Assessment of Ventricular Contractility During Cardiac Magnetic Resonance Imaging Examinations Using Normalized Maximal Ventricular Power

Normalized maximal ventricular power (nPWR^max) is an index of cardiac function which measures the innate blood pumping ability, or contractility, of the left ventricle (LV), and its noninvasive assessment could prove useful in a variety of patients. nPWR^max is defined as the maximum instantaneous product of LV pressure and the rate of change of LV volume, divided by the end diastolic volume squared. We have quantified nPWR^maxnoninvasively in humans by pairing magnetic resonance imaging (MRI) LV volume measurements with aortic pressure estimated using radial artery tonometry and a frequency domain transfer function. In healthy volunteers undergoing cardiac MRI we have tested the sensitivity of nPWR^max to LV contractility with dobutamine and to cardiac loading with methoxamine, a vasoconstrictor. We have found that aortic pressures can be reliably estimated using a transfer function, which we generated and validated in a group of patients undergoing cardiac catheterization. Furthermore, we found that nPWR^max was unchanged by methoxamine, yet sensitive to contractility, with a 325% increase at dobutamine levels half that given during routine clinical cardiac stress tests for ischemia. In conclusion, we have shown that ventricular contractility can be assessed independent of cardiac loading in patients during routine noninvasive cardiac imaging examinations. © 2001 Biomedical Engineering Society. PAC01: 8761Pk, 8719Hh, 8719Uv     

Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists

The positive inotropic effects of 2-pyridyl-ethylamine (PEA) and of 4-methylhistamine (4MeH) were studied in isolated guinea-pig ventricular strips electrically stimulated at a rate of 60 and 150/min. The increase in contractile tension induced by PEA (10^–7–3×10^–4 M) in the presence of cimetidine (10^–5 M) was associated with a slight increase in time to peak tension and with a lengthening of the relaxation phase; the positive inotropic effect of PEA was significantly higher at a frequency of 60/min than at 150/min. Conversely, the inotropic response to 4MeH (10^–8–3×10^–6 M)was not frequency dependent, and was associated with an evident decrease in relaxation time. Moreover, 4MeH consistently antagonized, in dosedependent manner, the negative inotropic effects induced by the calcium antagonistic drug D600 and by lowering calcium concentration in the medium, and was able to restore the contractility abolished by treatment of preparations with a high K⁺ medium. On the other hand PEA, in the presence of cimetidine, scarcely antagonized the negative inotropic effects induced either by D600 or by low calcium solution, and was unable to restore the contractility of K⁺-depolarized preparations. The characteristics of the inotropic response of the H₁-receptor agonist were very similar to those of the alpha-adrenoceptor agonist phenylephrine. This observation suggests that a common mechanism is probably involved in the inotropic effects mediated by H₁ and by alpha receptors, and that this mechanism does not include a stimulation of the calcium transmembrane influx.     

Effect of platelet-activating factor (PAF) on human cardiac muscle

The effect of platelet activating factor (PAF) on three mechanical [maximal mechanical tension (Pmax); time to peak tension; maximal rate of rise of tension (+dP/dt)] and four electrical [action potential duration (APD); resting membrane potential; overshoot; maximum rate of depolarization] parameters of cardiac function was studied on fragments of isolated human cardiac papillary muscle. 20 specimens of small tissue fragments excised from the left ventricle by open heart surgery were challenged with various doses of synthetic PAF (10(-10)-10(-6) M). PAF, but not its biologically inactive 2-lyso-derivative (lyso-PAF), induced a biphasic dose-dependent effect, characterized by a transient positive effect on inotropism (increased Pmax, +dP/dt) and of APD, followed by a marked, prolonged negative effect on both inotropism (decreased Pmax, time to peak tension, +dP/dt) and APD. No changes in resting membrane potential, overshoot and maximum rate of depolarization were detected after PAF challenge. Propranolol (2 X 10(-7) M) completely prevented the positive inotropic effect suggesting a stimulation of beta-receptors, possibly exerted by endogenous catecholamines. Indomethacin (1 X 10(-4) M) did not modify the initial positive effect, but markedly reduced the subsequent negative effect induced by PAF on inotropism. These findings are consistent with the interpretation that the effect of PAF on the inotropism is related to liberation of cyclooxygenase-derived metabolites.     

