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Optical mapping is an imaging technique that is extensively used in cardiovascular research, wherein parameter-sensitive fluorescent indicators are used to study the electrophysiology and excitation-contraction coupling of cardiac tissues. Despite many benefits of optical mapping, eliminating motion artifacts within the optical signals is a major challenge, as myocardial contraction interferes with the faithful acquisition of action potentials and intracellular calcium transients. As such, excitation-contraction uncoupling agents are frequently used to reduce signal distortion by suppressing contraction. When compared with other uncoupling agents, blebbistatin is the most frequently used, as it offers increased potency with minimal direct effects on cardiac electrophysiology. Nevertheless, blebbistatin may exert secondary effects on electrical activity, metabolism, and coronary flow, and the incorrect administration of blebbistatin to cardiac tissue can prove detrimental, resulting in erroneous interpretation of optical mapping results. In this “Getting It Right” perspective, we briefly review the literature regarding the use of blebbistatin in cardiac optical mapping experiments, highlight potential secondary effects of blebbistatin on cardiac electrical activity and metabolic demand, and conclude with the consensus of the authors on best practices for effectively using blebbistatin in optical mapping studies of cardiac tissue.

Coupling myoelectric and mechanical signals during voluntary muscle contraction is paramount in human–machine interactions. Spatiotemporal differences in the two signals intrinsically arise from the muscular excitation–contraction process; however, current methods fail to deliver local electromechanical coupling of the process. Here we present the locally coupled electromechanical interface based on a quadra-layered ionotronic hybrid (named as CoupOn) that mimics the transmembrane cytoadhesion architecture. CoupOn simultaneously monitors mechanical strains with a gauge factor of ~34 and surface electromyogram with a signal-to-noise ratio of 32.2 dB. The resolved excitation–contraction signatures of forearm flexor muscles can recognize flexions of different fingers, hand grips of varying strength, and nervous and metabolic muscle fatigue. The orthogonal correlation of hand grip strength with speed is further exploited to manipulate robotic hands for recapitulating corresponding gesture dynamics. It can be envisioned that such locally coupled electromechanical interfaces would endow cyber–human interactions with unprecedented robustness and dexterity., Designing efficient systems capable emulating the muscular excitation-contraction signatures, remains a challenge. Here, the authors propose cytoadhesion-inspired hybrids as locally-coupled electromechanical interfaces capable retrieving the myoelectric and mechanical signals.

The Bursztyn et al. (2007) paper proposes a mathematical model of excitation-contraction in a myometrial smooth muscle cell (SMC). The model incorporates processes of intracellular Ca^2+ concentration control, myosin light chain (MLC) phosphorylation and stress production. We create a modularized CellML implementation of the model, which is able to simulate these processes against the original data.

Many studies have shown the feasibility of in vivo cardiac transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in animal experiments. However, nano-structural confirmation of the successful incorporation of the engrafted iPSC-CMs including electron microscopy (EM) has not been accomplished, partly because identification of graft cells in EM has proven to be difficult. Using APEX2, an engineered ascorbate peroxidase imaging tag, we successfully localized and analyzed the fine structure of sarcomeres and the excitation contraction machinery of iPSC-CMs 6 months after their engraftment in infarcted mouse hearts. APEX2 made iPSC-CMs visible in multiple imaging modalities including light microscopy, X-ray microscopic tomography, transmission EM, and scanning EM. EM tomography allowed assessment of the differentiation state of APEX2-positive iPSC-CMs and analysis of the fine structure of the sarcomeres including T-tubules and dyads.

We present and study a mathematical model to simulate the calcium flux and contractile activity of the cardiomyocyte, resorting on the Finite Element Method. This Model of cardiac cells provide the possibility to understand the biochemistry and biomechanics of cardiac cells and cardiovascular diseases. Heart Failure is considered the ultimate cardiac disease, a condition with no effective cure which is highly related with the function of cardiomyocytes and consequently with the concentration of calcium, affecting the contractile activity of the cardiomyocyte.In order to test our model’s performance, several tests were applied varying the local active cellular tension driven by the intracellular calcium concentration and the localization of the main calcium influx. The results are expressed in the graphics of calcium concentration over time, maximum cardiomyocyte contraction and the gradient of calcium diffusion.Our results show that the behaviour of our models is faithful to what is known to be true with cell’s physiology and pathological conditions.

