Inotropic Effect Of Ouabain Research Articles

Effect of hypoxia on ouabain inhibition of sodium pump in newborn rabbit myocardium.

The effects of hypoxia and reoxygenation on the inotropic effect of ouabain and sodium pump were studied in the isolated, arterially perfused newborn rabbit heart. Myocardial 86Rb+ active uptake was used as a marker of the sodium pump activity. During reoxygenation after mild hypoxia, 86Rb+ active uptake and ouabain effect were not significantly different from control. After severe hypoxia (with glucose) and reoxygenation, the inotropic effect of ouabain was not different from control, but mechanical toxicity occurred sooner. Severe hypoxia (with glucose-free solution) and reoxygenation caused an increase in tissue calcium, an attenuated inotropic effect of ouabain, and earlier mechanical toxicity. 86Rb+ active uptake was similar in all severe hypoxia groups and was significantly less than control values. Ouabain inhibition of 86Rb+ uptake in the severe hypoxia groups was not significantly different from control. These data indicate that severe hypoxia and reoxygenation depress the sodium pump but the effect of ouabain on the sodium pump in these muscles is similar to control. The decreased inotropic effect and increased toxicity of ouabain during reoxygenation after severe hypoxia may be due to an increase in cytoplasmic calcium and decreased tissue ATP.

Developmental changes in the interactions of amrinone and ouabain in canine ventricular muscle.

We studied the effects of amrinone on contractility and aftercontractions of ouabain-superfused ventricular muscle from neonatal and 3-month-old dogs. In 3-month ventricular muscle, amrinone, 5.3 X 10(-4) M, alone, increased active tension by 150%. When amrinone was superfused over ouabain-treated ventricular muscle, the increment in contraction was greatest for those muscles in which ouabain had induced a small positive inotropic effect and diminished as the positive inotropic effect of ouabain increased. Amrinone alone did not induce aftercontractions but increased the amplitude of those induced by ouabain by 92 +/- 6%. In neonatal ventricular muscle, amrinone alone was negatively inotropic and it decreased the increment in active tension induced by ouabain.

Potentiation of toxicity and positive inotropic effect of ouabain by furosemide in guinea pig heart.

The present study was undertaken to elucidate the potentiation by furosemide of toxicity and positive inotropic effect of ouabain in guinea pigs. Arrhythmogenic responses to ouabain as well as the lowering of its lethal dose were potentiated by pretreatment with furosemide in guinea pigs. The potentiation of ouabain toxicity after furosemide administration was inhibited by pretreatment with potassium sparing diuretic, prorenoate. Furosemide-induced potentiations of contractile force and arrhythmogenic effect of ouabain were also observed in isolated guinea pig papillary muscle. However after pretreatment with furosemide, ouabain produced arrhythmias without any significant changes in either left ventricular or subcellular fractions binding of 3H-ouabain in guinea pigs. These findings suggest that furosemide-induced potentiation of ouabain toxicity is at least in part associated with the decreased intracellular potassium content of guinea pig heart. It was also demonstrated that the positive inotropic action induced by subtoxic dose of ouabain was potentiated by furosemide in guinea pig papillary muscle preparation.

Cardiotoxic and inotropic effects of ouabain on atria isolated from rabbits of different ages.

1 In sino-atrial node-right atrial preparations and left atrial preparations obtained from rabbits of different ages (2 to 360 days old), cardiotoxic and inotropic effects of ouabain were compared. Tachyarrhythmias were produced in immature and mature rabbit atria exposed for 6 to 8 min to ouabain (5 x 109(-6) M). The total number of contractions before the arrhythmias developed varied inversely with age (2 to 90 days old). Percentage reductions in the resting membrane potential, overshoot and maximum rate of rise induced by ouabain were greater in mature rabbit atria than in immature rabbit atria. 2 Reduction of Ca2+ in the bathing media suppressed the development of tachyarrhythmias. 3 In electrically-driven left atria isolated from immature and mature rabbits, similar frequency-contractile force curves were obtained, maximum contractions being attained at a frequency of 120/min. Ouabain at 2 x 10(-7) M shifted the curve upward and at 10(-6) M greatly potentiated the contractile force developed at low frequencies (6 to 30/min). Increase in contractions induced by ouabain relative to pre-drug concentrations at a frequency of 60/min were greater in immature rabbit atria (15 days old) but the positive inotropic effect of 2 x 10(-7) M ouabain relative to the effect seen at 10(-6) M was appreciably less. 4 It may be concluded that atria isolated from immature rabbits tolerate higher concentrations of ouabain than those isolated from mature rabbits.

