Inotropic Changes Research Articles

Chronotropic and inotropic effects on the dog heart of stimulating the efferent cardiac sympathetic nerves.

1. The chronotropic and inotropic responses of the dog heart to stimulation of the ansae subclaviae were studied.2. The maximum rate of rise of pressure in the left ventricle (dP/dt max) was used as an index of the inotropic changes.3. In experiments in which the secondary inotropic effects of changes in heart rate and blood pressure were prevented it was shown that, using stimuli which produced the same chronotropic response, stimulation of the left ansa subclavia resulted in an inotropic change which was about eight times greater than that which resulted from stimulation of the right ansa subclavia.4. In experiments in which heart rate and blood pressure were allowed to change freely it was shown that the secondary inotropic effects of changes in blood pressure and heart rate amounted to about 70% of the total inotropic change when the right ansa subclavia was stimulated and about 20% of the total change when the left ansa subclavia was stimulated.

The inotropic effect on the heart of stimulating the vagus in the dog, duck and toad.

1. The chronotropic and inotropic effects of stimulating the vagus on the hearts of the dog, duck and toad were studied.2. The maximum rate of rise of pressure in the left ventricle (dP/dt max) measured at a constant heart rate and mean aortic pressure was used as an index of the inotropic changes.3. The sensitivity of dP/dt max as an index of inotropic changes brought about by stimulating the vagus was established in the toad where a 49% reduction in heart rate was associated with a 30% reduction in dP/dt max.4. In the dog stimulation of the vagus resulted in a reduction in heart rate of 38% and only a small reduction in dP/dt max of 6%.5. Results similar to those found in the dog were obtained in the duck where the reduction in heart rate of 44% was associated with reduction in dP/dt max of only 3%.6. It is concluded that the vagus has only a small and negligible negative inotropic effect on the ventricles of the dog and duck.

Inotropic responses of the left ventricle to changes in aortic arch pressure in anaesthetized dogs.

1. Inotropic changes in the left ventricle in chloralose anaesthetized dogs were determined in response to changes in non-pulsatile pressure perfusing the vascularly isolated aortic arch.2. Inotropic responses were assessed by measuring the maximum rate of change of left ventricular pressure (dP/dt max) in preparations in which heart rate, mean ascending aortic pressure and brachiocephalic (i.e. carotid sinus and cerebral) perfusion pressure were held constant.3. dP/dt max increased (average +43%) when aortic pressure was reduced from a level above that which produced maximum depression of the myocardium to a level below which no further responses could be obtained; responses occurred as aortic arch pressure was changed between 250 and 90 mm Hg.5. In the same preparations changes in the brachiocephalic artery perfusion pressure with aortic arch pressure held constant resulted in similar inotropic responses.6. It is suggested that aortic arch baroreceptors may be of importance in the control of the inotropic state of the heart.

Drugs and heart muscle.

Some inconsistencies exist in the literature p ertine nt to the action of drugs on heart muscle, in regard to the question of how the action on myo­ cardial contractility should be measured in order to get the appropriate in­ formation for an adequate evaluation and classification of an inotropic drug. The reason for this derives mainly from the fact that the mechanical properties of heart muscle are more compl icated than those of skeletal mus­ cle and that concepts and methods originally developed for the study of skeletal muscle have been transferred more or less uncritically during the last two decades to the work on heart muscle, giving rise partly to mislead­ ing conclusions. The differences in mechanical propert ies need to be recalled here only as far as necessary for the topical discussion, since they have been described elaborately and expertly in recent reviews (1-3) : (a) only an iso­ metric twitch tension and no tetanus tension can be obtained with heart muscle, which prevents the measurement of its maximum force by tetanic stimulation; (b) high resting tensions develop in heart muscle after rela­ tively s hort extensions of its length, indicating the relative importance of a parallel elastic element in heart muscle in contrast to skeletal muscle; (c) whereas in skeletal muscle full contractile activity exists early in contrac­ tion, there is a relatively slow onset in contractility in cardiac muscle. Mea ­ surements of the time course of the cardiac active state at con stant length of the contractile element by controlled stretch have shown the active state rising somewhat ahead of isometric tension in the un stretched response and reaching a slightly earlier maximum (1); (d) there is a clear distinction between the influence on the isometric tension curve of skeletal and heart muscle by several ino tropic ally acting agents, such as epinephrine (4, 5) and different anions (6,7). Since the intention of the pharmacological study of an inotropic inter­ vention is to explain, if possible, its cellular mechanism, it is understandable that different experimental efforts have been undertaken in trying to ana­ lyze various mechanical factors involved in the inotropic change. It seems to be necessary to compare the different approaches to find out which of them procures the most relevant information and appears to be most feasi­ ble. It then will be evident that an analysis of the change in mechanical properties alone will not be sufficient for the evaluation of an inotropic drug because the possibilities of the heart muscle to develop an inotropic response by a distinguishable application of its mechanical means are extremely Iim-