Skeletal muscle energy metabolism plays a very important role in controlling movement of the whole body and has important theoretical guidance for making exercise training plans and losing weight. In this paper, we developed a mathematical model of skeletal muscle excitation–contraction pathway based on the energy metabolism that links excitation to contraction to explore the effects of different metabolic energy systems on calcium ion changes and the force during skeletal muscle contraction. In this paper, a membrane potential model, a calcium cycle model, a cross-bridge dynamics model and an energy metabolism model were established. Finally, the physiological phenomenon of calcium ion transport and calcium ion concentration change of the sarcoplasm was simulated. The results show that the phosphagen system has the fastest metabolic rate and the phosphagen system has the largest impact on the explosive power of skeletal muscle exercise. The specific characteristics of the three metabolic energy systems supporting skeletal muscle movement in vivo were also analyzed in detail.

During muscle contraction the excitation-contraction process mediates the neural input and mechanical output. Proper muscle function and body locomotion depends on the status of the elements in the same process. However, non-invasive and in-vivo methods to study this are not available. Here we show the existence of an optical response occurring during the excitation-contraction process in human biceps brachii muscle. We developed a non-invasive instrument from a photodiode array and light emitting diodes to detect spatially propagating (~5 m/s) and precontractile (~6 ms onset) optical signals closely related to the action potential during electrostimulation. Although this phenomenon was observed 60 years ago on isolated frog muscle cells in the lab, it has not been shown in-vivo before now. We anticipate our results to be a starting point for a new category in-vivo studies, characterising alterations in the excitation-contraction process in patients with neuromuscular disease and to monitor effects of therapy.

The mammalian heart is a muscular organ that acts to propel blood through the pulmonary and systemic circulation. It is two pumps in series; the right side of the heart supplies the pulmonary circulation and left side the systemic circulation. The role of the heart is vital in sustaining life, since it delivers oxygen from the lungs to tissues, and removes products of metabolism (principally CO2).

Clinical Neuroscience Division, IOP, King’s College, London, United Kingdom Department of Paediatric Neurology – Neuromuscular Service, Evelina Children’s Hospital, St. Thomas’ Hospital, London, United Kingdom Division of Pediatric Neurology, Pediatric Neuromuscular Clinic, 5328 BSRB, 109 Zina Pitcher Place, University of Michigan Medical Center, Ann Arbor, USA d INSERM UMR_582, Institut de Myologie, Groupe Hospitalier Pitie-Salpetriere, 75013 Paris, France UPMC Univ Paris 06, UMR_582, 75013 Paris, France Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital for Children, London, United Kingdom

Computational models of the human body must be accurate enough to use in hypothesis testing or biological function analysis. This is possible only when such models use physiological information from different scales-such as the cell, tissue, and organ levels. This model of excitation-contraction coupling in skeletal muscles links cell-level electro-physiological behavior with organ-level biomechanical behavior.

The zebrafish is an emerging model system for the study of cardiac electrophysiology and human arrhythmias. High resolution imaging techniques are powerful tools for the study of zebrafish cardiac electrophysiology, but these methods require the complete absence of cardiac contraction. Many pharmacological agents that uncouple cardiac contraction also markedly alter the cardiac action potential (AP). In this study, we compared the effects two uncoupling agents, 2,3-Butanedione monoxime (BDM) and blebbistatin, on contractility and AP parameters in embryonic zebrafish heart.Zebrafish hearts were explanted (48 hpf) and superfused with either BDM (15 mM) or blebbistatin (1, 5 or 10 microM), while recording atrial or ventricular APs with the disrupted patch technique. Calcium transients were recorded with a high-speed confocal scanning microscope in hearts loaded intracellularly with 10 microM fluo-4 and superfused with 10 microM blebbistatin.Despite abolishing cardiac contractility, BDM altered ventricular AP morphology and inhibited spontaneous APs. In contrast, blebbistatin (10 microM) abolished contractility without significantly altering AP morphology or generation of spontaneous APs. Blebbistatin allowed for high fidelity measurements of atrial and ventricular calcium transients.Blebbistatin is a potent and effective excitation-contraction uncoupling agent in embryonic zebrafish heart.

