(Circulation. 2000;101:1040.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Improved Mechanoenergetics and Cardiac Rest and Reserve Function of In Vivo Failing Heart by Calcium Sensitizer EMD-57033
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to David A. Kass, MD, Halsted 500, Division of Cardiology, Johns Hopkins Medical Institutions, 600 N Wolfe St, Baltimore, MD 21287. E-mail dkass{at}bme.jhu.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Myofilament Ca2+ sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca2+ concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca2+ sensitization in vivo with the use of EMD-57033 enhances both systolic and diastolic function in failing hearts at minimal energetic cost.
Methods and Results—Pressure-dimension data were measured with sonomicrometry/micromanometry in conscious dogs before (CON, n=9) and after tachycardia-induced heart failure (HF, n=11). In contrast to blunted dobutamine (DOB) responses in HF, low-dose EMD-57033 (0.4 mg · kg-1 · min-1 for 20 minutes) markedly enhanced contractility, doubling end-systolic elastance and raising fractional shortening similarly in CON-treated and HF hearts. EMD-57033 effects were achieved at a reduced heart rate, without vasodilation. EMD-57033 augmented blunted heart rate-dependent contractility responses in HF at a rate of twice that of DOB, despite matched basal inotropic responses. EMD-57033 also improved diastolic function, lowering left ventricular end-diastolic pressure and increasing the filling rate. At equipotent inotropic doses and matched preload, EMD-57033 lowered the oxygen cost of contractility by -11.4±5.8%, whereas it rose 64±18% with DOB (P=0.001) and 28±11% with milrinone. Doubling EMD-57033 dose further augmented positive inotropy in CON and HF, accompanied by vasodilation, increased heart rate, and other changes consistent with PDE3I coactivity, but the oxygen cost of contractility remained improved compared with the use of DOB.
Conclusions—Selective Ca2+ sensitization with minimal PDE3I in vivo is achieved with the use of EMD-57033, improving basal and rate-stimulated contractility and mechanoenergetics of HF without compromising diastolic function. Despite PDE3I activity at higher doses, energetic benefits persist.
Key Words: mechanics • calcium • diastole • contractility • heart failure
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
ß-Adrenoceptor agonists and phosphodiesterase III (PDE3I) inhibitors enhance inotropy by raising intracellular Ca2+ concentration ([Ca2+]i) while simultaneously reducing myofilament Ca2+ sensitivity and increasing sarcoplasmic reticulum (SR) Ca2+ influx. These changes in Ca2+ handling increase net energy demand and may elevate arrhythmia risk, limiting their efficacy for chronic heart failure (HF) treatment. Myofilament Ca2+ sensitizers, in contrast, improve contractility without changing [Ca2+]i1 and should thereby improve systolic function at a lower energetic cost. However, when administered in vivo, most Ca2+ sensitizers demonstrate inhibition of phosphodiesterase III (PDE3I).2 3 4 5 Accordingly, many such agents display far less than the anticipated benefit on in vivo mechanoenergetics.4 5
Agents highly selective for Ca2+ sensitization, on the other hand, can negatively affect diastole by facilitating cross-bridge activation at diastolic [Ca2+]i levels. This could impede their use in HF, which is typified by reduced basal distensibility and delayed Ca2+ cycling kinetics. EMD-57033 is one such agent that potently augments the force developed by actin-myosin cross-bridges6 7 8 with relatively low PDE3I activity. In vitro studies have reported adverse effects on relaxation and chamber stiffening,8 9 10 and although this is less pronounced in normal in vivo hearts,11 12 responses in failing hearts remain unknown. Furthermore, no study has tested the in vivo efficacy of EMD-57033 in altering mechanoenergetics in failure or enhancing contractile reserve.