Reflex effects on the heart of stimulating left atrial receptors.

1. Stimulation of left atrial receptors, by distension of the pulmonary vein/left atrial junctions, is known to cause a reflex increase in heart rate; the efferent pathway is known to be solely in the sympathetic nerves.2. In expectation of a concomitant positive inotropic response the effect of stimulating the left atrial receptors on the inotropic state of the left ventricle was studied, using as a known sensitive index of inotropic changes the maximal rate of rise of pressure in the left ventricle (dP/dt max).3. Stimulation of left atrial receptors resulted in an increase in heart rate but there were no significant concomitant changes in dP/dt max.4. It is concluded that activity in this discrete efferent pathway does not include an inotropic effect on the left ventricle and therefore the reflex involves only those sympathetic nerves which innervate the sinu-atrial node.5. The possible function of atrial receptors in the regulation of heart volumes is discussed.

The inotropic and chronotropic effects of catecholamines on the dog heart

1. The chronotropic and inotropic responses of the denervated dog heart to intravenous infusions of noradrenaline, adrenaline and isoprenaline were studied.2. The maximum rate of rise of pressure in the left ventricle of the heart, (dP/dt max) measured at a constant heart rate and mean systemic arterial pressure during each series of infusions, was used as an index of inotropic changes (Furnival, Linden & Snow, 1970).3. The order of potency of the catecholamines in producing both chronotropic and inotropic effects was isoprenaline > adrenaline > noradrenaline.4. For the same increase in heart rate produced by an infusion of a catecholamine, noradrenaline caused a greater inotropic effect than adrenaline, which in turn caused a greater increase than isoprenaline.5. The chronotropic and inotropic effects of noradrenaline were potentiated by an intravenous injection of cocaine HCl (5 mg/kg), whereas those of isoprenaline were unchanged.6. The relative difference between the responses to noradrenaline and isoprenaline was abolished by an intravenous injection of cocaine HCl.7. It is concluded that the different relative chronotropic and inotropic effects of isoprenaline and noradrenaline are due to the greater uptake of noradrenaline by sympathetic nerve endings in the sinu-atrial node than in the muscle of the left ventricle.

Inotropic changes in the left ventricle: the effect of changes in heart rate, aortic pressure and end-diastolic pressure.

1. Under conditions where heart rate, mean aortic pressure and enddiastolic pressure in the left ventricle are held constant, the intravenous infusion of isoprenaline is accompanied by large changes in dP/dt max in the left ventricle.2. Under similar conditions, during stepwise increments in the rate of infusion of isoprenaline the changes in dP/dt max (measured at a constant paced heart rate) were proportional to changes in the free (intrinsic) heart rate. It is concluded that dP/dt max is a quantitative index of inotropic changes in the left ventricle.3. In comparison to dP/dt max, three other variables which have been used to indicate inotropic changes in the heart (peak pressure in the left ventricle, duration of systole and stroke work at constant end-diastolic pressure), were shown to be unreliable indices of inotropic changes.4. Using dP/dt max to indicate inotropic changes, alteration in the heart rate while mean aortic pressure and end-diastolic pressure in the left ventricle were held constant, and in mean aortic pressure while heart rate ane end-diastolic pressure in the left ventricle were held constant, were each shown to be accompanied by small inotropic changes in the heart.5. Under similar conditions, changes in end-diastolic pressure in the left ventricle alone were not accompanied by inotropic changes as indicated by dP/dt max.

Effects of calcium and sodium on cardiac contractility and heat production in rabbit papillary muscle.

