Andrés Manring

Force-Frequency Relationship: A Basis for a New Index of Cardiac Contractility?

The way that contractility varies between beats—the force-frequency relationship—was determined for rabbit papillary muscles held at different lengths. When the maximum rate of rise of tension in a contraction, Fmax, was used as a measure of contractility, the way contractility changed between contractions was independent of length. That is, when the values of Fmax obtained at one length were multiplied by an appropriate scaling factor, the force-frequency relationship determined at that length was indistinguishable from the force-frequency relationship determined at another length. If, however, the peak tension in a contraction was used as a measure of contractility, the Force-frequency relationship generally was not independent of muscle length. Therefore, it is proposed that the ratio of two values of Fmax obtained by perturbing the rate of stimulation at any given length should be tried as a length independent index of the inotropic state of the muscle.

Cardiac muscle: An attempt to relate structure to function☆☆☆

Abstract Two structure-function hypotheses were tested in this paper: Are the physiological functions—the force-frequency relationship and/or the response to low sodium media—related to the degree of differentiation of the coupling [a specialized close association of sarcolemma and sarcoplasmic reticulum]? A comparative study of the ultrastructure of representatives of several vertebrate classes [mammalia, aves, reptilia, amphibia, pisces and chondrichthyes] revealed that the coupling rather than other structural differences was the best candidate for a structure-function study. A wide variation in the degree of differentiation of the coupling and the associated sarcoplasmic reticulum was found throughout the range of animal classes. Well-formed couplings occurred in all hearts except that of the frog and mudpuppy where they were sparsely distributed and poorly differentiated. Parallel comparative function studies—the force-frequency or interval-strength relationship and the response to low-sodium media—were performed on hearts from animals from the same classes. Although all hearts developed steady tensions when exposed to low-sodium media, there were microscopic differences: In the frog the sarcomeres shortened to a steady value, whereas in hearts from other animals, groups of sarcomeres twitched repeatedly and without synchrony among groups (vermiculation). The structure-function hypothesis implied by this functional difference was disproven: the sarcomeres in the chicken embryo hearts, both with and without identifiable couplings, vermiculated; sarcomeres in hearts of the turtle and salamander, with well-formed couplings, sometimes vermiculated and sometimes shortened like those of the frog. Using the maximum rate of rise of tension in a contraction as the measure of contractility, the hearts of all animals tested fell into two classes according to the characteristics of their force-frequency relationships. In one class, which included all but amphibian hearts, contractility increased between contractions, whereas in the other class, contractility declined or did not change between contractions. Hearts without well-differentiated couplings were never found in the first class, whereas hearts with or without couplings were found in the second class.

Biophysics of the developing heart: III. A comparison of the left ventricular dynamics of the fetal and neonatal lamb heart

Changes in heart rate, left ventricular dimensions, and inotropic state of chronically instrumented lambs from in utero to neonatal life are described and analyzed. Six lambs were instrumented from 5 to 23 days prior to parturition and studied prior to and after birth. Heart rate, aortic systolic and diastolic pressure, left ventricular end-diastolic and peak systolic pressure, and left ventricular minor axis end-diastolic (EDD) and end-systolic dimension (ESD) were monitored. The maximum rate of rise of left ventricular pressure (Pmax), percentage fractional shortening [(EDD - ESD divided by EDD) x 100%; %FS], and the Pmax -interval ratio (this ratio of Pmax of the postextrasystolic potentiated systole to Pmax of the previous regular systole is independent of volume) described contractility. Subsequent to birth: heart rate, aortic systolic and diastolic pressure and left ventricular dimensions increased; during spontaneous rhythm and at equal fetal and neonatal heart rates and ventricular dimensions, %FS and P max increased significantly; and P max -interval ratio changed significantly. An increase in myocardial inotropic state occurs with birth. This enhancement is in addition to the effects of the increase in heart rate and end-diastolic volume that occur with the adaptation to birth.

The force of contraction of isolated papillary muscle: a study of the interaction of its determining factors.