The mechanisms that account for the strength loss after contraction-induced muscle injury remain controversial. We present data showing that (1) most of the early strength loss results from a failure of excitation-contraction coupling and (2) a slow loss of contractile protein in the days after injury prolongs the recovery time.

This study examined the alterations in sarcoplasmic reticulum (SR) Ca2+ sequestration function in homogenates during eccentric exercise and recovery and following additional eccentric exercise, and correlated these alterations with changes in force output. Eight healthy, untrained females, aged 20-25 years, cycled for a total of 60 min on an eccentric cycle ergometer (30 min at 66 ± 3% O2 peak and 30 min at 76 ± 3% O2 peak, determined during concentric exercise). Biopsies (extracted from the vastus lateralis) were taken before and after the exercise as well as on days 2, 6 and prior to and following identical exercise on day 14. Ca2+-uptake (nmol/min/mg protein) was unaffected (p > 0.05) following the first session of eccentric exercise; however, by day 2 a depression in uptake (p < 0.05) was observed which persisted throughout the remainder of the experiment. Maximal Ca2+-ATPase activity (nmol/min/mg protein) was elevated (p < 0.05) immediately following the first exercise session, remained elevated through day 2 and returned to pre-exercise levels by day 6 of recovery and increased again by day 14. No changes in either Ca2+-ATPase activity or Ca2+-uptake were observed with exercise on day 14. Both eccentric sessions, performed on days 0 and 14, resulted in similar depressions in force (p < 0.05) immediately following exercise. By day 2 force had recovered to pre-exercise levels. The results demonstrate that a prolonged alteration in SR Ca2+-uptake occurs following eccentric work that is unaccompanied by parallel changes in either SR Ca2+-ATPase activity or mechanical performance.

Phorbol esters are activators of protein kinase C (PKC) and have been widely used to study the function of this enzyme. We investigated the effect of phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), on tension responses and free cytosolic Ca in small strips of chick embryo ventricle and on the 45Ca influx in primary cultures of chick embryo ventricular cells. TPA (10(-8) M) decreased twitch tension about 40% when driven at 1 Hz. The free cytosolic Ca measured with fura-PE3 was rapidly increased in 110 mM KCl solution and this high K-induced increase was slightly inhibited by TPA (10(-8) M), by 12%. The resting 45Ca uptake in 5 mM KCl was slightly increased by a low concentration of TPA (10(-9) M), but high K-induced 45Ca uptake was decreased by TPA in a dose-dependent manner, but to 40% at the utmost. 4 alpha-Phorbol, an inactive phorbol ester, did not inhibit 45Ca uptake. These results indicate that TPA decreased the depolarization induced transsarcolemmal Ca uptake and thus the excitation-contraction process was attenuated, but to 40% at most. PKC may participate in the modulation of myocardial Ca homeostasis and contractile state.

Heart failure is a leading cause of morbidity and mortality with a prevalence that is rising throughout the world. Currently the pharmaceutical therapy of heart failure is mainly based on inhibition of the neurohumoral pathways that are activated secondary to the deterioration of cardiac function, and diuretics to alleviate the salt and water overload. With our increasing understanding of the pathophysiology of heart failure, it is now clear that the macroscopic and functional changes in the failing heart result from remodeling at the cellular, interstitial, and molecular levels. Therefore, emerging therapies propose to intervene directly in the remodeling process at the cellular and the molecular levels. Here, several experimental strategies that aim to correct the abnormalities in receptor and post-receptor-function, calcium handling, excitation and contraction coupling, signaling, and changes in the extra-cellular matrix in the failing heart will be discussed. These novel approaches, aiming to reverse the remodeling process at multiple levels, may appear on the clinical arena in the coming years.

