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D T Yue

Publications and source records attributed to D T Yue.

54 records · Page 3Linked to original sources
PubMed1988

A novel cardiac potassium channel that is active and conductive at depolarized potentials.

We report the existence of a novel potassium channel revealed in single-channel recordings from guinea-pig ventricular heart cells. The channel, observed in approximately 10% of patches, demonstrates a 14 pS conductance at physiological potassium concentrations, does not rectify over the voltage range of the action potential, and is quite selective for K ions. The channel activates with depolarization, but does not require intracellular Ca2+ ions to open. Open channel probability increases rapidly (less than 10 ms) to a plateau in response to depolarizing voltage steps, and demonstrates no detectable inactivation (greater than 600 ms). These features clearly distinguish this channel from other known K channels in cardiac muscle. Because of its high activity at plateau potentials, we propose the name iKp.

Animals↗
PubMed1988

In vitro studies of isolated supported human hearts.

We developed methods to revive human hearts, obtained at the time of cardiac transplantation, and study them in the physiology laboratory. The hearts were arrested with cardioplegic solution at the time of explanation and transported to the laboratory at 4 degrees C. The hearts were perfused with a human blood based solution whose flow rate, temperature, and ionic concentration were controlled. Six hearts with various endstage cardiomyopathies were revived in this manner. Once perfusion was started, the hearts maintained a steady contractile state for approximately 30 min during which time data could be collected. Within this time period we could measure end-systolic and end-diastolic pressure-volume relations, the time courses of contraction and relaxation, and the influence of heart rate and premature stimulation on contractile state. The results suggest that evidence of specific cellular abnormalities in human heart disease might be obtained from measurements of global ventricular performance. Furthermore, the type of abnormality identified, namely sarcoplasmic reticulum dysfunction, in several forms of cardiomyopathy was in concordance with results obtained in muscle bath studies of similarly diseased human and animal myocardium.

Cardiomyopathy, Dilated↗
PubMed1988

Effect of isoproterenol on force transient time course and on stiffness spectra in rabbit papillary muscle in barium contracture.

To determine whether catecholamines produce alterations in myocardial myosin-actin cycling kinetics, we investigated the effects of isoproterenol upon mechanical characteristics of constantly activated heart muscle thought to reflect crossbridge behavior. In isolated rabbit right ventricular papillary muscles in barium contracture at 24 degrees C, we found that 10 microM isoproterenol caused: (a) a 23% reduction of the 10 to 90% rise time of slow tension recovery in force transients induced by rapid, small amplitude stretches; and (b) a 23% increase in the frequency of sinusoidal length perturbation at which stiffness amplitude exhibited a minimum. Based upon previous mechanistic interpretations of force transients, and on an analysis developed here to relate crossbridge events to the frequency-dependence of stiffness, we argue that our observations provide evidence that isoproterenol induces an acceleration of crossbridge cycling rate. This raises the intriguing prospect that beta-adrenergic stimulation regulates contraction, not only by well-known alterations in calcium metabolism, but also by intrinsic modulation of the force-generating machinery itself.

Animals↗
PubMed1987

Influence of ventricular contractility on non-work-related myocardial oxygen consumption.

The relationship between myocardial oxygen consumption (MVO2) and the total pressure-volume area (PVA), which represents the total mechanical work performed during a cardiac cycle, has been shown to be linear and independent of loading conditions: MVO2 = aPVA + b. When inotropic state is enhanced, the MVO2-PVA relation shifts upward (increase in b), and when inotropic state is depressed the relation shifts downward (decrease in b). However, the quantitative relationship between contractility and b (the non-work-related myocardial oxygen consumption) determined over a wide range of contractilities is not known. In seven isolated blood perfused canine hearts, left ventricular (LV) contractility was increased by dobutamine and decreased with nifedipine or reduction of coronary blood flow. At each level of contractility, the end-systolic pressure-volume relationship (ESPVR) and the MVO2-PVA relation were determined. For each heart, the resulting values of b (ml O2/beat) were plotted as a function of Emax (mmHg/ml), an index of contractility defined as the slope of the ESPVR. There was a linear relation between Emax and b over a wide range of contractilities; on average, b (ml O2/beat) = 0.0036 Emax (mmHg/ml) + 0.0101 [r = 0.929-0.978 (95% confidence interval)], when Emax was varied over an average range of 2.8-9.6 mmHg/ml. These results suggest a common underlying determinant of contractility and non-work-related oxygen consumption.