Abstract This paper investigates the ways examples of three categories of experimental variables, changes in muscle length, variations in the rate and pattern of stimulation, and changes in the composition of the bathing medium, interact to determine the force of contraction—in particular the maximum rate of rise of force, F max ,—of isometric rabbit and cat papillary muscle. The shape of the Ḟ max -length relationship was unaltered by a change in calcium concentration or exposure to histamine; i.e. the effect of a given concentration was to multiply F max obtained at every muscle length by the same factor. The way changes in the bathing composition modified the rate dependency of contractile force, the Ḟ max -interval relationship, was also investigated. The effect of a change in calcium concentration or exposure of the muscle to one of a variety of inotropic agents (ouabain, histamine, norepinephrine or pentobarbital) was to modify the Ḟ max -interval relationship, in some instances radically. These results can be combined with the previous finding that a change of muscle length only scaled and did not modify the shape of the Ḟ max -interval relationship [2]. The way F max depends on muscle length, rate and pattern of stimulation and composition of the bathing medium can thus be described as the product of two functions: one function, λ, dependent on muscle length but unaffected by a change in the pattern of stimulation or an inotropic agent; the other function, φ, dependent on the rate and pattern of stimulation. φ was found to depend on the composition of the bathing medium but to be unaltered by muscle length, i.e. F max = kλphiv ;( w ) where k is a proportionality constant with dimensions of grams/second; λ and φ are dimensionless; ω denotes the concentration of calcium or of one of the inotropic drugs tested. In most instances, the function φ (ω) for each agent was distinctly different, perhaps characteristically so, from that of any of the other agents.

Pressure-Induced Hypertrophy of Cat Right Ventricle An Evaluation with the Force-Interval Relationship

SUMMARY We evaluated the force-interval relationship for papillary muscle isolated from two groups of cats, one sham-operated (control group), the other having undergone pulmonary artery constriction (hypertrophy group) 18.6 ± 2.9 weeks prior to sacrifice. The right ventricular free wall muscle mass and the peak systolic right ventricular pressure were significantly greater in the hypertrophy than in the control group. The peak force and maximum rate of rise of force (Fmax) per cross-sectional area were not significantly different for the two groups. The qualitative features of the force-interval relationship, in particular postextrasystolic potentiation, were the same for both groups. There were quantitative differences between the groups, however. The amount of potentiation expressed, the ratio of Fmax of the potentiated to that of the previous regular contraction (i.e., the force-interval ratio), was significantly greater in the hypertrophied than in the control group. In both groups, the force-interval ratio was independent of muscle length, yet was altered by changing the inotropic state of the muscle (e.g., by alterations in calcium concentration). Increasing and decreasing the calcium concentration decreased and increased, respectively, the force-interval ratios in both groups. The application of these results to theories about the mechanisms underlying the alterations in mechanical performance induced by hypertrophy is discussed. CHANGES IN THE mechanical properties of isolated cardiac muscle accompanying pressure-induced hypertrophy have been the subject of a number of investigations, but no unanimous view has yet emerged. Bassett and Gelband,

Light diffraction of cardiac muscle: An analysis of sarcomere shortening and muscle tension

The time-course of sarcomere shortening and of overall muscle tension were determined for frog atrial strands (30–80 μm diam.) held isometric at a variety of lengths. A light diffraction technique was used to determine the sarcomere length: the cross-section of the strand was illuminated by a continuous He-Ne laser beam. Sarcomeres shortened considerably (up to 0.7 μm), and the velocity of shortening over most of the shortening phase was not affected by stretching the sarcomeres (initial lengths between 1.95 and 3.1 μm) in spite of the increase in muscle tension, (up to 0.65 kg/cm 2 ) and (presumably) a decrease in filament overlap. The incompatibility of these findings with the classical force-velocity relationship of skeletal muscle prompted two critical analyses of this interpretation, first, of the sarcomere length measurements and second, of the assignment of tension to the observed sarcomeres. The conclusions of the first analysis are that the sarcomere length measurements are reliable and that no physiologically important hidden population is likely to be present in the cross-section of the strand. The conclusion of the second analysis is that the assignment of tension to the observed sarcomeres is equivocal since, due to the unavoidably complex morphology of naturally occurring cardiac muscle, there can be no assurity that some unobserved passive element in the cross-section does not bear the active tension.

Can sympathomimetic agents be classified by their action on the force-interval relationship?

Abstract The use of the force-interval relationship, the dependence of cardiac contractility on the rate and pattern of stimulation, has been suggested as an index of cardiac contractility, e g. it differentiates among normal, hypertrophied and failing myocardium. In this paper, we describe the effects of sympathomimetic agents on the force-interval relationship and show that this relationship is useful in differentiating the actions of these drugs on the myocardium. Rabbit right ventricular papillary muscles were exposed to isoproterenol, norepinephrine, methoxamine and phenylephrine during a standard two-stage pacing experiment. The force-interval relationship is characterized by force-interval curves which describe how contractility, i.e. the maximum rate of rise of force (Ḟmax), changes between contractions. In the control solution the curves were monotonic and the force-interval ratio (FIR), a measure of post-extrasystolic potentiation, was always greater than unity. Isoproterenol and norepinephrine had similar actions on the force-interval relationship: Fmax was potentiated, FIR reduced and the curves became biphasic. Methoxamine had the same effect on FIR and the curves. Practolol or propranolol competitively inhibited these changes whereas phentolamine did not inhibit but accentuated them. Phenylephrine increased Fmax, but unlike the other agonists it increased FIR and the curves remained monophasic. These effects were inhibited competitively by phentolamine. Based upon the action of the competitive inhibitors, these patterns are separable into those produced by α- and β-agonists. The results suggest that the force-interval relationship may be used as a new basis for distinguishing the actions of sympathomimetic agents.