The present investigation was designed to test whether EMD-57033 can act principally as a Ca2+ sensitizer in the intact failing heart of conscious animals to augment rest and reserve systolic function and improve mechanoenergetics without compromising diastolic function. Studies were performed in dogs, with HF induced through long-term tachycardia pacing. The results support selective Ca2+ sensitization in vivo, with potent positive inotropic effects, marked oxygen sparing effects, and enhanced diastolic chamber performance.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Preparation
Twenty mongrel dogs of either sex (45 to 65 lb) were anesthetized with 1% to 2% halothane after induction with sodium thiamylal (3 to 5 mg/kg). The chest was opened via lateral thoracotomy. A micromanometer (P22; Konigsberg Instruments) was placed in the left ventricle (LV) at the apex. Right atrial and descending aortic catheters were placed, the latter for LV manometer calibration. Endocardial sonomicrometers were used to measure anteroposterior short-axis dimension, and a pneumatic occluder around the inferior vena cava enabled load reduction for LV pressure-dimension relation analysis. Epicardial pacing leads were sutured to the LV free wall and connected to a programmable stimulator (Spectrax; Medtronics) inserted within a subcutaneous pocket. Additional leads were secured to the left atrium for pacing during hemodynamic recordings. The chest was closed, and catheters and leads were externalized to the midscapulae. Morphine (10 mg SC) was administered postoperatively as required. Dogs were provided 10 days for recovery before the study. The surgical and experimental animal protocol was approved by the Johns Hopkins University Animal and Care Use Committee.
Conscious Protocol
Studies were performed in control (CON, n=9) and HF (n=11)
animals, with the latter induced by tachypacing (210 bpm x 3
weeks, 240 bpm x 1 week). Data were measured in conscious animals
standing quietly in a sling, with pacing suspended at least 30 minutes
before the study in HF dogs. Four principal interventions were studied
in each animal. First, a dose response to 5 to 15 µg ·
kg-1 · min-1
dobutamine (DOB) was determined, allowing 5- to 10-minute
stabilization at each dose. To assess the interaction between DOB and
heart rate (HR)-dependent contractile reserve, a constant dosage of 10
µg · kg-1 ·
min-1 was administered, and the atrial rate
increased from sinus to 240 bpm with pacing. DOB was then stopped, and
the baseline was reestablished. There were no significant differences
in systolic or diastolic function between initial
and second baseline levels (Table 1
). EMD-57033 (dissolved in
1,2-propanediol, infused over 20 minutes) was then administered at 0.4
or 0.8 mg · kg-1 ·
min-1. After the recording of
hemodynamics, data were again obtained during
incremental HR while EMD-57033 was continued. EMD-57033–related
responses were all referenced to the second (post-DOB) baseline. In 4
separate studies, we administered 1,2-propanediol alone at the
same infusion rate, and no significant effects on baseline
hemodynamics were observed (Table 1).
|
To further probe the mechanism of action of EMD-57033 in vivo (ie, Ca2+ sensitization versus PDE3I activity), the decay rate of postrest contractile potentiation was assessed. After several minutes of atrial tachycardia, pacing was stopped and HR returned to sinus rhythm. Contractile potentiation observed after pacing gradually declined over sequential cycles, and the rate of decay (recirculation fraction [RF]) reflected intracellular Ca2+ recycling by the SR.13 Because both PDE3I and ß-adrenergic stimulation enhance SR Ca2+ uptake due to phospholamban phosphorylation, this increases the RF.13 14 In contrast, pure Ca2+ sensitization has minimal influence on the RF.15 All of the preceding protocols were performed in every CON animal and 7 HF dogs.
Mechanoenergetic Studies
In 9 HF dogs, we contrasted the energetic costs of improving
contractility with DOB (n=5, 5 µg ·
kg-1 · min-1),
EMD-57033 (0.4 mg · kg-1 ·
min-1, n=5), EMD-57033 (0.8 to 1.0 mg ·
kg-1 · min-1,
n=4), or a PDE3I (milrinone, 10 µg ·
kg-1 · min-1).
Five studies were performed in anesthetized animals (n=5; 50
µg/kg fentanyl plus 1% to 2% isoflurane), with coronary
flow velocity measured in the proximal circumflex coronary
artery with intravascular Doppler probe (0.014 in; Cardiometrics),
and contrast imaging of the coronary was used to determine
cross-sectional diameter (CathView v1.36; Image Comm Systems). A
coronary sinus catheter provided blood sampling for oxygen
measurement. The remaining studies were conducted in conscious animals
preinstrumented with a coronary flow probe (Transonic) and a
coronary sinus catheter. There were no significant differences
in mechanoenergetic responses between conscious and sedated studies.