Uterine contractility is generated by contractions of myometrial smooth muscle cells (SMCs) that compose most of the myometrial layer of the uterine wall. Calcium ion (Ca2+) entry into the cell can be initiated by depolarization of the cell membrane. The increase in the free Ca2+concentration within the cell initiates a chain of reactions, which lead to formation of cross bridges between actin and myosin filaments, and thereby the cell contracts. During contraction the SMC shortens while it exerts forces on neighboring cells. A mathematical model of myometrial SMC contraction has been developed to study this process of excitation and contraction. The model can be used to describe the intracellular Ca2+concentration and stress produced by the cell in response to depolarization of the cell membrane. The model accounts for the operation of three Ca2+control mechanisms: voltage-operated Ca2+channels, Ca2+pumps, and Na+/Ca2+exchangers. The processes of myosin light chain (MLC) phosphorylation and stress production are accounted for using the cross-bridge model of Hai and Murphy ( Am J Physiol Cell Physiol 254: C99–C106, 1988) and are coupled to the Ca2+concentration through the rate constant of myosin phosphorylation. Measurements of Ca2+, MLC phosphorylation, and force in contracting cells were used to set the model parameters and test its ability to predict the cell response to stimulation. The model has been used to reproduce results of voltage-clamp experiments performed in myometrial cells of pregnant rats as well as the results of simultaneous measurements of MLC phosphorylation and force production in human nonpregnant myometrial cells.

The functional role of the sodium-calcium exchanger in mouse ventricular myocardium was evaluated with a newly developed specific inhibitor, SEA0400. Contractile force and action potential configuration were measured in isolated ventricular tissue preparations, and cell shortening and Ca2+ transients were measured in indo-1-loaded isolated ventricular cardiomyocytes. SEA0400 increased the contractile force, cell shortening and Ca2+ transient amplitude, and shortened the late plateau phase of the action potential. alpha-adrenergic stimulation by phenylephrine produced a sustained decrease in contractile force, cell shortening and Ca2+ transient amplitude, which were all inhibited by SEA0400. Increasing the contraction frequency resulted in a decrease in contractile force in the absence of drugs (negative staircase phenomenon). This frequency-dependent decrease was attenuated by SEA0400 and enhanced by phenylephrine. Phenylephrine increased the Ca2+ sensitivity of contractile proteins in isolated ventricular cardiomyocytes, while SEA0400 had no effect. These results provide the first pharmacological evidence in the mouse ventricular myocardium that inward current generated by Ca2+ extrusion through the sodium-calcium exchanger during the Ca2+ transient contributes to the action potential late plateau, that alpha-adrenoceptor-mediated negative inotropy is produced by enhanced Ca2+ extrusion through the sodium-calcium exchanger, and that the negative staircase phenomenon can be explained by increased Ca2+ extrusion through the sodium-calcium exchanger at higher contraction frequencies.

A mathematical model for the excitation-contraction mechanism (E-C coupling) in cardiac cells has been formulated, based on the works of Tang and Othmer (1994), Luo and Rudy (1994), Jafri (1998) and Hamam (2000). This new model includes the kinetics as well as the electric aspects involved in the excitation-contraction process. It has been simulated using Matlab/sup /spl reg// Simulink/sup /spl reg//, and validated with experimental data provided by the INSERM institute (Paris, France). Simulation results show the expected ionic calcium concentration variations during the E-C coupling process, namely the bell-form shaped curve found by Fabiato, (1985). They also show an evolution of the membrane potential similar to that obtained by Luo and Rudy. This model is intended to be the basis of a computer aided system, to be used by biologists and doctors, as a research tool in experiment design and cardiac pathology treatment.