Left Ventricular Contractility is Impaired Following Myocardial Infarction in the Pig and Rat: Assessment by the End Systolic Pressure–Volume Relation Using a Single-Beat Estimation Technique and Cine Magnetic Resonance Imaging

The end systolic pressure–volume relation (ESPVR) has been shown to be a relatively load independent measure of left ventricular (LV) contractility. Recently, several single-beat ESPVR computation methods have been developed, enabling the quantification of LV contractility without the need to alter vascular loading conditions on the heart. Using a single-beat ESPVR method, which has been validated previously in humans and assumes that normalized elastance is constant between individuals of a species, we studied the effects of myocardial infarction on LV contractility in two species, the rat and the pig. In our studies, LV pressure was acquired invasively and LV volume determined noninvasively with magnetic resonance imaging, at one week postinfarction in pigs and at 12 weeks postinfarction in rats. Normalized systolic elastance curves in both animal species were not statistically different from that of humans. Also, the slope of the ESPVR decreased significantly following infarction in both species, while the volume-axis intercept was unaffected. These results indicate that a single-beat ESPVR method can be used to measure the inotropic response of the heart to myocardial infarction, and that the basis for this method (i.e., constant normalized elastance) is applicable to a variety of mammalian species. © 2000 Biomedical Engineering Society. PAC00: 8719Uv, 8761Lh, 8719Hh, 8719Rr, 8719Ff     

Localization of beta adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle

1. Isoprenaline and noradrenaline were applied iontophoretically to cardiac Purkinje fibres. Intracellular application of the drugs had no effect, while extracellular application of the same amounts of charge caused acceleration of pace-maker activity and a shift of the plateau level of the action potential. These results indicate that beta-adrenergic receptors are located at the outside of the cardiac cell membrane.2. A systematic comparison of the effects of cyclic AMP derivatives and noradrenaline on action potentials and isometric tension of ventricular myocardial preparations showed that the nucleotides and the catecholamine increase the plateau height and the duration of the action potential and also increase tension. However, there are quantitative differences in the action of these drugs.3. Cyclic AMP derivatives and noradrenaline increase the slow inward current, I(Ca), in ventricular myocardial preparations. Voltage clamp analysis of I(Ca) showed that the kinetic parameters of this membrane current are not affected by these drugs. However, the membrane conductance to Ca ions is greatly increased by noradrenaline and to a smaller extent by dibutyryl cyclic AMP.4. Concentration-response relations of the membrane effects of noradrenaline on plateau height of the action potential and on I(Ca) could be fitted by the same theoretical log concentration-response curve. The Hill plot of this concentration-response curve had a slope of 2. The half maximal response occurred at 5 x 10(-7)M.5. The results are compared with other membrane effects of catecholamines and cyclic nucleotides in cardiac muscle. The effects on I(Ca) are related to the positive inotropic effect of the drugs.     

