Dog Heart-lung Preparation Research Articles

Cardiac Effects of Tyramine

The cardiac effects of tyramine ( p -hydroxyphenylethylamine) were studied in 22 dog heart-lung preparations. In six uncontrolled rate preparations, tyramine 250 to 500 µg. increased the heart rate an average of 21 per cent. In controlled rate preparations, tyramine 100 to 250 µg. consistently increased ventricular contractile force, cardiac output, and blood pressure; there was a consistent decrease of right and left atrial pressures. Comparable hemodynamic effects were produced by 1 to 2.5 µg. of levarterenol, except that the effects of tyramine tended to be of longer duration and were less likely to be followed by cardiac depression. It is concluded that tyramine has significant positive inotropic and chronotropic effects in the dog heart-lung preparation. In three animals pretreated with reserpine, tyramine had little effect. Its action appears to depend to a large extent upon the presence of myocardial catecholamines.

Factors Influencing Pulmonary Hypertensive Response to 5-Hydroxytryptamine

The pulmonary hypertensive response to 5-HT in the dog heart-lung preparation is largely due to pulmonary vasoconstriction. There is an unexpected fall in aortic blood flow but no rise in left atrial pressure. In intact dogs the pulmonary hypertensive response is accompanied by an increase in pulmonary blood flow which is in turn partly reduced by upper thoracic sympathectomy. It is suggested that the rise in pulmonary blood flow is partly a sympathetic reflex initiated by pulmonary vasoconstriction by 5-HT.

Effects of two rapid acting cardiac glycosides on dog's heart-lung preparation.

AbstractThe effects of two rapid acting cardiac glycosides, convallatoxin and acetyl strophanthidin, were investigated on heart lung preparations of dog. The positive inotropic effect, the ‘electrolyte’ effect (induction of cellular potassium loss), and the ‘toxic’ effect (induction of tachycardia and arrhythmia) were studied with special regard to magnitude and time course of response. Changes of plasma pH in the HLP were caused by changes of Pco2 in the inspired air. A difference was found between convallatoxin and acetyl strophanthidin. For acetyl strophanthidin, the magnitudes of the electrolyte and the inotropic effects showed positive correlation in different preparations; for convallatoxin, the inotropic effect tended to decrease with an increasing electrolyte effect. This difference in action between the glycosides supports the theory that the mechanisms for their inotropic and electrolyte effects are separate. Another difference between the two glycosides was that acetyl strophanthidin had an inotropic optimum at a lower plasma pH level than convallatoxin. The result further suggests that the electrolyte and the ‘toxic’ effects are related, at least more so than the electrolyte and the inotropic effects.

Direct cardiac effects of dopamine.

The cardiac effects of dopaminie, an epinephrine precursor, were studied in 20 dog heart-lung preparations. In 8 uncontrolled rate preparations. dopamine, 0.5 to 1 mg., increased the heart rate an average of 18 pet cent. In controlled rate preparations. dopamine, 100 to 500 µg ., consistently increased ventricular contractile force, cardiac output and blood pressure; there was a consistent decrease of right and left atrial pressure. Comparable hemodynamic effects were produced by 1 to 5 µg . of levarterenol, except that the effects of dopamine tended to be of longer duration and were less likely to be followed by cardiac depression. It is concluded that doparnine has significant positive inotropic and chronotropic effects in the dog heart-lung preparation.

Stellate ganglion stimulation and performance of dog heart-lung preparation.

Observations were made on the changes in cardiac function in the dog heart-lung preparation, brought about by stimulation of the left stellate ganglion, and were compared with observations obtained when the heart was driven by an artificial pacemaker, as well as with changes produced by epinephrine administration. During left stellate ganglion stimulation, cardiac output increased approximately 79%; stroke volume showed a mean increase of 55%, whereas the heart rate had a mean increase of 19%. When the heart was driven by an artificial pacemaker, cardiac output showed no change; heart rate had a mean increase of 28%. The stroke volume, on the other hand, decreased 22% below the control value. It is concluded that left stellate ganglion stimulation in the dog heart-lung preparation causes significant increases in both the stroke volume and heart rate.

Structure-activity relationships in a series of 6-thioxanthines with bronchodilator and coronary dilator properties.

The bronchodilator activity of 47 compounds on the isolated guinea-pig tracheal ring preparation and the coronary dilator activity on the dog heart-lung preparation is described. 1,3-Disubstituted xanthines and 6-thioxanthines (theophyllines and 6-thiotheophyllines) were more active as bronchodilators and as coronary dilators than were 3,7-disubstituted 6-thioxanthines (6-thiotheobromines) or 1,3,7-trisubstituted 6-thioxanthines (6-thiocaffeines). None of the 6-thioxanthines was of any interest as a diuretic and none of the 6-thiocaffeines was of any interest as a central stimulant. Structure-activity requirements for potent bronchodilator and coronary dilator activity are discussed.