This paper extends the model for Ca movement in the cardiac ventricular cell from the diadic cleft space to the entire sarcomere. The model predicts the following: 1) Shortly after SR release there is a [Ca] gradient >3 orders of magnitude from cleft center to M-line which, 50 ms after release, is still >30. Outside the cleft, 40 ms after cessation of release, the axial gradient from Z to M-line is >3. 2) At the end of SR release, >50% of the total Ca released is bound to low-affinity inner sarcolemmal phospholipid binding sites within the cleft. 3) Halving the SR release almost doubles the fraction of release removed from the cell via Na/Ca exchange and reduces average sarcomeric free [Ca] by 70%. 4) Adding 100 microM fluo-3, which doubles the buffering capacity of the cytoplasm, reduces peak average sarcomeric [Ca] by >50% and increases the initial half-time for [Ca] decrease by approximately twofold. 5) A typical Ca "spark" can be generated by an SR release 20% of maximum (4 x 10(-20) moles) over 2 ms. Fluo-3 (100 microM) significantly "shrinks" the spark. 6) The "spark" is a consequence of elementary events within the diadic cleft space. For example, removal of cleft binding sites would cause average sarcomeric Ca to increase by >10 fold, fall 10 times more rapidly, decrease latency for appearance of the spark by >20 times, and reduce spark duration by 85%. 7) Dividing SR Ca release between cleft and corbular SR produces a secondary [Ca] peak and a "flattening" of the sarcomeric [Ca] transient. These changes probably could not be resolved with current confocal microscopic techniques.

Everybody has probably seen already too many lists of the multiple roles of changes in [Ca2+]int in the control of cell metabolism and in cell function. In fact, these lists have become so encompassing that I have now seen bold generalizations claiming that [Ca2+] increase is the common final pathway to effect metabolic change. It is not sure that this is the case, but the purpose here is to point out that Ca2+ is in fact a very dominant intracellular messenger. Just as an example, our laboratory has come across two roles of Ca2+ in E-C (excitation contraction) coupling that had not been described before (see following Chapter). Moreover, Ca2+ has what one might call structural roles, functions that it plays merely by being present, hence not requiring changes in [Ca2+]int or Ca-transients. These roles have to do with the stability of proteins and membranes, and with steady block of ion channels. In summary, Ca2+ has many known static and dynamic roles, and probably many more that are still ignored.

The aim of this study was to determine what the feet1 are in E-C coupling, and to know how input process proceeds upon depolarization. Fortunately, we could extract a protein2 for E-C coupling using phenylglyoxal, PGO, (PGO-protein); and the protein was a glycoprotein. We have, therefore, used concanavalin A (Con A), a lectin, which inhibits the E-C coupling; while, according to the results so far, phytohemagglutinin-P, a lectin, had no effect on the coupling.

The mechanism of transmission in skeletal muscle EC coupling is still an open question. There is some indirect evidence in favour of the mechanical coupling hypothesis, deriving mostly from consideration of the structure of the Ca2+ release channel protein. A new functional approach is proposed, that consists in comparing the properties of the complete system — EC coupling in a skeletal muscle fibre — with those of the EC coupling molecules in bilayers. In this approach, those properties of the whole system that are not traceable to its constitutive molecules, are ascribed to the physiological interaction, and are expected to yield new information on the nature of this interaction.

Background:Whether or not the excitation-contraction (EC) uncoupler, diacetyl monoxime (DAM) and cytochalacin D (Cyto D) alter the ventricular fibrillation activation patterns is unclear. Methods:We recorded single cell action potentials and performed optical mapping in isolated perfused swine right ventricles at different concentrations of DAM and cyto D during ventricular fibrillation and dynamic pacing. Results:Increasing concentration of DAM results in progressively shortened action potential duration measured to 90% repolarization (APD 90), reduced slope of the action potential duration restitution (APDR) curve, decreased Kolmogorov-Sinai entropy, and reduced number of ventricular fibrillation wavefronts. In all right ventricles, 15 to 20 mmol/l DAM converted ventricular fibrillation to ventricular tachycardia. The ventricular fibrillation could be reinduced after the DAM was washed out. In comparison, cyto D (10 to 40 μmol/l) has no effects on APDR curve or the dynamics of ventricular fibrillation. The effects of DAM on ventricular fibrillation are associated with reduced number of wavefronts and dynamic complexities in ventricular fibrillation. Conclusion:These results are compatible with Restitution Hypothesis of ventricular fibrillation and suggest that DAM may be unsuitable as an EC uncoupler for optical mapping studies of ventricular fibrillation in the swine right ventricles. (Korean Circulation J 2000;30(12):1515-1523)