The effects of altering the concentrations of sodium (Na + ) and calcium (Ca 2+ ) ions on the isometric energy output of rabbit papillary muscle at room temperature were examined by a myothermic technique. The well-known inotropic changes resulting from these alterations were not correlated with parallel changes in the magnitude of the tension-independent heat. Instead, the magnitude of the tension-independent heat was directly correlated with both increasing (Na + ) concentration and with increasing (Ca 2+ ) concentration, and these effects were additive. The energetics of ions pumping in cardiac muscle are discussed quantitatively and it is suggested that the combined enthalpy consumption of both the (Na + ) and the (Ca 2+ ) pumps constitutes the major determinant of cardiac tension-independent heat production.

The dynamics of the inotropic change prduced by altered pacing of rabbit papillary muscle.

AbstractThe time course of the active state, the force‐velocity relationship and the series compliance of rabbit papillary muscles were studied at different inotropic states produced by altered pacing of the muscles within the range 18 to 72 stimulations per minute. The inotropic intervention produced a shift of the force‐velocity curve, without markedly changing the shape of the curve, suggesting that Vmax, the capacity to produce motion, and Pmax the capacity to produce tension, were affected to the same degree. Intensification of the active state in response to an increase in stimulation frequency was associated with a steeper rise of the active state and an earlier attainment of maximum. The series compliance was unaffected by the inotropic intervention. The results are taken as evidence (1) that the two parameters of the active state, Vmax and Pmax, are governed by a common control mechanism in the excitation‐contraction coupling and (2) that the inotropic effect is due to altered kinetics of this control function. The nature of the mechanism governing the active state is discussed in relation to the slicling‐filament theory of muscular contraction.

THE DYNAMICS OF THE INOTROPIC CHANGES PRODUCED BY OUABAIN AND INCREASED CONTRACTION RATE.

THE DYNAMICS OF THE INOTROPIC CHANGES PRODUCED BY OUABAIN AND INCREASED CONTRACTION RATE.

KINETIC STUDIES OF CALCIUM DISTRIBUTION IN VENTRICULAR MUSCLE OF THE DOG.

Five phases (0 to 4) were defined kinetically for calcium in the dog papillary muscle vascularly perfused for five to six hours with perfusate containing 5 m M /liter calcium. The mean rate constant, λ, (min -1 ), approximate calcium concentration (m M /liter muscle water) and suggested origin of each phase are respectively: (0) λ 0 = 3.5, 0.4, vascular; (1) λ 1 = 0.59, 1.8, interstitial; (2) λ 2 = 0.116, 1.7, "specialized" calcium transport system (?sarcoplasmic reticulum); (3) λ 3 = 0.021, 2.0, intracellular; (4) λ approx 0.004, <1.6, intracellular and/or connective tissue. Inotropism, occuring coincidentally with institution of perfusion by solution containing 25% normal sodium concentration, was marked by a mean 60% increase in peak isometric tension and a mean 87% increase in rate of tension development. These inotropic changes stabilized within 10 minutes despite maintenance of low sodium perfusion and regressed within 10 minutes upon return to normal sodium perfusion. There was a mean 0.5 m M /liter change in calcium concentration of the muscle associated with the inotropic changes. This fraction of tissue calcium could be ascribed entirely to kinetically-defined phase 2 and was freely exchangeable. Prolonged (40-minute) low sodium perfusion resulted in no inotropic changes beyond the first 10 minutes but was associated with a continued marked net increase in muscle calcium. This fraction of tissue calcium was irreversibly bound and inexchangeable. It was suggested that this fraction of calcium may be bound as its phosphate salt. The possibility that the Ca ++ content of the "specialized system" represented by phase 2 is controlled by movements of Na + into and out of this system is discussed. Ca ++ movements associated with increased frequency of contraction are also discussed in the context of their possible relation to Na + exchange.

A study of inotropic mechanisms in the papillary muscle preparation.

The length-tension diagram, the force-velocity relation, the characteristics of the series elasticity, and the duration of the active state have been studied on the papillary muscle preparation of the cat heart, and on other examples of cardiac muscle. Positive inotropic changes such as the staircase phenomenon and post-extrasystolic potentiation occur without lengthening, but frequently with shortening, of the duration of the active state. They are accompanied by an increased velocity of contraction, and may be caused either by an intensification of the active state or by an alteration of the force-velocity characteristics of the contractile component. The changes in the force-velocity relation point to an adaptation of the velocity-efficiency relation in dependence on the frequency of contraction.