a canine model of mild diabetes. The finding of tissue Na + accumulation and a potential relation to alteration of left ventricular inositol as observed in other tissues in diabetes form the basis of this investigation. Diabetes was induced with alloxan in three groups of male mongrel dogs who were studied after 1 yr. In the initial experiment the tissue compartment volumes, determined with intravenous 51Cr EDTA as a marker, were found to be normal. Calculated cell sodium was increased to 32.8 ± 2.6 mEq/kg cell H 2O vs 18.7 ± 1.1 in controls ( p < 0.01). Cell potassium in diabetes was normal. In the second group, myocardial polyols were analyzed by gas-liquid chromatography. Inositol was diminished in diabetes to 0.61 ± 23 μM/g of left ventricle, vs the respective control levels of 1.9 ± 0.57 μM/g ( p < 0.02). Sorbitol concentration was unaltered. Left ventricular sodium increments were not associated with altered tissue calcium. In group III the hypothesis that inhibition of Na +K + ATPase in diabetes might not elicit the expected alteration of K + transport was assessed during intracoronary infusion of acetyl strophanthidin. No difference in cation responses from control was observed. It is postulated that a change in the conformation of Na +K + ATPase, with high affinity sodium binding sites facing the intracellular compartment, may render sodium less releasable from cell membrane.

Termination of digitalis-induced ventricular tachycardias by clonidine involves central alpha 2-adrenoceptors in cats.

1. Effects of intravenous (i.v.) and intravertebral arterial (i.a.) administration of the alpha 2-adrenoceptor agonist, clonidine (Clon) and its antagonist, yohimbine (Yoh, 0.5 mg kg-1, i.v.; 0.05 mg kg-1, i.a.), on ventricular tachycardia (VT) induced by intravenous acetylstrophanthidin (AS) were studied in cats anaesthetized with intraperitoneal chloralose. 2. AS dose-dependently produced cardiac arrhythmias including complete atrioventricular conduction block (118 +/- 14 micrograms kg-1, i.v.), junctional tachycardia (128 +/- 20 micrograms kg-1, i.v.), multiform ventricular premature beats (157 +/- 21 micrograms kg-1, i.v.) and sustained VT (220 +/- 23 micrograms kg-1, i.v.). 3. Doses of Clon (i.v.) required for termination of VT following i.v. Yoh (62.9 +/- 5.2 micrograms kg-1) or i.a. Yoh (88.5 +/- 16.3 micrograms kg-1) were higher than those for termination of VT without Yoh administration (28.3 +/- 6.2 micrograms kg-1). Doses of Clon (i.a.) required for termination of VT without or with i.a. Yoh administration were 5.8 +/- 1.0 or 14.8 +/- 3.7 micrograms kg-1, respectively, and they were significantly different. 4. These experiments demonstrate that either i.v. or i.a. Yoh antagonizes the antiarrhythmic effect of Clon on AS-induced VT. Since small doses of Clon administered i.a. act predominantly on the central nervous system, we suggest that its antiarrhythmic effect is likely to be on central alpha 2-adrenoceptors in the central nervous system.

Mechanisms of action of beta-adrenergic agents on the arrhythmogenic transient inward current in rabbit Purkinje fibers