Surface strains in the anterior leaflet of the functioning mitral valve

The mitral valve (MV) is a complex anatomical structure whose function involves a delicate force balance and synchronized function of each of its components. Elucidation of the role of each component and their interactions is critical to improving our understanding of MV function, and to form the basis for rational surgical repair. In the present study, we present the first known detailed study of the surface strains in the anterior leaflet in the functioning MV. The three-dimensional spatial positions of markers placed in the central region of the MV anterior leaflet in a left ventricle-simulating flow loop over the cardiac cycle were determined. The resulting two-dimensional in-surface strain tensor was computed from the marker positions using a C ⁰ Lagrangian quadratic finite element. Results demonstrated that during valve closure the anterior leaflet experienced large, anisotropic strains with peak stretch rates of 500%–1000%/s. This rapid stretching was followed by a plateau phase characterized by relatively constant strain state. We hypothesized that the presence of this plateau phase was a result of full straightening of the leaflet collagen fibers upon valve closure. This hypothesis suggests that the MV collagen fibers are designed to allow leaflet coaptation followed by a dramatic increase in stiffness to prevent further leaflet deformation, which would lead to valvular regurgitation. These studies represent a first step in improving our understanding of normal MV function and to help establish the principles for repair and replacement. © 2002 Biomedical Engineering Society. PAC2002: 8719Hh, 8719Uv, 8719Rr     

An Experimentalist's Approach to Accurate Localization of Phase Singularities during Reentry

A phase variable that uniquely represents the time course of the action potential has been used to study the mechanisms of cardiac fibrillation. A spatial phase singularity (PS) occurs during reentrant wave propagation and represents the organizing center of the rotating wave. Here, we present an error analysis to investigate how well PSs can be localized. Computer simulations of rotating spiral waves scaled appropriately for cardiac tissue were studied with various levels of noise added. The accuracy in identifying and localizing singularities depended on three factors: (i) the point chosen as the origin in state space used to calculate the phase variable; (ii) signal to noise ratio; and (iii) discretization (number of levels used to represent data). We found that for both simulation as well as experimental data, there existed a wide range for the choice of origin for which PSs could be identified. Discretization coupled with noise affected this range adversely. However, there always existed a range for choice of the origin that was 20% or more of the action potential amplitude within which the accuracy of localizing PSs was better than 2 mm. Thus, a precise determination of origin was not necessary for accurately identifying PSs. © 2001 Biomedical Engineering Society. PAC01: 8719Nn, 8710+e, 8719Hh     

Negative inotropic influence of hyperosmotic solutions on cardiac muscle.

In cardiac muscle, moderate degrees of hyperosmolality of the type encountered physiologically or clinically (i.e., less than 200 mosM above control) characteristically exert a positive inotropic effect, which presumably is mediated by increased Ca2+ availability for binding to troponin. In contrast, skeletal muscle displays significant contractile depression on exposure to hyperosmotic solutions, even at mild degrees of hypertonicity. To determine whether a similar potential for hyperosmolarity-induced depression also exists in cardiac muscle, right ventricular papillary muscles from cats were exposed to hypertonic solutions of mannitol or sucrose under circumstances in which positive inotropic effects were precluded by prior exposure to a bathing solution of 4.0 mM Ca2+ and paired electrical stimulation to maximize intracellular Ca2+ before addition of the hyperosmotic substances. In contrast to their usual positive inotropic effects, hypertonic solutions under these conditions caused cardiac depression at all osmolarities tested. Developed tension and its maximal rate of development (dT/dt) decreased by 18% at 50 mosM above control, by 30% at 100 mosM, by 36% at 150 mosM, and by 42% at 200 mosM (P less than 0.01 for all). Time to peak tension and resting tension were not changed significantly. When the muscles were returned to control solutions, tension development also returned toward normal. The data are compatible with the hypothesis that, within the range tested, all degrees of hyperosmolarity exert a significant negative inotropic influence on cardiac muscle, as is true in skeletal muscle; manifestation of this effect of increased tonicity normally would be obscured at low degrees of hyperosmolality, however, by an overriding positive influence that is absent in skeletal muscle.     

