Starling Heart-lung Preparation Research Articles

Cardiovascular physiology: simulation of steady state and transient phenomena by using the equivalent electronic circuit

By using commercially available software it is readily possible to design electronic circuits and to analyze them. By introducing the concept of equivalent quantities a simulation of various physiological phenomena is possible. This includes the steady state as well as various complex transient phenomena. This paper describes the use of an equivalent electronic circuit in simulating the cardiovascular system. It allows a stepwise upgrading. The first step is a one-ventricle circuit similar to the Starling heart-lung preparation. The final step is an equivalent circuit allowing simulation of various normal as well as pathological states (e.g. effects of heart rate, negative intrathoracic pressure, exercise, hemorrhage, heart failure, and hypertension). The degree of disturbance can be set by adjusting the value of single components. Following this, the optimal type of compensation (e.g. the increase in blood volume in failure of the right ventricle; systemic venoconstriction in failure of the left ventricle) of the basic disturbance can be searched for, activated and the consequences studied. The described approach has been found a useful tool in teaching physiology and pathophysiology for postgraduate medical students.

Effect of dexmedetomidine, an α2-adrenergic agonist, in the isolated heart

Dexmedetomidine (DM) was studied in the isolated dog heart in the form of a Starling heart-lung preparation, (HLP). Hearts were subjected to increased loading by (a) increasing cardiac output, and (b) increasing systemic resistance. Results are depicted by cardiac function curves, prepared by plotting left atrial pressure against either systemic cardiac output or mean arterial pressure. DM, given in divided doses up to 44 μg, had no effect on heart rate or cardiac function, nor did injection of 0.5 mg of atipamezole, a selective alpha 2-antagonist. Additional injections of very large doses of DM, up to 4,444 μg, caused an increase in heart rate and a leftward shift of the function curves, ie, positive chronotropic and inotropic effects. Plasma catecholamine levels increased markedly between the 444 μg and the 4,444 μg cumulative doses of DM. Administration of 1 mg of prazosin had no effect, but 1 mg of propranolol returned the rate to baseline and markedly shifted function curves to the right and depressed their slopes. Thus, whereas low doses (corresponding to between 1 and 30 wg / kg in intact animals) of DM, given acutely IV, have been shown to depress cardiac function in intact and denervated dogs, this effect is not due to a direct effect on the myocardium. High doses, far beyond doses maximally effective in intact animals and man, release catecholamines from cardiac stores. Plasma DM levels after low doses in the HLP were between 1 to 10 times those seen in intact animals and human volunteers after the usual doses given clinically for their central effects. Because DM caused no myocardial depressant effect in the isolated, blood-perfused canine HLP, decreases in cardiac function seen after this drug is given to intact and autonomically denervated dogs must be due to factor(s) other than a direct action on the myocardium.

ChemInform Abstract: 7-Heteroaryl-1,2,3,5-tetrahydroimidazo(2,1-b)quinazolin-2(1H)-one Derivatives with Cardiac Stimulant Activity.

A series of 7-heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin++ +-2 (1H)-ones was synthesized and evaluated in dogs for cardiac stimulant activity. Compounds were obtained by a palladium-catalyzed cross-coupling reaction between a heteroarylzinc chloride and a 7-iodo-1,2,3,5-tetrahydroimidazo [2,1-b]quinazolin-2(1H)-one or by cyclization of an N-[(2-aminophenyl)methyl]glycinate with cyanogen bromide. Compared to the parent ring system (3), introduction of a 2,6-dimethylpyridin-3-yl (6), 2,4-dimethylimidazol-1-yl (7), or 1,2,4-triazol-1-yl (8) moiety at the 7-position led to a 13-17-fold increase in positive inotropic activity (percentage increase in dP/dtmax) in anesthetized dogs. Potency could be further enhanced with a 9-methyl substituent (10-12). The most potent member of the series, 7-(2,4-dimethylimidazol-1-yl)-9-methyl-1,2,3,5-tetrahydroimidaz o [2,1-b]quinazolin-2(1H)-one (11) (23% increase in dP/dtmax, 2 micrograms/kg), was 80 times more active than 3 and displayed a 5-fold advantage over milrinone. In conscious dogs, 6 elicited marked and sustained positive inotropic activity (decrease in QA interval) after oral administration (1 mg/kg), whereas 10-12 were 10 times more potent. 11 produced an obvious increase in cardiac contractility (20% increase in dP/dtmax) at low dose levels (25 micrograms/kg) while, after 100 micrograms/kg, the marked response (50% increase in dP/dtmax) was maintained for the whole 7-h test period. In these experiments, 11 had no effect on heart rate, and the compound also displayed exceptional selectivity for increasing the force rather than the rate of cardiac contraction (greater than 150% increase in dP/dtmax) in the Starling heart-lung preparation. These studies demonstrate that the tetrahydroimidazoquinazolinone nucleus is an effective bioisostere for the 2(1H)-quinolinone system and that 11 displays improved cardiac stimulant activity and duration of action when compared to milrinone.