Catecholamines increase the amplitudes of oscillatory afterpotentials (OAP) and peak magnitude of the transient inward current ( I ti) responsible for OAP. The objectives of this study were to determine whether β-adrenoceptor stimulation can induce I ti, and to determine the mechanism by which β-adrenoceptor stimulation increases the magnitude of I ti. Experiments were performed using standard two electrode voltage-clamp techniques in isolated rabbit Purkinje fibers. Holding potential was either −50 or −80 mV. The I ti was elicited by repolarizing steps, following 1.5 or 3 s activating steps to potentials near 0 mV. Isoproterenol (ISO) failed to induce the I ti at concentrations from 10 −8 to 10 −6 m. However, ISO (10 −7 m) significantly increased peak magnitude of spontaneously occurring I ti ( P < 0.05), or I ti induced by acetylstrophanthidin (AS) ( P < 0.05). ISO also shifted the minimum activation voltage 10 mV more negative ( P < 0.05). The currentvoltage relationship demonstrated that ISO significantly increased the range of potentials over which I ti≥5 nA occurred, but did not significantly shift the voltage at which maximum peak current was observed. Effects of ISO on I ti were blocked by 10 −7 m propranolol or atenolol. Mn 2+ (2 m m) or verapamil (2 μ m) blocked the slow inward current ( I si) more than 80% before substantially decreasing peak I ti. Either agent blocked stimulation of I si but not I ti by ISO at 10 −7 m. In contrast, quinacrine (20 μ m), an inhibitor of Na +Ca 2+ exchange, abolished stimulation of I ti by ISO while having no significant effect on I si. Our results indicate that β-adrenoceptor stimulation cannot induce I ti in rabbit Purkinje fibers, but can enhance the I ti induced by other means, by stimulating Na +Ca 2+ exchange.

Effects of alpha-adrenergic agents on generation of oscillatory afterpotentials and triggered activity in rabbit Purkinje fibers

Effects of α 1- and α 2-adrenergic agonists and antagonists on oscillatory afterpotentials (OAP) and triggered activity induced by acetylstrophanthidin (AS) or 8 m m Ca 2+ (with 2 m m K +) were studied with standard microelectrode techniques in isolated rabbit heart Purkinje fibers. Experiments were conducted in the presence of 0.5 μ m propranolol. Phenylephrine (PE, 0.5 to 10 μ m) increased the amplitude of OAP and induced triggered activity when subthreshold OAP were caused by high Ca 2+. In contrast, PE decreased the amplitude of OAP and suppressed triggered activity induced by acetylstrophanthidin. Prazosin at 0.5 μ m did not affect the amplitudes of OAP by itself, but abolished both the inhibitory effect of PE on AS-induced OAP and the stimulatory effect of PE on high Ca 2+-induced OAP. At 2 μ m, prazosin alone reduced the amplitude of OAP and suppressed triggered activity induced by either acetylstrophanthidin or high Ca 2+. While clonidine (0.5 to 10 μ m) did not affect OAP or induction of triggered activity, yohimbine (2 μ m) decreased the amplitude of OAP and abolished triggered activity induced by either acetylstrophanthidin or high Ca 2+. Thus, specific α 1-adrenergic actions of phenylephrine may exert either pro-arrhythmic or antiarrhythmic effects on OAP and triggered activity depending on the method of induction of OAP. The α 1- and α 2-antagonists prazosin and yohimbine both exert direct antiarrhythmic effects in addition to their adrenergic blocking actions.

Effects of acetyl strophanthidin on duration of atrial fibrillation in the neurally-intact and blockaded dog.

Although the inotropic and dromotropic effects of cardiac glycosides in atrial fibrillation (AF) are well recognized, their action on AF itself is not clear. Accordingly, to determine whether cardiac glycosides prolong AF, the duration of electrically induced AF, atrioventricular conduction, and left ventricular function were assessed for 30 minutes before and for 30 minutes following intravenous administration of acetyl strophanthidin (AS), 20 micrograms/kg, in neurally intact, beta-blocked, and beta-blocked and vagotomized dogs. In the intact dog, AS, 20 micrograms/kg, increased peak dp/dt by 132 +/- 35 mmHg.sec-1, p less than 0.05, and slowed ventricular response by 16 +/- 7 min-1, p less than 0.05, but had a variable effect on AF duration. While the increased left ventricular peak dp/dt persisted for 15 minutes after AS, an increased duration of AF was evident only at 20 minutes, when the effects of AS on left ventricular (LV) inotropy were no longer apparent. Moreover, the subset of dogs that did not demonstrate prolongation of average duration of AF after AS had a greater increment of peak dp/dt than those that showed prolongation, 237 +/- 52 versus 53 +/- 31 mmHg.sec-1, p less than 0.05. An additional 20 micrograms/kg, which produced ventricular extrasystoles, prolonged AF duration when compared to both control and 30-minute measurements. Acetyl strophanthidin, 20 micrograms/kg, had a variable effect on duration of AF with beta-blockade but prolonged duration by 114 +/- 34%, p less than 0.05, with both vagotomy and beta-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha 2-adrenoceptor blockade prevents cardiac glycoside-evoked neurotransmitter release from sympathetic nerves in dog saphenous vein.