Phase Shifting Prior to Spatial Filtering Enhances Optical Recordings of Cardiac Action Potential Propagation

Optical imaging of cardiac electrical activity using a voltage-sensitive dye provides high spatial resolution maps of action potential propagation and repolarization. Charge-coupled-device (CCD) camera-based imaging systems, however, are limited by their low signal-to-noise ratio. We have developed an image processing method to enhance the quality of optical signals recorded using a CCD camera. The method is based on the observation that within a small neighborhood of adjacent pixels, the morphology of the optical action potential varies little except for a phase shift in time resulting from the propagation of the wavefront. The method uses a phase-correlation technique to first correct for this time shift before spatially filtering with a 5 × 5 Gaussian convolution kernel ( =1.179). A length 5 median filter is then applied to further reduce noise by filtering in the temporal domain. The image-processing scheme allows for more accurate extraction of maps of electrical activation, repolarization, and action potential duration. © 2001 Biomedical Engineering Society. PAC01: 8780Tq, 8719Hh, 8719Nn, 8757Ce     

Tension Responses to Rapid (Laser) Temperature-jumps during Twitch Contractions in Intact Rat Muscle Fibres

We examined the tension responses induced by rapid temperature-jumps (T-jumps) applied at different times during twitch and tetanic contractions in small intact fibre bundles (5–10 fibres) isolated from a fast foot muscle (flexor hallucis brevis) of the rat. A rapid T-jump of 2–4°C was induced by a 0.2 ms infrared (λ = 1.32 μm) laser pulse applied to the fibre bundle immersed in a 50 μl trough of physiological saline, the temperature of which was clamped at different steady temperatures ranging from 10 to 30°C. In a tetanic contraction, the tension increased to the same steady level when a standard T-jump was applied at different intervals after the onset of stimulation; thus, with maximal activation, an enhanced force generation by T-jump leads to a new steady state. In a twitch contraction, a T-jump induced a large, potentiation of tension when it was applied during the rising phase. Whereas the twitch relaxation subsequent to a T-jump was faster in all cases, the amplitude of the twitch tension potentiation decreased as the T-jump was delayed with respect to the stimulus, and there was no increase of tension when a T-jump was placed on the relaxation phase of the twitch. The increase of tension induced by a T-jump applied on the rising phase resulted in peak tension that was greater than the tension in control twitches at the steady post-T-jump temperature; therefore tension was higher than that expected on the basis of steady state temperature dependence of twitch tension. Whether these effects on a twitch contraction arise from differential fibre-heating by a T-jump that leads to shortening and development of sarcomere length disorder etc remain unclear. However, the findings may be interpreted as indicating that twitch tension increment by a T-jump occurs when excitation (the action potential) leading to calcium release and thin filament activation occur at the low temperature, whereas the crossbridge force-generation processes (and Ca -uptake) proceed at the higher temperature.     

Onset of contractility in cardiac muscle

1. A technique is described whereby (i) quick stretches and releases of controlled velocity, amplitude and time of onset can be applied to muscle. (ii) Releases from isometric to isotonic contraction can be performed at controlled delays relative to the stimulus, and displayed on a delayed expanded oscilloscope sweep. An isotonic lever system with an equivalent mass of 12·8 mg is described.

2. Quick stretch of rabbit or cat papillary muscle after excitation does not result in a level of tension equal to or greater than normal peak isometric tension appropriate to the stretched length. Stretches applied during the first half of the rising phase of tension development give responses nearly identical to the same stretches applied before the stimulus (indicating that Starling's Law of the heart holds until this time). Stretches applied in the later phase of tension development or during relaxation result in diminished peak isometric tensions or accelerated relaxation.

3. The rate of tension development following quick releases of isometrically contracting muscle to zero tension is not maximal until the releases are made 150-200 msec after excitation.

4. Shortening velocity with light afterloads is not initially maximal nor constant for an appreciable period of time. The shortening velocity with heavy afterloads reaches its maximum more rapidly when the load is not lifted within the first 200 msec of a contraction which, if maintained isometric, would have required 400-500 msec to reach peak tension. With these heavier loads, a period of 100-200 msec of constant shortening velocity may occur.

5. Freeloaded isotonic contractions show an inflexion in their shortening curves occurring 150-200 msec after excitation.