7-Heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin -2(1H)-one derivatives with cardiac stimulant activity.

A series of 7-heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin++ +-2 (1H)-ones was synthesized and evaluated in dogs for cardiac stimulant activity. Compounds were obtained by a palladium-catalyzed cross-coupling reaction between a heteroarylzinc chloride and a 7-iodo-1,2,3,5-tetrahydroimidazo [2,1-b]quinazolin-2(1H)-one or by cyclization of an N-[(2-aminophenyl)methyl]glycinate with cyanogen bromide. Compared to the parent ring system (3), introduction of a 2,6-dimethylpyridin-3-yl (6), 2,4-dimethylimidazol-1-yl (7), or 1,2,4-triazol-1-yl (8) moiety at the 7-position led to a 13-17-fold increase in positive inotropic activity (percentage increase in dP/dtmax) in anesthetized dogs. Potency could be further enhanced with a 9-methyl substituent (10-12). The most potent member of the series, 7-(2,4-dimethylimidazol-1-yl)-9-methyl-1,2,3,5-tetrahydroimidaz o [2,1-b]quinazolin-2(1H)-one (11) (23% increase in dP/dtmax, 2 micrograms/kg), was 80 times more active than 3 and displayed a 5-fold advantage over milrinone. In conscious dogs, 6 elicited marked and sustained positive inotropic activity (decrease in QA interval) after oral administration (1 mg/kg), whereas 10-12 were 10 times more potent. 11 produced an obvious increase in cardiac contractility (20% increase in dP/dtmax) at low dose levels (25 micrograms/kg) while, after 100 micrograms/kg, the marked response (50% increase in dP/dtmax) was maintained for the whole 7-h test period. In these experiments, 11 had no effect on heart rate, and the compound also displayed exceptional selectivity for increasing the force rather than the rate of cardiac contraction (greater than 150% increase in dP/dtmax) in the Starling heart-lung preparation. These studies demonstrate that the tetrahydroimidazoquinazolinone nucleus is an effective bioisostere for the 2(1H)-quinolinone system and that 11 displays improved cardiac stimulant activity and duration of action when compared to milrinone.

2(1H)-Quinolinones with cardiac stimulant activity. 3. Synthesis and biological properties of 6-imidazol-1-yl derivatives

A series of 6-imidazol-1-yl-8-methyl-2(1H)-quinolinones was synthesized and evaluated for cardiac stimulant activity in dogs. The majority of compounds were prepared from an appropriate 6-imidazol-1-yl-2(1H)-quinolinone precursor or by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide. Introduction of a range of 5-substituents into 6-(2,4-dimethylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (1) reduced inotropic activity in anesthetized dogs (percentage increase in dP/dtmax) although replacement of the 2-methyl group by iodo (10) or cyano (11) substituents was well tolerated. The 2-methyl-4-chloro (15) and 2-methyl-4-(methylthio) (22) derivatives displayed similar potency to 1 (40-50% increase in dP/dtmax, 10-12.5 micrograms/kg) and these compounds were 3-5 times more potent than milrinone. Introduction of iodo (14), cyano (16), or acetyl (17) substituents into the 4-position approximately halved inotropic activity. In conscious dogs, 11 (0.25 mg/kg) and 16 and 17 (0.125 mg/kg) produced similar increases in cardiac contractility (decrease in the QA interval) to 1 (0.125 mg/kg) and maximum responses were maintained for at least 3 h. Dose-related (25, 125, 250 micrograms/kg) cardiac stimulant activity was demonstrated by 17 and after the higher doses a marked response (approximately 30% increase in dP/dtmax) was still observed after 7 h, in contrast to milrinone. The substantial increases in cardiac contractility observed with 16 and 17 in the conscious dog were not accompanied by any tachycardia. These compounds also displayed an overwhelming selectivity for increasing the force of cardiac contraction (greater than 120% increase in dP/dtmax) rather than heart rate (5-10 beats/min decrease) in the Starling heart-lung preparation. As a result of this beneficial pharmacological profile, 6-(4-acetyl-2-methylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (17, UK-66,838) was selected for preclinical development studies.