1 The effect of alpha-adrenoceptor antagonists upon neurotransmitter release evoked by cardiac glycosides from sympathetic nerve terminals has been investigated in dog saphenous vein. 2 In rings of saphenous vein preloaded with [3H]-noradrenaline, acetylstrophanthidin (ACS) caused a concentration-dependent efflux of 3H (EC50 ca. 4.4 microM) that was attenuated by phentolamine and yohimbine but not by prazosin. 3 In helical strips of saphenous vein superfused with ACS at EC50 the efflux of 3H-compounds in general, and of [3H]-noradrenaline in particular, occurred after a short delay and increased with time to a maximum reached at 75 min. Phentolamine and phenoxybenzamine, but not prazosin reduced the efflux of [3H]-noradrenaline and of total 3H-compounds throughout the time-course of the ACS-evoked effect. 4 In helical strips of saphenous vein the glycoside ouabain also caused an increase in [3H]-noradrenaline and in total 3H-efflux that was attenuated by phentolamine. 5 By contrast with the above, in bovine adrenal medullary chromaffin cells, which appear to have no functional alpha-adrenoceptors, ACS caused a small, but significant increase in 3H-efflux which was not prevented by phentolamine. 6 Phentolamine, at concentrations that attenuate markedly the ouabain- or ACS-evoked increase in 3H-efflux from dog saphenous vein, did not cause significant inhibition of cocaine-sensitive [3H]-noradrenaline uptake nor did it reduce the extent of the 3H-efflux evoked either by tyramine or by reduced extracellular Na+. These findings imply that phentolamine does not affect ACS-evoked neurotransmitter release by an action on the catecholamine uptake mechanism. 7. It is concluded that the cardiac glycoside-evoked increase in neurotransmitter release from noradrenergic nerve terminals ofdog saphenous vein is modulated by a mechanism that involves an alpha2- adrenoceptor.

Mechanisms of action of diltiazem in isolated human atrial and ventricular myocardium

A comparative study of human atrial fibers (HAF), human ventricular fibers (HVF), frog ventricle, and frog skeletal muscle demonstrated marked differences in tension development in the presence of diltiazem. There was no significant difference between the tension developed by HAF and by HVF over a range of diltiazem concentrations when the differences in resting membrane potential were corrected by increasing external K+ concentration. In human myocardium, diltiazem resulted in both a voltage and use-dependent blockade of the calcium channel. Comparison of the tension-dose response curves in human myocardium, frog ventricle and skeletal muscle showed that diltiazem was most effective at decreasing tension in frog heart, and least effective in skeletal muscle with human myocardium being intermediate. In skeletal muscle, neither tension development nor the birefringence signal related to the Ca2+ release from the sarcoplasmic reticulum was significantly altered by Diltiazem in concentrations less than 10(-6) M, but in concentrations greater than 10(-5) M both were suppressed. Diltiazem suppressed tension in human myocardium over the range of membrane potentials associated with Ca2+ channel activity, while at more positive potentials, diltiazem appeared to have little effect on the tension-voltage relations. Diltiazem had no effect upon tension development induced by acetyl strophanthidin in human myocardium or upon the Ca2+ sensitivity of chemically skinned atrial or ventricular fibers. Thus the tension-suppressant effect of diltiazem in human myocardium appears to be mediated by a combination of voltage-dependent block of the Ca2+ channel and inhibition of Ca2+ release from internal stores, and not from alterations in either Na+-Ca2+ coupled transport or Ca2+ sensitivity of the myofilaments.