The contractility of guinea pig ileum and frog skeletal muscle is inhibited in solutions containing 0.4 to 2.5 M formamide (FMD). Contrary to mammalian vis ceral muscle, this blocking action is not reversed when frog muscles are transferred back to isotonic Ringer's after FMD treatment. Under these conditions the water content of the skeletal muscles is markedly increased and electronmicrographs show a swellingof the transverse tubules. These changes are not observed when frog muscles are transferred to ethylene glycol solutions that are isosmotic with the FMD containing Ringer's solution. In addition, over 50% of the contractility is recovered in these muscles. These observations provide direct evidence of the occurrence of an osmotic shock in frog muscles transferred from FMD solutions to isotonic Ringer's. It is concluded that the resulting alterations in the triad structure and function are re sponsible for the irreversibility of the FMD uncoupling action in these muscles.

Simultaneous transmembrane action potential (TAP) and isometric contraction measurements were made in thin right ventricular papillary muscles isolated from senescent (S, 24-26 mo) and young adult (YA, 6-8 mo) rat hearts. At the peak of the length-tension curve in the steady state at 24 min-1 at 29 degrees C in perfusate [Ca2+] [( Ca2+]e) of 0.375 or 2.5 mM, contractile tension developed in response to excitation (DT) and the maximum rate of tension development (dT/dt) were not age-related; contraction duration (CD) was 17 and 27% greater in S than YA in the low and high [Ca2+]e, respectively (P less than 0.001); resting membrane potential was not age related. TAP time above zero mV, integrated area above zero mV, and times to 75% (T75) and 90% (T90) repolarization were approximately twofold greater in S than in YA in both [Ca2+]e (P less than 0.001). Changes in steady-state T75 and T90 due to an increase in [Ca2+]e from 0.375 to 2.5 mM were significantly correlated with those in CD, DT, and dT/dt in S but not in YA. We conclude that in the senescent myocardium a prolonged and greater extent of depolarization is related to the prolonged CD and may also be a determinant of the peak force developed in response to excitation under some conditions.

Aus den vorgelegten Befunden ergibt sich folgendes Gesamtbild: β-Receptorenblocker, Segontin und Isoptin setzen den gesamten Tatigkeitsstoffwechsel des Myokards auf dem Weg uber eine Frequenzsenkung und eine Einschrankung der mechanischen Funktionen durch Eingriff in die elektromechanischen Koppelungsvorgange herab. Daruber hinaus sind dampfende Effekte auf die Erregungsbildung, Erregungsleitung und Flimmerbereitschaft des Myokards nachweisbar. Der oxydative Ruhestoffwechsel des Herzmuskels wird dagegen durch die genannten Stoffe nicht mesbar verandert. Fur die negativ-inotropen Effekte der β-Receptorenblocker und ihrer Verwandten durfte eine Reduktion der ATP-Spaltung an den contractilen Myofibrillen entscheidend sein. Hierdurch wird die Utilisation von energiereichem Phosphat fur die contractilen Zwecke des Myokards gehemmt. Die Aktivitat der Myofibrillen-ATPase kann dabei prinzipiell auf 2 Wegen herabgesetzt werden. a) durch unspezifische Behinderung des Ca++-Influx wahrend Erregung bzw. durch Ca++-Verdrangung am contractilen System; b) durch spezifische β-Receptorenblockade, d.h. durch Verdrangung endogener Catecholamine, die in den Myokardfasern mit Ca++-Ionen „co-katalytisch“ zusammenwirken. Segontin und Isoptin wirken offenbar an der Myofibrillen-ATPase in erster Linie als Ca++-Antagonisten und erst in zweiter Linie als Catecholaminverdranger an β-Receptoren. Hinzu kommt im Falle von Segontin eine Senkung der Catecholaminvorrate. Infolgedessen wird das Myokard nach Gabe von Segontin und Isoptin fur sympathische Ubertragerstoffe nicht refraktar. Dagegen ist die Herabsetzung der Kontraktilitat nach Verabreichung „spezifischer“ β-Receptorenblocker vom Typ Inderal, Alderlin, Dichlorisoproterenol mit einer Aufhebung der sympathischen Regulation der Herztatigkeit verbunden. Eine Reaktivierung der Utilisation von energiereichem Phosphat kann durch geeignete Dosen von Ca++-Salzen, sympathomimetischen Stoffen (speziell Isoproterenol) oder Herzglykosiden erreicht werden, wobei sich die Kontraktilitat — selbst in Anwesenheit stark hemmender Konzentrationen von β-Receptorenblockern, Segontin und Isoptin — wieder erholt. Die Hohe des myokardialen O2-Bedarfs ist dabei jeweils mit der Intensitat der Umsetzungen von energiereichem Phosphat quantitativ korreliert.