6. Maximum rate of isotonic shortening following releases from isometric to isotonic contraction with a given load is not maximal until the releases occur about 200 msec after the stimulus.

7. It is concluded that contractility in cardiac muscle is relatively slow in its onset with maximum capacity to shorten occurring about midway through the rising phase of isometric tension development.

     

The contractile and electrophysiological effects of rolipram in guinea-pig papillary muscles and isolated ventricular myocytes

Isometric force, action potentials and in voltage-clamp 1st (second inward current) and its current voltage relation were recorded in papillary muscles from guinea-pigs and from guinea-pig isolated ventricular myocytes (35–37 ^oC, 0.5-1 Hz). Rolipram (1–100 µM) had no significant effect on peak isometric twitch. The rate of rise of force and time to peak tension (TPT) was likewise unaffected. Time to half relaxation (THR) was increased in a dose-dependent manner and at 30 µM THR was prolonged by 25.3 ± 6% (n= 10, P < 0.001). The effect of 30µM rolipram on isometric force was frequency dependent. At 0.25 Hz peak force was increased by 6.3 ± 3.1% (n= 7, P < 0.05). At 2 Hz rolipram exhibited a negative inotropic effect of 9.8 ± 3.3% (n= 5, P < 0.02). Action potential duration at 90% repolarization was prolonged by 13 ± 6 ms (n= 7, P < 0.05), and there was usually no effect on resting potential or action potential amplitude. Sometimes, however, a depressed plateau was recorded. Rolipram was without effect on I¹_st and its current-voltage relations. Time to full mechanical restitution after a test interval was not changed but the shape of the restitution curve was altered. The restitution process was much slower in the presence of rolipram. Hence, peak force was lower at test intervals shorter than 800 ms. Likewise, the shape of the curve relating postextrasystolic potentiation to test interval was altered by rolipram. The interval required for maximum potentiation was increased by rolipram and did not significantly affect the recirculation fraction of activator calcium.     

Length-dependent activation of in situ canine skeletal muscle.

This study was designed to assess the contribution of length-dependent activation to the peak isometric twitch tension developed and the maximal rate of tension development (dP/dt) of in situ canine skeletal muscle. Length-developed tension and length-dP/dt relationships were generated for the dog gastrocnemius-plantaris muscle group at three different levels of inotropic state as determined by stimulation frequency. These relationships were then normalized with respect to maximal developed tension and maximal dP/dt and the normalized curves were superimposed for comparison. At progressively shorter muscle lengths the augmentation of tension production by a given increment in inotropic state was greater as measured by either developed tension or dP/dt. Thus, a given change in muscle length produced a greater change in performance in less potentiated muscles. These findings are similar to those from studies of isolated cardiac muscle and illustrate the lack of independence between activational state and muscle length for in situ skeletal muscle.     

Elastance-Based Control of a Mock Circulatory System

A new control strategy for a mock circulatory system (MCS) has been developed to mimic the Starling response of the natural heart. The control scheme is based on Suga's elastance model, which is implemented using nested elastance and pressure feedback control systems. The elastance control loop calculates the desired chamber pressure using a time-varying elastance function and the ventricular chamber volume signal. The pressure control loop regulates the chamber pressure according to this reference signal. Simulations and tests on MCS hardware showed that the elastance-based controller responds to changes in preload, afterload, and contractility in a manner similar to the natural heart. Since the elastance function is an arbitrary function of time, the controller allows modification of ventricular chamber contractility, giving researchers a new tool to mimic various pathological conditions which can be used in the evaluation of cardiac devices such as ventricular assist devices. © 2001 Biomedical Engineering Society. PAC01: 8719Uv, 8780-y, 8719Rr     

Electromechanical studies on the inotropic effects of acetylstrophanthidin in ventricular muscle.