The effect of mephentermine on isolated dog hearts, normal and pretreated with reserpine.

The inotropic activity of the non-catechol sympathomimetic amine, mephentermine sulphate, on the failing dog heart-lung preparation, was 1/10 to 1/20 that of adrenaline. Mephentermine showed no inotropic effect on preparations from animals pretreated with reserpine. The chronotropic and "calorigenic" actions of mephentermine were tested on modified heart-lung preparations to permit a more accurate measurement of coronary flow, and were found to be greater than its inotropic effect relative to adrenaline. Furthermore, the action of mephentermine was longerlasting than that of adrenaline. If adrenaline was infused 15 min after the termination of mephentermine administration and when the action of the latter was still at a maximum, a further increase in heart rate and especially oxygen consumption was observed. In preparations from dogs treated with enough reserpine to deplete the heart of noradrenaline, mephentermine had only slight chronotropic and calorigenic actions. However, further addition of adrenaline after a 15 min pause caused a rise in heart rate, oxygen consumption, and coronary flow which almost duplicated the additive effects of both amines on the preparations not treated with reserpine. It would appear that adrenaline acted on its own and in addition "restored" the action of mephentermine on the reserpinized preparations. The action of adrenaline alone on reserpinized preparations was not increased compared with that on normal preparations. These observations are relevant to a consideration of the mechanism of action of non-catechol sympathomimetic amines on the heart, and are in harmony with the concept that mephentermine, a non-catechol amine, requires the presence of added or stored catechol amines for its action. Reserpine treatment did not alter the mechanical efficiency of the heart despite its depletion of noradrenaline.

A comparison of the pharmacology of two potent analgesic agents, piminodine (Win 14,098-2) and Win 13,797, with morphine and meperidine

The toxic and lethal effects of piminodine and Win 13,797 were studied in mice, dogs, and monkeys. The analgesic actions of both drugs were tested in mice and rats and were found to be more potent than morphine. Vascular studies on pimincdine and Win 13,797 have shown peripheral vasodilation and acute vascular tolerance to the hypotensive effect in dogs with partial crossed tolerance to morphine. Dogs anesthetized with pentobarbital were sensitive to the respiratory depressant actions of these drugs. Nalorphine readily antagonizes this respiratory depression. Piminodine and Win 13,797 are myocardial depressants on the dog heart-lung preparation and the cat papillary muscle, but only in doses or concentrations much higher than would be used therapeutically. The actions of piminodine and Win 13,797 on the isolated rabbit jejunal segment are minimal. The qualitative actions of piminodine and Win 13,797 on EEG effects in dogs with chronically implanted electrodes were like those of morphine. Quantitatively, Win 13,797 was equipotent to morphine, and piminodine one-half as effective. Studies on single-dose suppression in monkey and primary physical dependence in dogs and monkeys indicate that piminodine and Win 13,797 have high addiction liability at least in these species. Nearly all the administered piminodine or Win 13,797 is altered chemically when injected into dogs. There is no evidence for marked local tissue deposition for either drug.

Cardiac actions of methoxamine with special reference to its antagonistic action to epinephrine.

The cardiac action of large doses of methoxamine and its antagonistic action to epinephrine were studied, using a dog heart-lung preparation. In doses of 4 mg. and above, methoxamine showed a marked negative inotropic action, while it produced only a slight decrease in the heart rate. Pretreatment of animals with 0.1 mg./Kg. of reserpine did not modify the inotropic action, but the decrease in the heart rate disappeared. Simultaneous with these changes, a decrease in the coronary flow and a rise of the pulmonary arterial pressure were observed. Methoxamine in doses of 1 mg. and more abolished both the positive inotropic and the positive chronotropic actions of epinephrine. The negative inotropic action of methoxamine was ascribed to a nonspecific, as yet undetermined mechanism, and the antagonistic action was ascribed to the competitive antagonism at the receptor site (thus methoxamine may be looked upon as a blocking agent of adrenergic β receptor). The weak negative chronotropic action was taken to be an expression of the blockade of the humoral effects of the intrinsic sympathomimetic amines.

Thioxanthines with potent brochodilator and coronary dilator properties.