Animals↗
PubMed1987

Intracellular free calcium concentration measured with 19F NMR spectroscopy in intact ferret hearts.

Changes in the intracellular free Ca2+ concentration, [Ca2+]i, mediate excitation-contraction coupling in the heart and contribute to cellular injury during ischemia and reperfusion. To study these processes directly, we measured [Ca2+]i in perfused ferret (Mustela putorius furo) hearts using 19F NMR spectroscopy to detect the 5,5'-difluoro derivative of the Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). To load cells, hearts were perfused with the acetoxymethyl ester derivative of 5,5'-F2-BAPTA. We measured 19F NMR spectra and left ventricular pressure simultaneously, at rest and during pacing at various external Ca concentrations [( Ca]o). Although contractile force was attenuated by the Ca2+ buffering properties of 5,5'-F2-BAPTA, the decrease in pressure could be overcome by raising [Ca]o. Our mean value of 104 nM for [Ca2+]i at rest in the perfused heart agrees well with previous measurements in isolated ventricular muscle. During pacing at 0.6-4 Hz, time-averaged [Ca2+]i increased; the effect of pacing was augmented by increasing [Ca]o. [Ca2+]i more than tripled during 10-20 min of global ischemia, and returned toward control levels upon reperfusion. This approach promises to be particularly useful in investigating the physiology of intact hearts and the pathophysiology of alterations in the coronary circulation.

Animals↗
PubMed1987

Intracellular [Ca2+] related to rate of force development in twitch contraction of heart.

The relation between the rate of rise of tension (dF/dt) and intracellular free Ca2+ concentration ([Ca2+]i) during twitch contraction was investigated in mammalian ventricular myocardium. [Ca2+]i was assessed from luminescence emitted by ferret papillary muscles microinjected with the calcium-regulated photoprotein aequorin. Evidence was found that during the phase of rising tension following maximum positive dF/dt, there was an approximately linear relationship between dF/dt at a given instant and the estimated [Ca2+]i at that same instant. A single such instantaneous relationship held true for physiological contractions of widely varying strength (n = 5 preparations), up to 65.3 +/- 6.0% (means +/- SE) of maximal Ca2+-activated force, as assessed from maximally activated cardiac tetani. Furthermore, the identical relationship determined from physiological contractions also held true for virtually the entire rising phase of tension in contractions with [Ca2+]i transients slowed (approximately 4- to 5-fold) by exposure of muscles to 5 microM ryanodine (n = 5 preparations). That a unique relation applies to contractions of both vastly different strength and time course provides evidence that the correlation between instantaneous dF/dt and [Ca2+]i is not merely fortuitous but indicates a fundamental property of myocardium. Such a property provides considerable insight into many features of physiological contraction and may represent a central clue as to the mechanism of activation in mammalian cardiac muscle.

Aequorin↗
PubMed1987

Contractility-dependent curvilinearity of end-systolic pressure-volume relations.