Three phases in the inotropic response of acetyl strophanthidin (AcS) on the electromechnical activity of the frog ventricular myocardium were identified and studied using a single sucrose voltage-clamp technique and other conventional electrophysiological methods. 2. the positive inotropic response of the drug was accompanied by a shift in tension-voltage relation, so that more tension developed with every depolarization step above the mechanical threshold (-50mV). Only at higher drug concentrations or with long exposure times did the mechanical threshold shift to more negative membrane potentials (-60 to-70 mV). 3. In tetrodotoxin-treated muscles AcS produced marked potentiation of twitch tension and an appropriate shift in the tension-voltage relation. 4. the positive inotropic response of the drug was not related to the magnitude of the direction of the fast or slow Na current. 5. in tetrodotoxin-treated ventricular strips the direction or the magnitude of the secondary inward current (ICa or INa) were not related to the inotropic effect of AcS. 6. AcS shortens the action potential markedly during the later stages of its positive inotropic response. When Ca2+ is omitted from the bathing solution AcS not only fails to shorten the action potential, but often prolongs it. 7. The shortening of the action potential in the presence of AcS is accompanied by an increase in the "instantaneous" membrane conductance both at rest and during the time course of the plateau. 8. The decline in the positive inotropic response of the drug was accompanied by the shortening of the action potential. Electrical or chemical prolongation of the action potential restored the full positive inotropic response if the membrane had not depolarized. 9. Membrane depolarization and the development of diastolic tension always occurred at later stages of drug action. Elevation of [Mg+2]degrees to 5 or 10 mM prevented or suppressed the membrane depolarization and the diastolic tension. 10. KCl-induced contractures were potentiated throughout the duration of drug exposure. The tonic component of the contracture tension was markedly elevated especially at later stages of drug action. 11. The experimental evidence suggests that no unitary mechanism could account for multiple actions of acetyl strophanthidin. However, the contributions of the Na pump, the Ca+2 sequestering system, and the K-efflux system to the various stages of drug action are discussed.     

Mechanism of adenosine 3′,5′-monophosphate (cAMP)-induced increase in Ca2+ uptake by the sarcoplasmic reticulum in functionally skinned myocardial fibers

The increased rate of Ca²⁺ uptake and ATPase activity in isolated cardiac sarcoplasmic reticulum (SR) by adenosine 3,5-monophosphate (cAMP) has been shown to be activated by a cAMP-dependent protein kinase (cAMP kinase). Functionally skinned myocardial fiber preparations were used to study the mechanisms of cAMP action on the SR at the same time that tension was monitored. cAMP effects were studied on Ca²⁺-activated tension of the contractile proteins, and on Ca²⁺ uptake and release from the SR using caffeine-induced tension transients. Neither cyclic AMP (0.1–5 M) nor the catalytic subunit of cAMP kinase (0.1–1 M) (PK-C) significantly changed either the maximal or the submaximal Ca²⁺-activated tension. The areas of the tension transients were unchanged when cAMP was present in the releasing solution (release phase), and were significantly increased up to a mean of about 80% when cAMP or PK-C was present in the Ca²⁺ loading solutions (uptake phase). The increased tension transient was blocked by the heat-stable inhibitor of cAMP kinase. We conclude that cAMP-induced increases in Ca²⁺ uptake by the SR could play an important role in the positive inotropic effect. cAMP kinase could thus play a crucial role in the regulation of myocardial contractility.     