Interaction of ischemia and reperfusion with subtoxic concentrations of acetylstrophanthidin in isolated cardiac ventricular tissues: Effects on mechanisms of arrhythmia

The aim of this study was to determine if "ischemia" and/or reperfusion potentiate digitalis toxicity through effects on oscillatory afterpotentials. Isolated canine Purkinje tissue-papillary muscle preparations were studied using standard microelectrode techniques. Tissues were superfused for 10 min with an "ischemic" solution that mimicked hypoxia, acidosis, elevated lactate, zero substrate and normo- or hyperkalemia. Reperfusion with "normal" Tyrode's solution was then reinstated for 60 min. Next, subthreshold oscillatory after potentials were induced with acetylstrophanthidin (ACS) and the protocol was repeated with ACS in all solutions. Without ACS, ischemic conditions with 4 mM KCl caused depolarization of Purkinje and muscle tissues. Reperfusion resulted in hyperpolarization of Purkinje tissue followed by mild depolarization, and then recovery. Purkinje tissue exposed to ischemic conditions with hyperkalemia responded similarly, except that hyperpolarization upon reperfusion was absent. In the presence of ACS, ischemic conditions with 4 mM KCl abolished oscillatory afterpotentials and caused marked depolarization of Purkinje tissue. Reperfusion decreased the coupling intervals and increased the amplitude of oscillatory afterpotentials relative to pre-ischemic levels, and frequently elicited arrhythmic activity. Arrhythmias ceased and tissues recovered by 60 min of reperfusion. Ischemic conditions incorporating hyperkalemia also abolished ACS-induced oscillatory afterpotentials and delayed their reappearance upon reperfusion. All other reperfusion responses were similar. This study demonstrates that "ischemic" suppresses oscillatory afterpotential-mediated effects of digitalis in canine Purkinje tissue, whereas reperfusion potentiates oscillatory afterpotential-induced arrhythmias.

Uphill sodium transport driven by an inward calcium gradient in heart muscle.

Heart cells were loaded with sodium by treatment with toxic doses of acetyl strophanthidin. After this treatment, an increase in extracellular calcium resulted in a transient net outward sodium flux against its electrochemical gradient and in net cellular uptake of calcium. It is concluded that the free energy for the net outward sodium movement was derived from the increased calcium gradient and that these ion movements took place through the sodium-calcium exchange. While in the normal physiological state the sodium-calcium exchange produces calcium extrusion from the cell, these experiments demonstrate its reversibility.

Biphasic effects of acetylstrophanthidin on automaticity in guinea pig ventricular muscle

The effects of acetylstrophanthidin (AS) on depolarization-induced automaticity and contractility of guinea pig papillary muscle were studied in a single sucrose gap chamber with microelectrode and current-clamp techniques. The concentration used, 1.4–1.8 μM, never induced automaticity in preparations at their normal resting potential. Twenty min after superfusion with AS, action potential duration (APD) was prolonged and the force of contraction increased. These were associated with an increase in slope of phase 4 depolarization and an increase in the membrane resistance (R m) of muscles depolarized with small constant current pulses. With longer (50–80 min) periods of AS superfusion, APD became shorter, R m decreased to less than predrug values, and in depolarized preparations, the slope of phase 4 decreased. Contractility remained unchanged throughout this second phase. All of these effects were fully reversible upon 60 min of superfusion with AS-free Tyrode solution. We suggest that the biphasic effects of AS on the automaticity of depolarized ventricular muscle cells are caused by an initial decrease followed by a later increase in transmembrane potassium conductance.

Sodium efflux in rabbit myocardium: relationship to sodium-calcium exchange.