The shape of the end-systolic tension-length relationship (ESTLR) changes when contractile state is changed, whereas the end-systolic pressure-volume relationship (ESPVR) remains linear despite changes in contractility. To investigate this disparity, the ESPVR was determined with contractility altered extensively by dobutamine, BAY K 8644, nifedipine, lowering coronary blood flow, and the introduction of extrasystolic and postextrasystolic stimulations. The ESPVRs were fitted by nonlinear regression analysis to the parabolic equation Pes = aVes2 + bVes + c, where Pes is end-systolic pressure, Ves is end-systolic volume, and a, b, and c are parameters. There was a negative, statistically significant correlation between a, which serves as a shape index of the ESPVR, and E'max, the slope of the ESPVR in a low volume range. When E'max was large a was negative, indicating increasing concavity of the ESPVR to the volume axis at high contractility. When E'max was small a was positive, indicating convexity of the ESPVRs to the volume axis at low contractility. Within the average range of E'max between 3.4 and 7.8 mmHg/ml, however, the parabolic fit to the data was not statistically better than a linear fit over the range of volumes testable in the isolated heart. We conclude that the shape of the ESPVR measured in the isolated canine heart changes with contractile state. In accordance with previous interpretations of shape changes in the muscle ESTLR, these results are consistent with the existence of length-dependent activation of cardiac muscle in the intact heart.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

Quantitative comparison of canine right and left ventricular isovolumic pressure waves.

The mechanical properties of the right and left ventricles (RV and LV) have previously been studied separately. However, because of differences in RV and LV architecture, geometry, and muscle mass, it is not obvious how the properties of the two chambers would relate to each other. This study compared the time courses of RV and LV isovolumic pressure waves (LVP, RVP, respectively) measured simultaneously in the same heart. We compared RVP and LVP in each of five isolated, supported canine hearts after pentobarbital anesthesia. RV and LV volumes were varied independently so that on various beats peak LVP exceeded, equaled, or was less than peak RVP. There was a delay of approximately 35 ms between the onset of LV and RV pressure waves with atrial pacing, but only 5 ms with ventricular pacing. LVP and RVP were measured and digitized at a sampling rate of 200 Hz. Pressure waves were offset and rescaled by their respective amplitudes so that for each beat the pressure wave had a minimum value of 0% at end diastole and a maximum value of 100% at end systole. RVP was then shifted in time so that its upstroke was synchronous with that of the LVP at the point of 50% of maximal developed pressure. The rescaled, time-shifted RVP was plotted as a function of the rescaled LVP for each point of the cardiac cycle, and the relation between the two was quantified by their root mean square difference (Drms). Drms averaged 2.3 +/- 1.5% (SD) for the first half of contraction, 1.5 +/- 0.4% for the second half of contraction, and 4.6 +/- 1.6% during relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Relationship between force and intracellular [Ca2+] in tetanized mammalian heart muscle.

To determine features of the steady state [Ca2+]-tension relationship in intact heart, we measured steady force and intracellular [Ca2+] ([Ca2+]i) in tetanized ferret papillary muscles. [Ca2+]i was estimated from the luminescence emitted by muscles that had been microinjected with aequorin, a Ca2+-sensitive, bioluminescent protein. We found that by raising extracellular [Ca2+] and/or by exposing muscles to the Ca2+ channel agonist Bay K 8644, tension development could be varied from rest to an apparently saturating level, at which increases in [Ca2+]i produced no further rise in force. 95% of maximal Ca2+-activated force was reached at a [Ca2+]i of 0.85 +/- 0.06 microM (mean +/- SEM; n = 7), which suggests that the sensitivity of the myofilaments to [Ca2+]i is far greater than anticipated from studies of skinned heart preparations (or from previous studies using Ca2+-sensitive microelectrodes in intact heart). Our finding that maximal force was reached by approximately 1 microM also allowed us to calculate that the steady state [Ca2+]i-tension relationship, as it might be observed in intact muscle, should be steep (Hill coefficient of greater than 4), which is consistent with the Hill coefficient estimated from the entire [Ca2+]i-tension relationship derived from families of variably activated tetani (6.08 +/- 0.68; n = 7). Finally, with regard to whether steady state measurements can be applied directly toward understanding physiological contractions, we found that the relation between steady force and [Ca2+]i obtained during tetani was steeper than that between peak force and peak [Ca2+]i observed during physiological twitches.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Intracellular calcium transients underlying the short-term force-interval relationship in ferret ventricular myocardium.