Functional and metabolic features of an isolated perfused guinea pig heart performing pressure-volume work.

Cardiac performance and some parameters of glycolytic and oxidative metabolism were analyzed in isolated perfused guinea pig hearts performing pressure-volume work. Perfusion medium was an oxygenated Krebs-Henseleit bicarbonate buffer (pH 7.4) which contained glucose and physiological concentrations of pyruvate and insulin. The pressure-flow relationship in the coronary vascular bed indicated autoregulation of coronary flow. Left ventricular function was influenced by aortic pressure (Pa) and venous filling pressure (Pv) in accordance with the Frank-Starling principle, i.e. stroke work increased as a function of Pa or Pv to a certain maximum and then decreased. Myocardial oxygen consumption (MVO2), on the other hand, was linearly correlated with Pa and Pv, respectively, over the entire pressure range. Efficiency of the left ventricle, therefore, increased to an optimum (16%) and decreased at higher pressures. Myocardial contents of glycogen, ATP and creatine phosphate were not markedly influenced by a change in Pa or Pv. L-Noradrenaline (0.08 micrometer, NA) stimulated stroke work and MVO2 at a all Pv tested; efficiencies reached physiologic values (21%) at high volume loads. The increased MVO2 was associated with an acceleration of pyruvate decarboxylation and lactate release up to 10- and 15-fold, respectively, at elevated but physiological NA concentrations (0.2 micrometer). Our results demonstrate that the isolated perfused working guinea pig heart compares favourably with the non-failing Starling heart-lung preparation and hearts in situ, as far as coronary function, left ventricular performance and oxidative metabolism are concerned.

The cardiodynamic and metabolic effects of glucagon.

The cardiac effects of a continuous infusion of glucagon at the rate of 10 mug/min were studied in the Starling heart-lung preparation, modified to measure coronary flow and myocardial oxygen consumption. A maximal increase in myocardial contractility, as reflected by maximal rate of rise of left ventricular pressure, dp/dt, of 31% was observed at a total dose of glucagon of 50 mug and was accompanied by an increase in heart rate and in myocardial oxygen consumption of 59% and 57%, respectively. At a total dose of glucagon of 100 mug, there was an additional and comparable increase only in heart rate and myocardial oxygen consumption of 11.2% and 6.4% respectively. Similarly, at a total dose of glucagon of 150 mug, only heart rate and myocardial oxygen consumption increased additionally by increments of 2.6% and 2.9% respectively. These effects occurred at constant aortic pressure and left ventricular volume. Further infusion of glucagon led to an additional increase only in myocardial oxygen consumption of 4.2%. When the increase in heart rate was largely prevented by prior treatment with veratramine, an increase in dp/dt, not significantly different from the maximal increase obtained with glucagon alone, was accompanied by much lower and closely comparable increases in heart rate and in myocardial oxygen consumption of 15% and 19%, respectively. Coronary flow increased more markedly when glucagon was administered alone and it paralleled the increase in myocardial oxygen consumption. It may be concluded from this study that, in the isolated dog heart preparation, glucagon increases contractility, heart rate and myocardial oxygen consumption and that the increase in myocardial oxygen consumption is related more closely to the increase in heart rate than to the increase in contractility, but a minor increment is referable to a calorigenic action. The increase in coronary flow is of a secondary nature, resulting from the increase in myocardial metabolic demands.

The metabolic effect of noradrenaline on the isolated canine heart after blockade of the chronotropic action by veratramine

The present study was undertaken to explore the relationship between noradrenaline-induced increases in myocardial contractility, as reflected by the maximal rate of rise of left ventricular pressure, dp/dt, and myocardial oxygen consumption in the nonfailing Starling heart-lung preparation, modified to measure coronary flow and in which the cardioaccelerator action of noradrenaline was prevented with doses of veratramine ranging between 3–7 mg (average 5 mg). At constant aortic pressure, heart rate and left ventricular circumference, cumulative doses of noradrenaline of 5 μg, 10 μg, 20 μg and 38.75 μg administered in 5 min, 10 min, 15 min and 20 min respectively, increased the maximal rate of rise of left ventricular pressure by an average of 18%, 29%, 52% and 72% respectively, without a concomitant significant increase in myocardial oxygen consumption. In the same kind of preparation but in which myocardial failure is induced with pentobarbitone no more than a total dose of 5 μg of noradrenaline, administered in 5 min, is needed to effect complete correction of the failure. It may therefore be concluded from this study that a dose of noradrenaline greater than a “therapeutic” dose in the heart-lung preparation, administered to the non-failing preparation in which heart rate and aortic pressure are kept constant, increases contractility without necessarily increasing myocardial oxygen consumption and without at the same time inducing an appreciable change in any of the parameters known to influence myocaridal oxygen consumption.