Recent observations showing the presence of predominantly longitudinally oriented triads in the leg muscle fibers of newborn rats suggest a difference between the excitation-contraction (E-C) latencies in the leg muscles of newborn and adult rats. The extensor digitorum longus (EDL) and soleus (SOL) muscles were prepared in situ and stimulated indirectly through the peripheral segment of the crushed sciatic nerve. The preparations were maintained at a constant temperature of 37 C. Muscle action potentials were recorded with extracellular electrodes. The time between the beginning of the action potential and the beginning of the recorded development of tension in the muscle was measured in 98 young rats ranging in age from 1 to 40 days. This time was used as an indication of the E-C latency of the muscles. The average E-C latency in the EDL of 1-day rats was found to be about 6 msec. This latency rapidly declines during the first 10–15 days after birth to an average E-C latency of 2.8 msec by day 15 and then gradually approaches the average adult latency of 2.5 msec. Similar decreases in latency occur in the SOL muscle. Recent observations on the rat EDL and SOL, indicating that there is a change from the predominantly longitudinal to a predominantly transverse orientation of the triads during the first 10–15 days after birth, suggest that changes in the triads may be related to the observed decrease in E-C latency.

Twitch, tetanus, K contracture, and caffeine contracture tensions, and extracellularly recorded action potentials were measured in frog toe muscles bathed in hypotonic Ringer solutions. Tetanic tension is potentiated in these solutions down to 0.4 normal tonicity (0.4T), but falls off sharply to about 15% of the 1T value at 0.25T. The extracellularly recorded action potential also falls off at low tonicities but still is at 99% of the 1T value at 0.25T where the tetanus is only 15% of the 1T value. By contrast, the caffeine contracture tension is maintained at all tonicities indicating that hypotonic solutions have little direct effect on contractile proteins. It is shown that the decline of tension in very hypotonic solutions is due both to a loss in excitability and a true uncoupling of excitation and contraction. Raising [Ca] 0 to 3 times normal (5.4mM) allows recording of action potentials with no contraction. The loss of excitability and the decline of tension are not purely due to the decreased [Na] 0 because when NaCl is replaced with an osmotic equivalent of sucrose, tension and compound action potentials did not decline to zero. The loss of excitability may be due to the membrane depolarization observed in microelectrode studies.

The impact of adult aging on many aspects of myocardial function in animals and man has recently been reviewed (1,2,3). The present discussion will focus on excitation-contraction and aging of the myocardium. I will try -to integrate the findings of recent and earlier studies in order to formulate alternative hypotheses regarding the mechanisms of age-related alterations of excitation-contraction coupling.

With advancing age the ability of the cardiovascular system to respond to stress declines. The present discussion examines several mechanisms at both the organismal and cellular level that are known to determine cardiovascular performance, and analyses the current state of knowledge regarding the effect of aging on these processes. The conclusion reached is that aging does not result in a generalized decline in all parameters that regulate cardiovascular function, but rather a few specific functional deficits can be identified. Notably, these include a diminished responsiveness to catecholamines and altered vascular loading of the myocardium during high work load states.