Some of the pharmacological properties of two new compounds, choline 6-thiotheophyllinate and the choline salt of 3-isobutyl-1-methyl-6-thioxanthine (M&B 5924), are described. Both these 6-thioxanthines are structurally related to theophylline and pharmacologically they are very similar to that compound, the main differences in their actions being essentially quantitative. They were more potent than choline theophyllinate as bronchodilators on the isolated guinea-pig tracheal ring preparation and as coronary dilators on the dog heart-lung preparation. Choline 6-thiotheophyllinate was about as effective as its oxygen analogue in protecting guinea-pigs against the lethal effects of a bronchoconstrictor aerosol; M&B 5924 was more effective in this respect, but the relative bronchodilator activity was much less than on the isolated preparation. Both thioxanthines were less potent than choline theophyllinate as diuretics. One outstanding qualitative difference in their properties was in their effect on the voluntary motor activity of mice; choline theophyllinate in low doses was stimulant whereas the thioxanthines were either inactive at low doses or sedative at higher doses. In dogs, on the other hand, there were indications that M&B 5924 had a stimulant action.

The effects of veratramine on atrio-ventricular nodal rhythm and on auricular flutter in the dog heart-lung preparation

A-V nodal rhythm was established in the dog HLP by crushing the S-A node. The resulting mean decrease in heart rate was 100 beats/min. Ephedrine, in doses up to 3 mg increased the A-V nodal rate to the mean maximal rate of 187 beats/min. This represents a mean maximal acceleration of 140 beats/min. The log dose-response curves for ephedrine acceleration during S-A rhythm and A-V rhythm are similar. The ED50 in both cases is about 0.2 mg.

Effect of guanethidine and bretylium on the dog heart-lung preparation.

Inotropic and chronotropic effects of guanethidine and bretylium have been observed in heart-lung preparations made from normal and chronically reserpinized dogs. Guanethidine (0.3 to 30 mg.) in the untreated preparation had marked positive inotropic and chronotropic effects, whereas after pretreatment with reserpine it had a striking negative inotropic effect and no effect on heart rate. Guanethidine given to preparations made from animals pretreated with guanethidine had a negative inotropic effect smaller than that seen after reserpine pretreatment. Bretylium (0.3 to 30 mg.) in the untreated preparation had both positive inotropic and positive chronotropic effects. In the chronically reserpinized animal, the positive inotropic effect of bretylium persisted though it was reduced to about one-quarter of the original size. The positive chronotropic effect of bretylium in this circumstance was reversed to a negative chronotropic effect. These effects are interpreted as indirect but strong evidence that: (1) guanethidine and bretylium exert at least part of their initial positive inotropic and chronotropic effects by a release of catecholamines; and (2) in the amine-depleted heart, guanethidine has an intrinsic negative inotropic effect, whereas bretylium has an intrinsic positive inotropic effect.

1,3-Dialky1-6-thioxan-thines: a new series of bronchodilators and coronary vasodilators.

1,3-DIMETHYLXANTHINE (theophylline) is readily converted into the corresponding 6-thio derivative by treatment with phosphorus pentasulphide in pyridine. The choline salt (M. and B. 4926A) of this derivative is more active than choline theophyllinate in relaxing the bronchial muscle (guinea pig tracheal ring preparation) and in dilating the coronary vessels (dog heart-lung preparation). This result led us to prepare and examine a series of homologous compounds, the most active in these two respects being 3-isobutyl-1-methyl-6-thioxanthine (M. and B. 5924).

Investigation of the mechanism of the hemodynamic effects of ganglionic blockade produced by mecamylamine

Preceding investigations have demonstrated, in general, a decrease in cardiac output and an increase in peripheral resistance after the administration of ganglionic blocking agents. 1–3 Mecamylamine has been shown to have hemodynamic effects similar to ganglionic blocking agents used previously. 4 It has not been established, however, whether the effects of these agents are due purely to the reduction in cardiac filling pressure secondary to peripheral pooling of blood, 3–5 or whether additional factors, such as a decreased discharge from the sympathetic nervous system, are significant as a mechanism of the decreased output. 6 Submersion of the human subject in water after the administration of hexamethonium bromide restored the arterial blood pressure nearly to control values, but no data on cardiac output was recorded during this experiment. 7 In the dog heart-lung preparation or isolated papillary muscle strip, hexamethonium produces an increased force of myocardial contraction; hence, it seems that a direct depressant effect on the myocardium is not likely from this agent. 8,9 Mecamylamine, on the other hand, is reported to decrease contractility of heart muscle strips in vitro. 10 The present report describes a series of experiments designed to test the hemodynamic effect of increasing the central venous pressure after the production of ganglionic blockade.

Relationship between cardiac toxicity of K and acute alterations of blood pH and pCO2.