The effect of theophylline alone and in combination with ouabain on the isolated dog heart

A comparative study of the inotropic effects of theophylline and ouabain as well as a study of the interaction between the two pharmacological agents were carried out in the nonfailing Starling heart-lung preparation modified to permit metabolic studies. Single doses of theophylline ranging between 100 to 200 mg added to the venous reservoir produced consistent increases in myocardial contractile force, as gauged by the maximal rate of rise of left ventricular pressure, dp/dt, 73%; systemic output, 28%; coronary output, 277%; total cardiac output, 41%; heart rate, 27%; left ventricular work, 45% and myocardial oxygen consumption, 43%. In addition, systolic time decreased consistently by 15%. 20 min and 30 min after the onset of an ouabain infusion of 5μg per min, which was started 15 min after the addition of theophylline, there was further increase in dp/dt to 87% and 107%, respectively, with no significant change in the remaining parameters from the levels attained 15 min after the administration of theophylline. As compared to ouabain administered alone, ouabain administered at peak effect of theophylline led to an earlier occurence of ventricular arrhythmias and death. It may be concluded from this study that maximally effective doses of theophylline brought about an increase in dp/dt which is greater than that brought about by maximal “therapeutic” doses of ouabain. Secondly, ouabain administered after the peak effect of theophylline was exerted led to an additional increase in dp/dt implying that the mechanisms underlying the inotropic action of each drug are different. Thirdly, at constant aortic pressure, heart rate, left ventricular enddiastolic and left atrial pressures, ouabain in the presence of theophylline brought about an increase in myocardial contractility, as gauged by an increase in dp/dt, without a concomitant increase in myocardial oxygen consumption, thus confirming earlier results obtained with ouabain alone. Fourthly, ouabain administered at peak effect of theophylline led to an earlier occurrence of ventricular arrhythmias and death.

The effect of endogenous catecholamines and norepinephrine administration on the performance of the isolated canine heart.

The effect of endogenous catecholamines on the ability of the isolated canine heart to handle a volume load was studied in the Starling heart-lung preparation, modified to measure coronary flow and myocardial oxygen consumption. The isolated hearts were subjected to progressively increasing volume loads, and total left ventricular output and oxygen consumption were measured. Four groups of preparations were compared; controls, preparations from reserpine-pretreated dogs (0.5 mg/kg intraperitoneally 48 hrs and again 24 hrs prior to experimentation), preparations treated with 20 mg of pronethalol and preparations infused with norepinephrine (1 Μg/min for the duration of the experiment). The results show that the isolated heart depleted of its catecholamine content, or treated with pronethalol is capable of handling the same maximal volume load as a control heart. Similarly the isolated heart subjected to an infusion of norepinephrine of 1 Μg/min does not handle a bigger maximal volume load than a control heart. One may conclude from these results that in the isolated dog heart, augmentation of myocardial function, which accompanies an increase in volume work, is neither dependent on release of endogenous catecholamines, nor is it promoted by exogenously administered catecholamines.

The effect of ouabain-induced contractility on myocardial oxygen consumption.

The present study was undertaken to explore the relationship between various doses of ouabain, myocardial contractility as reflected by the maximal rate of rise of left ventricular pressure and oxygen consumption, in the canine, nonfailing Starling heart-lung preparation modified to measure coronary flow. Concentrations of ouabain, previously found to be within “therapeutic” limits, as tested in the failing preparation, namely those attained 20 min and 30 min from the start of an infusion of ouabain (5μg/min), increased the maximal rate of rise of left ventricular pressure by an average of 13.4% and 24.2%, respectively, with no concomitant measurable increase in myocardial oxygen consumption. Changes in left ventricular work, left ventricular circumference, left ventricular end-diastolic and left atrial pressures were neither significant nor consistent. Concentrations of ouabain which induced ventricular tachycardia increased the maximal rate of rise of left ventricular pressure and myocardial oxygen consumption by an average of 205.2% and 81.4%, respectively. It may therefore be concluded from these results, that at constant aortic pressure and left ventricular dimensions an appropriate dose of ouabain induces in the isolated nonfailing heart an increase in contractility unaccompanied by a measurable increase in myocardial oxygen consumption.