The influence of short-term changes in stimulation pattern, both on the strength of contraction and on the amplitude of intracellular free-Ca2+ transients, was investigated in ferret papillary muscles. Intracellular free-Ca2+ concentration ([Ca2+]) was assessed from the luminescence emitted from muscles microinjected with the Ca2+-sensitive photoprotein aequorin. The relationships between the strength of contraction and changes in stimulation pattern lasting 1-2 beats could be described by monoexponential functions, all with very similar time constants (approximately 750 ms at 30 degrees C). Over the entire range that could be obtained, the strength of contraction, quantified by either peak tension or peak rate of tension development, was found to be linearly correlated with peak estimated [Ca2+]. Potential errors in the estimation of [Ca2+] from aequorin luminescence were analysed. To assess the influence of spatial non-homogeneities of [Ca2+] on the estimate of [Ca2+], a model of Ca2+ diffusion in heart muscle was developed. The possible effect of using an inaccurate calibration curve was also examined. The results of these analyses indicate that [Ca2+] estimated from aequorin luminescence should be proportional to, if not equal to, true spatial average [Ca2+] (errors less than 7%). Given the conclusion of the analysis described above, it is inferred from points 2 and 3 that the relationships between peak spatial average [Ca2+] and short-term changes in stimulation pattern are also represented by monoexponential functions, with time constants closely similar to those for the mechanical measurements. Exposure to ryanodine, a substance believed to inhibit the release of Ca2+ from sarcoplasmic reticulum, produced striking alterations in the pattern of variations in [Ca2+] mentioned above. These alterations are consistent with the hypothesis that the functions described above depend essentially upon properties of the sarcoplasmic reticulum.

Aequorin↗
PubMed1986

Maximal Ca2+-activated force elicited by tetanization of ferret papillary muscle and whole heart: mechanism and characteristics of steady contractile activation in intact myocardium.

Rapid (8-12 Hz) stimulation of intact heart muscle treated with ryanodine results in steady contractile activation known as tetanus, the amplitude of which can be graded by changing extracellular Ca2+ concentration ([Ca2+]o). The mechanism of the sustained force generation was explored in ferret papillary muscles by measuring membrane potential and by determining the responsiveness of force and intracellular free Ca2+ concentration ([Ca2+]i, estimated with aequorin) to dihydropyridine Ca channel ligands. Membrane potential during tetani ranged from -25 to -60 mV, suggesting that fast or slow Ca channels, or Na-Ca exchange, might be mediating Ca2+ entry. Dihydropyridine effects indicated that slow Ca channels play a predominant role: The agonist Bay K 8644 (0.3-1 microM) increased force and aequorin luminescence, whereas the antagonist nitrendipine (1-30 microM) abolished the tetanus. Under conditions analogous to those in the papillary muscle experiments, tetani were produced in whole Langendorff-perfused ferret hearts following exposure to ryanodine. Contraction saturated as a function of [Ca2+]o in both papillary muscles and whole hearts; i.e., as [Ca2+]o was increased above 10 mM, no further increase in force or pressure generation occurred. In contrast, aequorin luminescence measured in the papillary muscles showed no such saturation. Thus, maximal Ca2+-activated force (or pressure) was achieved during tetani at [Ca2+]o greater than or equal to 10 mM. Calculations of wall stress during tetani in whole heart (15 mM [Ca2+]o) agree well with direct measurements of maximal tension in papillary muscles (5.84 g/mm2 vs. 6.41 g/mm2, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Estimation of intracellular [Ca2+] by nonlinear indicators. A quantitative analysis.

When spatial gradients of intracellular free [Ca2+] are present, intracellular calcium indicators that have a nonlinear response to [Ca2+] may yield an estimate of [Ca2+] that differs from the spatial average [Ca2+]. We present two rules that provide (a) general criteria to distinguish those classes of indicators that will yield an overestimate of spatial average [Ca2+] from those that will yield an underestimate, and (b) limits on the extent to which spatial average [Ca2+] might be over- or underestimated. These rules are used to interpret quantitatively the aequorin luminescence signals obtained from cardiac ventricular myocardium.