110 DEVELOPMENTAL CHANGES IN FETAL AND NEONATAL CARDIAC CONTRACTILITY

In order to better understand how cardiac contractility changes with development in the infant, six fetal lambs (119-132 days gestation) were chronically instrumented to monitor left ventricular pressure, peak first derivative of pressure (Pmax), and end-diastolic (ED) and end-systolic (ES) dimensions. The lambs were studied up to and following birth (gestational age 137-142 days). Descriptors of contractility were Pmax, percent fractional shortening (ED-ES/ED;FS) and post-extrasystolic potentiation (Pmax of potentiated systole/Pmax of previous regular systole; FIR). ED increased with gestational age (e.g. 15.8 ± 0.4 mm, ± SD, 122 days gestation; 22.9 ± 0.3 mm, 140 days), but mean Pmax for the lambs (1462-2452 mmHg/s) did not increase significantly until 24 hours prior to delivery, rose by 50-120% at 3 hours of age, and then fell back to fetal levels by 7-10 days of age. Fetal FS (21-31%) followed a time course similar to that of Pmax. In contrast, fetal FIR increased significantly until 24 hours prior to delivery, fell significantly with delivery and then rose back to fetal values and higher by 30 days of life. All the changes around birth are similar to those induced by isoproterenol infusions and may reflect changes in sympathetic tone. In contrast, the long term increase in FIR is similar to that induced by mild hypertrophy suggesting that developmental changes in contractility share a common origin with those of mild hypertrophy.

CATECHOLAMINE EFFECT ON THE FORCE-INTERVAL RELATIONSHIP

Catecholamines (isoproterenol, norepinephrine, methoxamine) have an effect on the force-interval relationship (FIR) (the way the force of contraction depends on the rate and pattern of stimulation) which is unique among inotropic agents. Although the effect on the FIR of a low dose of isoproterenol (10−8M) is similar to that of other agents (e.g. elevation of calcium concentration), intermediate doses (10−7, 10−6M) cause the curves that characterize the FIR (monophasic for the control and the low dose) to become biphasic; large doses (10−5M) strikingly accentuate this effect turning post-extrasystolic potentiation into post-extrasystolic depression. Propranolol (10−7M) and practolol (10−6M) blocked these effects competitively whereas phentolamine (5 × 10−6M) and isopropylmethoxamine (5 × 10−6M) did not. Thus, the effect of changing the FIR from a monophasic to a biphasic function can be deemed a β1 action, unrelated to α or β2 sites. Norepinephrine (10−7, 10−6, and 10−5M) produced the same results. Methoxamine (10−3, 10−4M), not usually considered a β agonist, also produced this same effect on the FIR. These results demonstrate the potential usefulness of the FIR as a means of identifying and classifying inotropic agents as well as providing a method of analysis for testing hypotheses concerning the mode of action of β1 agonists.

THE FORCE FREQUENCY RELATIONSHIP: A BASIS FOR CATALOGING CHANGES IN CONTRACTILITY

The force frequency relationship (FFR) describes the way cardiac contractility depends on the rate and pattern of stimulation. The FFR fulfills one of the requirements for an index of contractility: When the maximum rate of tension developed in a contraction (Fmax) is used to measure contractility, the FFR is independent of muscle length. (Circ. Res. 33:665, 1973) We show here that the FFR also fulfills another requirement for an index of contractility, namely that changes in the inotropic state of the muscle are distinguishable from changes in muscle length. Inotropic changes in the FFR fell into three classes: 1. Both ouabain (5×10−7M) and increase in Ca concentration (up to 10mM) increased contractility following the regular contraction much more than following an extrasystolic contraction. 2. Phenylephrine 5×10−5M increased contractility following the extrasystolic contraction much more than following the regular one. 3. The actions of isoproteranol and norepinephrine in small doses < 10−7M were similar to those in (1) but with increasing doses, > 10−6M, Fmax in the steady state contraction exceded that of the post extrasystolic contraction. We conclude that the FFR provides a valuable basis for distinguishing length changes from changes in inotropy and cataloging the actions of positive inotropic agents.