The direct effects of endotoxin on the heart.

SummaryThe direct effects of gram-negative bacterial endotoxin on the heart were studied, using a Starling heart-lung preparation. The technique was modified so as to have a preparation that was anesthetic free and had a physiologic pH. The data show that endotoxin does not have a depressant action on the heart but that it did delay the onset of cardiac failure in this preparation. Such a phenomenon may be due to a weak supportive action of endotoxin on the heart which can only be detected in the absence of anesthetics, since anesthetics generally depress the heart. A possible explanation for such a phenomenon is offered.

The mechanical efficiency of the Starling heart-lung preparation.

1. The Starling heart-lung preparation, from mongrel dogs has been modified by cannulating the aorta with the intent of improving the output and mechanical efficiency of the left ventricle. 2. A specially devised cannula served the dual purpose of perfusing the lungs and collecting right ventricular output, representing 90% of coronary flow. 3. An average maximal left ventricular output of 4.1±0.28 l. (S.E. of mean) and efficiency of 24.7±3.2% (S.E. of mean) was obtained in the new preparation as compared to 2.97±0.2 l and 12.8±0.6% in the conventional Starling preparation, in response to an increase in venous inflow. 4. Average mean aortic pressure remained constant at around 9.8 cm Hg throughout except at maximal output in the conventional preparation, where manipulation of the Starling resistance failed to lower aortic pressure beyond an average of 14.4 cm Hg. 5. The new preparation offers the advantage of producing high output, high mechanical efficiency at maximal output, control of aortic pressure at desired levels and simplification over methods previously described.

Effect of Temperature Change on Heart Performance (Heart-Lung Preparation)

SummaryThe relationship between left ventricular stroke work and left atrial pressure was studied in the Starling heart-lung preparation at various temperatures.Cooling from 37° to 28.5°C consistently improved the performance. Warming from 37° to 42°C produced variable effects, but all hearts warmed to 44°C performed better than at 37°C.We conclude that over a temperature range which is detrimental to the total physiology of most mammals the myocardium is not a limiting factor.

CARDIAC ACTION OF DIMORPHOLAMINE

Since the introduction of dimorpholamine (N, N'-dibutyl-N, N'-dicarboxymorpholineethylenediamine, 1064 Th) as a potent analeptic agent, not a few papers have appeared concerning its stimulating action on respiration and blood pressure. However, to the authors' knowledge, only two works have ever been published with respect to its action on the isolated heart. Using the isolated frog's heart, Fukushima (1) observed a positive inotropic action with 0.75 mg/ml of this compound, although the action was very weak and evanescent. According to his study, an isolated preparation of the dog's heart (Starling's heart-lung preparation) responded to this compound in a similar manner, whereas only a slight negative inotropic action could be induced in the isolated perfused rabbit heart. Kanda et al. (2) studied the action of dimorpholamine on the isolated frog heart. They used a higher dosage range of 0.15 to 0.3 mg/ml and found a definite positive inotropic action ; still higher doses produced more marked positive inotropic action, followed after a lapse of time by a disturbance of heart rhythm. As an exact knowledge of the cardiac action of an analeptic is important in evaluating usefulness of that compound in clinical medicine, the authors felt the necessity to reinvestigate the cardiac action of dimorpholamine in more detail. In the course of the study, a marked positive inotropic action was observed both in the isolated frog's heart (which was essentially the same as reported by Kanda et al.) and in the heart-lung preparation of the dog. Even in the isolated perfused rabbit heart, the authors could produce a positive inotropic action under certain conditions, which the authors at present are not able to specify (see Fig. 6). This report pertains to the detailed description of the action of this potent analeptic agent on the heart-lung preparation of the dog, with special reference to the possible role played by the adrenergic mechanism in the observed positive inotropic action.

Studies on Starling's law of the heart. I. The circulatory response to acute hypervolemia and its modification by ganglionic blockade.