Myocardial effects and pharmacokinetics of digoxin and ouabain in protein-deficient guinea pigs.

Myocardial effects and pharmacokinetics of digoxin and ouabain were studied in male albino guinea pigs fed ad libitum either a 21% (control) or a 5% (low) protein diet for 4 weeks. Dietary protein deficiency was associated with a decrease in body weight gain, ventricular weight, total plasma proteins and plasma albumin, hepatic total and microsomal proteins, cytochrome P-450, and protein:DNA ratios; serum potassium was slightly but insignificantly decreased. No significant differences were found in the following experiments with digoxin and ouabain in control and protein-deficient animals: inotropic effects of ouabain on isolated papillary muscles and left atria; uptake of [3H]ouabain by isolated papillary muscles; ventricular fibrillatory doses of digoxin and ouabain in anesthetized animals and the concentrations of digoxin in plasma and papillary muscles at the onset of ventricular fibrillation in these animals; plasma half-life of digoxin in unanesthetized guinea pigs. It is concluded that although dietary protein deficiency influences several physiological and biochemical parameters it does not alter the myocardial effects and pharmacokinetics of digoxin and ouabain in guinea pigs.

Direct positive chronotropic and inotropic effects of ouabain in the isolated and blood-perfused canine atrium.

Using isolated, blood-perfused canine atrial preparations the effects of ouabain on sinus rate and contraction were investigated in 20 preparations. A continuous infusion of ouabain (1 microgram/min) usually induced a significant increase in sinus rate but occasionally a slight but no significant decrease followed by a clear increase, and then finally decrease followed by atrial arrest. On the inotropy, ouabain induced only distinct positive inotropic effect from the earlier stage, and the time to the maximum positive inotropic effect was much earlier than that to the maximum chronotropic effect. The positive chronotropic effect of norepinephrine was not affected by ouabain in the dose for inducing marked positive inotropic effect. On the other hand, the positive inotropic effect of norepinephrine was suppressed in percent changes by ouabain but not abolished. The negative chronotropic and inotropic effects of ACh were not significantly affected by ouabain in the dose for inducing marked positive inotropic effect. During atrial arrest by ouabain infusion, distinct staircase phenomenon disappeared. In this condition, atrial muscle responded more readily to higher frequencies of electric pacing (above 2 Hz) than to lower frequencies (under 1 Hz).

Effect of digitalis on left ventricular function in exercising dogs.

The effect of ouabain on left ventricular function in nonfailing hearts was assessed in 14 chronically instrumented dogs during graded treadmill exercise. At rest, ouabain increased the maximum first derivative of the left ventricular pressure (dp/dtmax) and stroke volume by 38% and 16%, respectively. No change occurred in end-diastolic left ventricular diameter or peak systolic left ventricular pressure. During exercise, ouabain reduced maximum running speed and limited the increments in heart rate and systolic pressure but did not alter dp/dtmax, stroke volume, or end-diastolic diameter. When atropine and ouabain were given and severe exercise was performed, there were no differences from controls in running speed, heart rate, dp/dtmax, or other parameters. When ouabain and propranolol were given dp/dtmax increased at rest and during exercise, compared with results with propranolol alone. It is concluded that the inotropic effect of ouabain is negligible during strenuous physical activity because of the presence of high levels of sympathetic stimulation. However, during exercise in the presence of beta-adrenergic blockade, increases in myocardial contractility do occur in response to ouabain.

Inhibitory effect of taurine on decrease in the inotropic action of ouabain at high concentrations in isolated atria

In vitro, taurine was shown to inhibit the decrease in the inotropic effect of ouabain at large doses in the normal and also low K+ medium in which this decrease in the inotropism of ouabain was facilitated. This inhibitory effect of taurine was, at least in part, due to the inhibition of the efflux of intracellular K+ in the isolated heart.

Antagonistic effect of morphine on the positive inotropic response of ouabain on the isolated rabbit heart.