1. The washout of (22)Na, (45)Ca and (58)CoEDTA(-) has been observed in arterially perfused rabbit interventricular septa both in the presence and absence of intoxicating doses of the aglycone, 3 acetylstrophanthidin (ACS).2. The washout of (22)Na from paced septa (21.0/min) was rapid with approximately 99% of the exchange occurring in 30 min.3. Septa labelled with (22)Na and washed out in the presence of 10(-5)m-ACS were quiescent, exhibited marked contracture and a slowed (22)Na exchange with 99% of the initial (22)Na leaving the tissue in approximately 200 min.4. Comparison of the washout of the extracellular marker (58)CoEDTA(-) from paced and intoxicated septa revealed no differences, suggesting that regions of the extracellular space had not become inexchangeable as a result of the contracture that these septa exhibited.5. Simultaneous measurements of the distribution of (22)Na and (58)CoEDTA(-) in the presence of 10(-5)m-ACS revealed an apparent cellular Na concentration of 54.8+/-10.4 (s.e.). This was considerably in excess of the maximum amount of Na contributing to the slowest component of Na efflux from intoxicated septa. Origins of this discrepancy are considered.6. The slowest component of (22)Na efflux from intoxicated septa could be markedly stimulated by increasing the external Ca concentration from a nominal 1.5 to 16 mm. The magnitude of stimulation was 44.3+/-7.8% (s.e.). Increases in the concentration of Mg from 1.0 to 16.0 mm were without effect on the (22)Na efflux.7. Application of 10(-5)m-ACS produced marked depolarization of the membrane to new stable levels that lay between -10 and -20 mV.8. Washout of ACS after several hours of intoxication resulted in a partial decline in contracture tension, an acceleration of Ca efflux, little change in (22)Na efflux and a repolarization of the cell membrane.9. Some of the Na and Ca movements reported in this paper have been interpreted by supposing that there is, in this preparation, a coupled exchange of three Na ions for a single Ca ion.

Effects of hyperkalemia and glycoside on thallium exchange in rabbit ventricle.

The exchange characteristics of thallium-201 (201Tl) were studied using the isolated arterially perfused rabbit interventricular septum to gain insight into the mechanisms that govern its uptake and subsequent washout from myocardial tissue. The results were compared to potassium-42 (42K) exchange. Unlike 42K, the uptake and tissue washout exchange rates for 201Tl were not equal. The 201Tl washout exchange rate was slower than that for the uptake. Hyperkalemia increased the efflux of both 42K and 201Tl, but the increase in 201Tl efflux was not due to an increase in permeability, as was true for 42K, but to a hyperkalemia, induced increase in compartment size of exchangeable 201Tl. Acetylstrophanthidin (ACS) resulted in an increase in 201 Tl efflux similar to the increase in 42K efflux seen with ACS. However, ACS did not inhibit 201Tl influx, in contrast to the known inhibition of 42K influx. This indicated that influx of tracer amounts of 201Tl was not dependent on the sodium-potassium pump. A model of Tl exchange in rabbit ventricles is proposed.

The effects of acetylstrophanthidin and ouabain on the sympathetic adrenergic neuroeffector junction in canine vascular smooth muscle.

We performed experiments to determine the effects of acetylstrophanthidin (ACS) and ouabain on the adrenergic neuroeffector junction in dog saphenous veins. In quiescent strips incubated with 3H-norepinephrine (3H-NE), the drugs caused contraction and a progressive increase in overflow of 3H-NE and O-methylated metabolites; 3,4-dihydroxyphenylglycol (DOPEG) decreased. Tissue uptake of 3H-NE was partially inhibited. After surgical sympathectomy, both contraction and 3H-NE overflow were markedly attenuated. Following chemical sympathectomy with 6-hydroxydopamine, ouabain contractions were 11% of control, whereas the contractions due to exogenous norepinephrine were exaggerated. The initial overflow of 3H-NE was unaffected by tetrodotoxin, but the later and larger overflow with prolonged exposure was depressed. The former occurred in the absence of Ca2+, but the latter was Ca2+ dependent. Inhibition of the neuronal amine carrier by cocaine or desipramine and blockade of the neuronal alpha-adrenoceptors with phentolamine or phenoxybenzamine attenuated the release of 3H-NE evoked by ACS and ouabain. During electrical stimulation, ACS augmented the overflow of 3H-NE. This was attenuated by cocaine, desipramine, and the alpha-adrenolytic drugs. ACS, like pargyline, augmented the overflow of 3H-NE evoked by tyramine and depressed that of DOPEG. These experiments suggest that acetylstrophanthidin and ouabain (1) cause contraction of vascular smooth muscle by displacement of norepinephrine from neuronal stores, (2) reduce neuronal monoamine oxidase activity, (3) facilitate and may trigger Ca2+-dependent exocytotic release of norepinephrine, (4) partially inhibit the neuronal amine carrier mechanism but do not interfere with extraneuronal disposition of norepinephrine, and, finally (5) may have unexplained interactions with prejunctional alpha-adrenoceptors.