The application of Starling's law of the heart to the circulation of man has been the subject of intensive interest and investigation. Infusions of intravenous fluids have been employed in attempts to simulate in man the increase in venous return to the Starling heart-lung preparation. A variety of fluids has been utilized in such studies in man, including saline (1-4), dextran (4-6), glucose solutions (4), and human serum albumin (2, 7). In general, the results have been conflicting, with a few investigators noting an increase both in filling pressure and cardiac output (1, 5), while in the majority of studies no consistent relationship between these parameters was noted (2-4, 6, 7). Indeed, in most human subjects the augmentation of the total blood volume has failed to be associated with a rise in cardiac output, even in the face of a decline in hematocrit (2-4, 6, 7). The possibility was considered that the presence of an actively functioning autonomic nervous system in the intact state and its absence in the heart-lung preparation accounts for the difference in the cardiac response to infusion in man and increased venous return to the heart-lung preparation. The present study was therefore designed to determine whether the circulatory response to acutely induced hypervolemia is modified by reducing the activity of the autonomic nervous system by means of ganglionic blockade.

Integrative cardiovascular physiology: a mathematical synthesis of cardiac and blood vessel hemodynamics.

The cardiovascular system is analyzed as a feedback regulator. The controlling system is identified as being the medullary cardiovascular centers as well as those endocrine glands which operate upon the heart and blood vessels; the controlled system comprises the mechanical and gas exchanger elements of the cardiovascular system. The present analysis is restriced to the mechanical section of the controlled system. Equations are first formulated to define the steady-state operation of an isolated ventricle and of an isolated "circuit." Two ventricles are then combined with a single "open" circuit, the pulmonary, to obtain equations describing the operation of the Starling heart-lung preparation. Finally, the system is "closed" by introducing a second circuit, the systemic, and equations are obtained for the behavior of this complete mechanical system. These equations define steady-state valvues for each of the system's dependent variables (cardiac output; ventricular volumes and work; systemic arterial and venous pressures; pulmonary arterial and venous pressures; systemic and pulmonary blood volumes and their distribution between artery and vein) for any given set of values for the 14 independent variables (cardiac frequency; "strength," viscance, and compliance of each ventricle; systemic and pulmonary arteriolar resistances; systemic arterial and venous compliances; pulmonary arterial and venous compliances; and total blood volume). Comparison of predicted behavior with experimetal data indicates that the mathematical model so obtained is a useful one.

THE CARDIAC FACTOR IN THE "PRESSOR" EFFECTS OF RENIN AND ANGIOTONIN

Upon the isolated hearts of cats perfused with Ringer-Locke solution renin produced no significant effect. Angiotonin, on the other hand, brought about decrease in coronary flow and increase in amplitude of beat without any consistent effect upon heart rate. Both renin and angiotonin augmented the cardiac output and raised the "arterial" pressure in the Starling heart-lung preparation; here too without influence on the heart rate. Electrocardiograms recorded before, during and after the pressor effects of renin and angiotonin in the anesthetized cat showed no abnormalities until the blood pressure had risen above 190 mm. Hg when various types of cardiac arrhythmias appeared. These were prevented, or normal rhythm was restored, by cutting the vagus nerves or injecting atropine. It is concluded that the "pressor" effects of renal pressor substances include direct stimulation of the myocardium and augmentation of ventricular beat. Unless these actions lead to excessive decrease in diastolic volume of the ventricles, the cardiac output will be increased. The significance of this in the production of the pressor effect is discussed.

Influence of Ethyl Alcohol on Energy Metabolism of the Mammalian Heart.

The use of the older methods of studying the isolated heart led to contradictory conclusions regarding the effect of alcohol on cardiac contraction. Sulzer, using the Starling heart-lung preparation, at present the most sensitive and reliable method for this purpose, found no stimulating effect in any concentration and showed that concentrations commonly reached in the human blood stream in alcoholic intoxication produce dilatation without an increase in the work of the heart. We have confirmed this effect and studied the changes in energy metabolism associated with it. We have used a modified heart-lung preparation, which has been previously described. In some experiments the diastolic volume was allowed to increase when alcohol was added (Table I), while in others (Table II) the external diastolic volume was maintained constant throughout the experiment by adjustment of the venous return. In all cases the venous pressure had to be lowered in order to keep diastolic volume constant after alcohol. A piston recorder was used for ventricular volume recording and the heart was held in a glass cardiometer, following the technique of Starling and Visscher. After a control period of 15 to 30 minutes, during which the volume output and oxygen usage remained constant, the desired amount of alcohol was injected into the tubing between the stromuhr and the venous reservoir so as to insure thorough mixing before reaching the heart. Within 30 to 40 minutes after the injection the variables recorded had generally reached a new fairly constant level, and then in some experiments alcohol was injected again and the effect of the higher concentration determined. The concentration of alcohol injected was 20% except in Exp. 4/10/33, in which 95% alcohol was added to the blood undiluted for purposes of comparison. The time of injection was generally 2 to 3 minutes.