The antagonistic effect of morphine on the positive inotropic response of ouabain was studied in 96 isolated rabbit hearts, using a modified Langendorff preparation. Decreased calcium (Ca) in the perfusate resulted in increased depression of peak left ventricular dP/dt by morphine (10(-4) gm/ml), and the number of beats required to reach the depression was proportionally reduced with the reduction of calcium chloride from 2.16 mM to 0.54 mM. Likewise, the positive inotropic effect of ouabain (10(-6) gm/ml) was proportionally reduced by the same reduction of calcium chloride concentration in the perfusate, but the number of beats required to reach the cardiotonic effect was proportionally increased with Ca deficiency. The opposing effects of ouabain and morphine were mutually antagonistic regardless of the order of drug administration. When the hearts had been previously exposed to morphine, ouabain stimulation was no longer beat-dependent. Following prior exposure to ouabain, the beat-dependency of morphine depression on the heart also was partially antagonized. These results suggest that the level of maximal dP/dt during morphine depression or ouabain stimulation is directly related to the extracellular concentration of Ca. The number of beats required to attain the depression or stimulation is probably a reflection of the rate at which equilibrium is established between the mobile fraction of extracellular and intracellular Ca, since transmembrane movement of Ca is believed to occur during each beat. A possible common site of morphine and ouabain effect may be the cellular membrane, where ionic flux occurs.

Sodium dependence of the rate of onset of the ouabain-induced positive inotropic effect on cardiac muscle.

WORK on squid axon1 has shown a requirement for external Na for the ouabain-induced Na efflux inhibition, for when Na was replaced by choline chloride the rate of Na efflux inhibition was greatly reduced. It is possible that the positive inotropic effect of ouabain on cardiac muscle is connected with its action on the Na + K activated ATPase involved in the transport of Na2,3. It has been shown4 that the extent of the positive inotropic effect on guinea-pig heart is reduced by lowering the concentration of Na and, in atrial muscle5, this reduces the rate of onset of the ouabain-induced toxic action. I have therefore investigated the effect of decreasing the external concentration of Na on the rate of onset of the ouabain-induced positive inotropic effect. Because the experiments were carried out in conditions which keep the contraction strength far from maximum6, the effect was particularly marked.

Influence of reserpine, heart failure, and immunosympathectomy on the cardiac effects of ouabain.

A possible relationship between myocardial noradrenaline and the cardiac effects of ouabain has been investigated. Pretreatment with reserpine, with or without acute adrenalectomy, failed to reduce the positive inotropic effect of ouabain in cats. Similarly, reserpine did not reduce the positive inotropic effect of ouabain in cats which had developed congestive heart failure from chronic pulmonary artery stenosis and which had approximately 40% of the normal amount of myocardial noradrenaline. The positive inotropic effect of ouabain on isolated papillary muscles from reserpine-treated rabbits and on the isolated left atria from reserpine-treated rats or rats with immunosympathectomy was also normal. Depletion of myocardial noradrenaline did not influence the toxicity of ouabain except in cats with congestive heart failure. In these cats, pretreatment with reserpine increased the arrhythmic and the lethal dose of ouabain. Reserpine or immunosympathectomy produced a marked depletion of myocardial noradrenaline stores. It is concluded that the positive inotropic effect of ouabain is not due to a release of noradrenaline from the heart. The mechanism by which pretreatment with reserpine reduces the toxicity of ouabain in cats with congestive heart failure is not clear. It may or may not be due to a depletion of myocardial noradrenaline.

Inotropic Effects of Ouabain on Rabbit Left Atria in Presence of Beta-Adrenergic Blocking Drugs.

SummaryThe positive inotropic effects of ouabain on electrically driven rabbit left atrial preparations was studied in the presence of 3 drugs known to be potent and specific beta-adrenergic receptor antagonists (pronethalol, propranolol and MJ-1999). Ouabain alone (6.9 × 10-7 M) produced a highly significant increase in contraction force compared to untreated controls. Pronethalol (3.76 × 10-6 M) and propranolol (1.35 × 10-6 M) were found to produce significant decreases in contraction force. The methanesulfonanilide substituted isopropylphenylethylamine (MJ-1999) had no significant effects on contraction force in a concentration of 1.3 × 10-5 M. Administering ouabain after pretreatment with and in the presence of either pronethalol, propranolol, or MJ-1999 failed to modify significantly the normal positive inotropic effect of the glycoside. Therefore, no evidence was found to indicate that beta-adrenergic receptor blockade could prevent the positive inotropic effect of ouabain on isolated rabbit left atria.

Positive inotropic action of ouabain on rat ventricle strips.

SummaryA positive inotropic effect of ouabain has been demonstrated on the rat ventricle strip. At a given ouabain concentration the magnitude of the response was quite uniform. The effects of variation in the concentration of ouabain, calcium, and phosphate, and in initial tension on the positive inotropic response have been investigated.