Comparison of the response of depressed and normal myocardium to acetyl strophanthidin

Comparison of the response of depressed and normal myocardium to acetyl strophanthidin

Digitalis drugs and vulnerability to ventricular fibrillation

The effect of acetylstrophanthidin (AS), a rapid-acting digitalis-like agent, on the ventricular fibrillation (VF) threshold was examined in normal and denervated chloralose-anesthetized dogs. In neurally intact dogs an intravenous bolus of AS (0.075 mg/kg) increased the VF threshold up to a maximum 50% (P < 0.01) within 30 min after injection. The augmented VF threshold following intravenous administration of AS was not altered by vagotomy. Bilateral stellectomy in vagotomized dogs, as well as carotid sinus and aortic arch denervations, however, prevented the AS induced increase in VF threshold. In neurally intact dogs β-adrenergic blockade with propranolol (0.25 mg/kg) precluded AS effects. These data suggest that the increase in the VF threshold resulting from AS administration in the normal canine ventricle is due to withdrawal of sympathetic tone mediated via the baroreceptor reflex. The direct effect of AS on the myocardium is to decrease the VF threshold.

Acetylstrophanthidin-induced reflex inhibition of canine renal sympathetic nerve activity mediated by cardiac receptors with vagal afferents.

The present experiments were performed to determine whether digitalis-induced augmentation of cardiac receptor discharge could induce reflex reductions in renal sympathetic nerve activity. Intracoronary injection or epicardial application of acetylstrophanthidin (AS) in chloraloseanesthetized dogs caused large decreases in renal sympathetic nerve activity which were accompanied by modest decreases in heart rate and arterial pressure. Vagotomy prevented these reflex responses. Cholinergic blockade with atropine markedly attenuated the heart rate responses to AS but had little effect on the arterial pressure or renal nerve activity responses. Epicardial application of lidocaine blocked cardiac vagal afferents and the reflex responses to intracoronary AS. In sinoaortic denervated dogs, the relationships between doses of AS and mean arterial pressure, heart rate, and renal nerve activity responses were linear. Decreases in renal nerve activity were evoked by doses of AS which did not reflexly change heart rate or arterial pressure. These data show that AS can evoke reflex bradycardia, hypotension, and withdrawal of renal sympathetic nerve activity solely by augmenting the inhibitory influence of cardiac receptors with vagal afferents. This reflex effect may contribute to the changes in renal function and thus to the diuresis that occurs when heart failure is treated with digitalis.

The effect of heart rate on myocardial ouabain uptake and on the susceptibility to ouabain cardiotoxicity in the dog.

SUMMARY1. Tissue ouabain concentrations were estimated 30 min after intravenous 3H‐ouabain administration to sedated dogs, the heart rates of which were adjusted to range between 50 and 200 beats/min. Significant correlations were present between heart rate and ouabain content in left ventricle (r=0.93, P&lt; 0.001), in right ventricle and left atrium. In contrast, no significant correlations were present between heart rate and ouabain content in liver, in renal cortex, skeletal muscle or plasma.2. To determine the functional effect of the greater myocardial ouabain uptake associated with higher heart rate, anaesthetized open‐chest dogs were studied. The heart rates of two groups were controlled at 199 ± 9 (s.d.) beats/min and 90 ± 14 beats/min during ouabain administration, and 30 min later, at a common heart rate, acetyl strophanthidin tolerance tests were performed.3. Acetyl strophanthidin infusion induced ventricular tachycardia significantly earlier, after a correspondingly lower dose in the fast heart rate group (P&lt;0.01). Significant inverse correlations were present between the concentrations of ouabain in both left and right ventricular muscle and the duration of acetyl strophanthidin infusion.4. The results indicate that higher heart rate is associated with greater myocardial ouabain uptake and that this ouabain is functionally active.