Dog heart-lung preparations were studied to determine the relationship between the toxicity of elevated potassium and the blood pH and pCO2. During hyperkalemia, a) a change from hypercapneic acidosis to hypocapneic alkalosis produced electrocardiographic deterioration after a delay of 3–5 minutes; cardiac function improved during alkalosis until ECG deterioration occurred; b) increase of pH produced by hypertonic bicarbonate infusion during hypercapnia improved mechanical performance; ECG also improved, even when pCO2 was later decreased; c) infusion of hypertonic NaCl during hypercapnia partially prevented ECG deterioration after reduction of pCO2. These experiments indicate that potassium toxicity is aggravated by acute reduction of pCO2. This may not be due solely to the change in pH, since similar pH increase from bicarbonate infusion did not make the ECG worse. Reduction of [Ca++] by pH increase is not the cause of ECG deterioration; if it were, ECG should be more affected in bicarbonate and NaCl infusion experiments than in the others. The cause of ECG deterioration with reduction of pCO2 remains unknown.

The uptake of radioactive beta-carotene in the dog heart-lung preparation.

The uptake of radioactive beta-carotene in the dog heart-lung preparation.

THE EFFECTS OF ADRENALINE AND NORADRENALINE ON THE METABOLISM AND PERFORMANCE OF THE ISOLATED DOG HEART

In 16 dog heart-lung preparations modified to permit a more accurate measurement of coronary flow, adrenaline or noradrenaline was infused at a rate of 4 mug. base/min. After a 30-min. pause during which the increased oxygen consumption and heart rate, but not the coronary flow, returned to pre-infusion levels, the other sympathomimetic amine was infused for the same length of time. It was found that, mole per mole, noradrenaline is as effective, and probably more so, than adrenaline in raising the oxygen consumption of the heart-lung preparation. The positive chronotropic and coronary dilating action of both amines appear to be equal. It was observed that in any one experiment the second dose of the sympathomimetic amine was slightly more effective than the first dose in raising the oxygen consumption. The level of high-energy phosphorus compounds does not change after adrenaline or noradrenaline administration even at the time when the oxygen consumption rises to as much as 200%. During this period there are no signs of cardiac hypoxia, as can be judged by the good oxygen saturation of coronary venous blood. Single doses of 5 mug. adrenaline or noradrenaline have a consistent positive inotropic effect that lasts about 15 min. when tested on a failing heart. In 12 experiments on non-failing modified heart-lung preparations, a single dose of 5 mug. adrenaline fails to cause a measurable increase in oxygen consumption after 1, 3, 6, or 11 min. in spite of a mild positive chronotropic action. The significance of these findings is discussed and the suggestion made that, when noradrenaline infusions are effective in treating cardiogenic shock in man, part of this effect may be due to its positive inotropic action, thus correcting an element of heart failure that might exist.

Electrocardiographic changes due to varied work loads in dog heart-lung preparations.

Electrocardiographic changes due to varied work loads in dog heart-lung preparations.

A STUDY ON THE MECHANISM OF THE HEART FAILURE INDUCED BY PENTOBARBITAL, QUININE, FLUOROACETATE AND DINITROPHENOL IN DOG’S HEART-LUNG PREPARATION AND EFFECTS OF SYMPATHOMIMETIC AMINES AND OUABAIN ON IT

Recently, there has been much discussion about a hypothesis that there are two kinds of experimental heart failures, namely the one caused by impaired utilization of energy and the other by impaired libera, ion of energy (1-5). Spontaneous failure and many druginduced failures belong to the former group, and such failures induced by metabolic inhibitors belong to the latter. It was pointed out that, in general, cardiac glycosides are effec, ive in the first group of failures, but not in the second, suggesting that the mechanisms of failure are different from each other. In the present study, the authors reinvestigated this problem systematically, using dog's heart-lung preparation.

Ouabain-induced ventricular tachycardia and its effect on the performance and metabolism of the dog heart.

At constant pressure work there was an increase in the oxygen consumption of the dog heartlung preparation after tachycardia due to auricular stimulation and a far greater increase in consumption after ouabain-induced ventricular tachycardia, as compared with control hearts beating at their own sinus rhythm. In neither condition was the increase in coronary flow greater than the spontaneous increase in the controls. It is suggested that an increase in oxygen demand, under certain circumstances, may be met primarily by an increased desaturation of coronary blood. "Therapeutic" doses of ouabain did not improve the mechanical efficiency of the preparation. "Toxic" doses of ouabain which gave rise to ventricular tachycardia did not decrease the phosphocreatine or labile nucleotide phosphorus content of the heart provided there was no hypoxia of the heart muscle.