Animals↗
PubMed1985

Postextrasystolic potentiation of the isolated canine left ventricle. Relationship to mechanical restitution.

We established, for the isolated, isovolumically beating canine left ventricle, a comprehensive description of postextrasystolic contractile strength (dP/dtmax) as a function of extrasystolic and postextrasystolic stimulus intervals. In contrast to previous studies of postextrasystolic beats in in situ hearts, these isolated ventricles contracted isovolumically so that dP/dtmax was not affected by fluctuations in preload and afterload and was therefore considered to be a reliable index of intrinsic contractility. With the interval preceding extrasystoles constant, postextrasystolic contractile strength increased monoexponentially to a plateau as the interval preceding postextrasystoles lengthened, with a mean time constant (+/- SD) of 182 +/- 44 msec (n = 53). The onset of this increase in postextrasystolic contractile strength coincided with repolarization of the extrasystolic action potential. With the interval preceding postextrasystoles held constant and long (1200 msec), postextrasystolic contractile strength decreased according to a monoexponential function as the interval preceding extrasystoles lengthened [mean time constant (+/- SD) of 176 +/- 18 msec (n = 10)]. These phenomena could be quantitatively summarized by a single equation description of postextrasystolic contractile strength which involved monoexponential functions with one time constant. The mathematical form of this description led us to a simple interpretation of these phenomena in terms of currently proposed excitation-contraction coupling models of the heart.

Animals↗
PubMed1985

Mechanoelectrical feedback: independent role of preload and contractility in modulation of canine ventricular excitability.

Mechanoelectrical feedback, defined as changes in mechanical state that precede and alter transmembrane potential, may have potential importance in understanding the role of altered load and contractility in the initiation and modulation of ventricular arrhythmias. To assess the independent effects of preload and contractility on myocardial excitability and action potential duration, we determined the stimulus strength-interval relationship and recorded monophasic action potentials in isolated canine left ventricles contracting isovolumically. The strength-interval relationship was characterized by three parameters: threshold excitability, relative refractory period, and absolute refractory period. The effects of a threefold increase in left ventricular volume or twofold increase in contractility on these parameters were independently assessed. An increase in preload did not change threshold excitability in 11 ventricles but significantly shortened the absolute refractory period from 205 +/- 15 to 191 +/- 14 ms (P less than 0.001) (mean +/- SD). Similarly, the relative refractory period decreased from 220 +/- 18 to 208 +/- 19 ms (P less than 0.002). Comparable results were observed when contractility was increased as a result of dobutamine infusion in 10 ventricles. That is, threshold excitability was unchanged but the absolute refractory period decreased from 206 +/- 14 to 181 +/- 9 ms (P less than 0.003), and the relative refractory period decreased from 225 +/- 17 to 205 +/- 18 ms (P less than 0.003). Similar results were obtained when contractility was increased with CaCl2, indicating that contractility associated changes were independent of beta-adrenergic receptor stimulation. An increase in preload or contractility was associated with shortening of the action potential. A threefold increase in preload and twofold increase in contractility were associated with a decrease in action potential duration of 22 and 24 ms, respectively. There was a significant linear correlation between action potential duration and excitability (absolute refractory period). The similar effects of increased preload and contractility on threshold excitability and refractoriness can be explained by the action these perturbations have on the time course of repolarization. Therefore, excitability of the ventricle is sensitive to and is modulated by alteration of load or inotropic state. The similar effects of either increased preload or contractility on excitability may be mediated by a common cellular mechanism which results in a rise in intracellular free Ca2+ and secondary abbreviation of the action potential.

Action Potentials↗
PubMed1985

Effects of ryanodine on intracellular Ca2+ transients in mammalian cardiac muscle.