Effects of Mixed Herbal Extracts from Parched Puerariae Radix, Gingered Magnoliae Cortex, Glycyrrhizae Radix and Euphorbiae Radix (KIOM-79) on Cardiac Ion Channels and Action Potentials

KIOM-79, a mixture of ethanol extracts from four herbs (parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix), has been developed for the potential therapeutic application to diabetic symptoms. Because screening of unexpected cardiac arrhythmia is compulsory for the new drug development, we investigated the effects of KIOM-79 on the action potential (AP) and various ion channel currents in cardiac myocytes. KIOM-79 decreased the upstroke velocity (V_max) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased V_max and plateau potential, the peak amplitude of Na⁺ current (I_Na) and Ca²⁺ current (I_Ca,L) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K⁺ current; increase of depolarization phase current (I_depol) and decreased tail current at repolarization phase (I_tail). The increase of APD was suspected due to the decreased I_tail. In computer simulation, the change of cardiac action potential could be well simulated based on the effects of KIOM-79 on various membrane currents. As a whole, the influence of KIOM-79 on cardiac ion channels are minor at concentrations effective for the diabetic models (0.1-10 µg/mL). The results suggest safety in terms of the risk of cardiac arrhythmia. Also, our study demonstrates the usefulness of the cardiac computer simulation in screening drug-induced long-QT syndrome.     

H1- and H2-receptors in the guinea-pig heart: an electrophysiological study

The mechanical and electrophysiological effects of 2-pyridylethylamine (PEA) and 4-methylhistamine (4MeH) in different sections of guinea-pig heart were examined.4MeH produced a dose-dependent increase in contractility in the right ventricle and the right atrium, and a decrease in functional refractory period (FRP) in all the sections studied; the action potential duration was decreased and the plateau phase was usually heightened in both atria and the ventricle. These effects were consistently antagonized by cimetidine.PEA-induced changes in contractility, FRP and the action potential profile were studied in the presence of cimetidine. Triprolidine antagonized PEA effects on FRP and the action potential profile only in the left atrium.The results obtained are discussed in terms of the functional role of both H₁ and H₂ receptors in the various guinea-pig heart sections.     

Predicting the Responses of Mechanoreceptor Neurons to Physiological Inputs by Nonlinear System Identification

The nonlinear dynamic properties of action potential encoding were studied in mechanosensory neurons innervating the slits of a slit-sense organ in the tropical wandering spider, Cupiennius salei. The organ contains two types of neurons that are morphologically similar but have different dynamic properties. Type A neurons produce only one or two action potentials in response to a mechanical or electrical stimulus of any suprathreshold amplitude, while type B neurons can fire prolonged bursts of action potentials in response to similar stimuli. Neurons were stimulated with pseudorandomly modulated intracellular current while recording the resultant fluctuations in membrane potential and action potentials. A parallel cascade method was used to estimate a third-order Volterra series to describe the nonlinear dynamic relationship between membrane potential and action potentials. Kernels measured for the two types of neurons had reproducible forms that showed differences between the two neuron types. The measured kernels were able to predict the responses of the neurons to novel pseudorandomly modulated inputs with reasonable fidelity. However, the Volterra series did not adequately predict the difference in responses to step depolarizations. © 2001 Biomedical Engineering Society. PAC01: 8719Bb, 8717Nn, 8719La, 8719Nn, 8716Uv     

Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine.

The effects of insulin (In) on contractile activity of isolated cardiac muscle were studied in right ventricular moderator band (MB) of piglets and papillary muscle (PM) of cats and kittens. The muscles were bathed in modified Krebs solution containing 5.6 mM glucose at 30 degrees C and gassed with 95% O2 and 5% CO2. They were paced at 24 contractions per minute isometrically at Lmax. Addition of In (1 U/ml) to the bath induced a biphasic inotropic response to piglet MB. The initial negative effect was due to the preservative (0.2% phenol) in the regular commercial In solution. Following the transitory depression, both active isometric tension (AT) and maximal rate of tension development increased to a maximum (about 120% of control) within 15 min and then declined slightly toward control. Similar positive responses were observed in both cat and kitten PM, but without the initial negative effect. Maximal responses were not diminished by the absence of glucose in the bath. Increases in AT and dT/dt of both MB and PM in response to NE were significantly attenuated in the presence of In compared with untreated muscle. These findings demonstrate that In elicits a positive inotropic effect on mammalian cardiac muscle and that it impairs the inotropic action of NE.