We observed the effects of ryanodine on the aequorin luminescence, membrane potential, and contraction of canine cardiac Purkinje fibers and ferret ventricular muscle. In canine Purkinje fibers, ryanodine (10 nM to 1 microM) abolished the spontaneous spatiotemporal fluctuations in [Ca2+] that occur as a result of Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR) during exposure to low-Na+ solutions. Ryanodine strongly reduced the twitch and both components of the intracellular aequorin luminescence signal (L1 and L2), which normally accompanies contraction. The small luminescence signals that remained in ryanodine could be abolished by a Ca2+ channel blocker (nitrendipine, 10 microM). The plateau phase of the action potential was reduced by nitrendipine in the presence of ryanodine, which suggests that Ca2+ current was not blocked by ryanodine. In ferret ventricular tissue, ryanodine (1 microM) prolonged the action potential and reduced the peak amplitudes of both the aequorin transient and the twitch, while greatly prolonging the time-to-peak of both signals. Increases in extracellular [Ca2+] restored the peak amplitudes of the twitch and the aequorin luminescence, but did not restore the normal time-to-peak. The results show that in both tissues, the negative inotropic effect of ryanodine is due to the reduction of the intracellular [Ca2+] transient. Inasmuch as neither Ca2+ entry via surface membrane Ca2+ channels nor Na+-Ca2+ exchange appears to be blocked by ryanodine, the most probable cause of reduction of the [Ca2+] transient is an inhibition of Ca2+ release by the SR.

Aequorin↗
PubMed1984

Mechanical restitution of isolated perfused canine left ventricles.

We measured cardiac mechanical restitution curves, which describe the time course of recovery of ventricular contractile strength following a steady-state beat. In the first series of experiments, we studied left ventricles that beat isovolumically throughout the experiment, allowing use of dP/dtmax as a reliable index of contractile strength independent of the influence of changing ventricular pre- and afterload. The commencement of mechanical restitution was found to be associated with the onset of electrical diastole; thereafter, contractile strength rose monoexponentially to a plateau that was maintained for test pulse intervals as long as 15 s. The time constant of restitution (typically 245 ms) was independent of priming frequency and ventricular volume. These findings were interpreted in terms of a model of intracellular calcium fluxes within the myocardial cells. In a second series of experiments, we measured mechanical restitution curves from isolated ventricles that ejected against a simulated arterial impedance system. Under this condition, we did not observe the monoexponential time course of mechanical restitution as was measured under isovolumic conditions. The differences between the mechanical restitution curves measured under isovolumic and ejecting conditions were attributed to the influences of changing hemodynamic conditions on dP/dtmax that caused it to be an unreliable index of contractile strength.

Animals↗
PubMed1984

Quantitative comparison of the force-interval relationships of the canine right and left ventricles.

We quantitatively compared the extrasystolic and postextrasystolic responses of the right ventricle and left ventricle of the same heart, which have vastly different geometries, architectures, and muscle masses. We studied nine isolated, supported canine hearts whose right and left ventricles were made to contract isovolumically with balloons placed in both chambers. The ventricles were paced with the following pattern: 20 regularly timed priming stimulations, followed by a test stimulation at a variable test pulse interval, and, finally, by a second test stimulation which was always delivered 1200 msec after the first test pulse. In each heart, approximately 15 different test pulse intervals between 300 and 1200 msec were investigated. Both the maximum developed pressure and maximum rate of pressure development, expressed as a percentage of their steady state values during the priming period were used to quantify the extra- and postextrasystolic responses. For each extrasystolic and postextrasystolic test beat, the normalized response of the right ventricle was plotted vs. that of the left ventricle. The regression line and correlation coefficient between the two were determined. The average result from nine hearts gave a slope of 0.96 +/- 0.05, an intercept of 4.52 +/- 4.05% and a correlation coefficient of 0.995 +/- 0.004. This analysis indicated that, despite the differences in right and left ventricular geometry, architecture, and mass, their force-interval behaviors were nearly identical.

Animals↗