Hemodynamics, coronary flow, and arteriovenous
oxygen difference were measured under basal conditions and at steady
state with each drug and dose.
Hemodynamic and Energetic Analysis
Pressure-dimension data were digitized at 250 Hz. Rest
parameters were determined from data averaged from 10 to 20
consecutive beats, whereas data measured during transient
inferior vena caval occlusion were used to determine
pressure-dimension relations. Systolic function was indexed on
the basis of stroke dimension, fractional shortening (stroke
dimension/end-diastolic dimension [EDD]), peak rate of
pressure rise (dP/dtmax), end-systolic
elastance (Ees, slope of end-systolic
pressure–dimension relation [ESPDR]), and the slope of the relation
between dimension work (pressure-dimension loop area) and EDD.
The latter 2 indexes provide relatively load-insensitive measures of
contractility. dP/dtmax was
calculated from a running 5-point weighed slope, and ESPDR was derived
through perpendicular regression of end-systolic points, with
the use of an iterative method.16
The use of pressure-dimension relations included the assumption that
they correspond to pressure-volume data. Although previously reported
in normal hearts,17 we confirmed this correlation in
several animals after the induction of HF. Figures 1A and 1B displays
representative simultaneously derived
pressure-dimension and pressure-volume relations (volume assessed with
the use of a conductance catheter). Volume-dimension plots from these
same data (Figure 1C) revealed an excellent correlation
(r=0.96), with an average r value of 0.92±0.04
from 22 such comparisons. Figure 1D shows a strong correlation
between Ees change assessed with either method
for the same inotropic changes.
|
Diastolic function was indexed on the basis of
end-diastolic pressure (EDP), time constant of relaxation
(
) with a logistic fit, peak filling rate normalized by EDD, and the
EDP-dimension relation measured during caval occlusion. The logistic
was used because it provides a more stable parameter in
failing hearts than that derived from monoexponential
models.18 Peak filling rate was calculated from a smoothed
first derivative of the dimension signal. Arterial
afterload was assessed by effective arterial elastance,
equal to the ratio of end-systolic pressure to stroke
dimension.
Recirculation fraction was measured from the linear regression slope of relations between dP/dtmax(n) and dp/dtmax(n+1), where n represents data from the nth beat after the cessation of rapid pacing and return to sinus rhythm.18 dP/dtmax served as a reliable index for contractile function in this setting because preload is nearly identical for the postpaced beats at sinus rhythm.18
In the animals that underwent energetic analysis, myocardial
oxygen consumption (M
O2) was
indexed from the product of coronary flow and
arterial-venous oxygen difference. Relative changes in
oxygen consumption were determined and compared with relative changes
in dP/dtmax and stroke work to yield the oxygen
cost of contractile enhancement and changes in efficiency.
Statistical Analysis
Data are presented as mean±SD unless otherwise stated.
Dose-dependent drug effects were tested by repeated measures ANOVA,
with a multiple comparisons test (Tukey). Comparisons of DOB- and
EMD-57033–induced changes were tested with a paired t test.
Comparisons for baseline data and drug responses between CON and HF
were analyzed with an unpaired t test. Differences
in the force-frequency response between CON and HF animals with and
without DOB or EMD-57033 were performed with the use of 2-way repeated
measures ANOVA.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Inotropic and Loading Effects of EMD-57033
Figure 2A
shows typical
pressure-dimension data before and after 0.4 or 0.8 mg ·
kg-1 · min-1
EMD-57033, along with responses to 15 µg ·
kg-1 · min-1 DOB.
EMD-57033 substantially enhanced contractility at both
doses, with similar changes in CON and HF hearts. This contrasts with
DOB, which enhanced contractility far more in CON than
in HF. Table 2 summarizes group
systolic data, which support these findings with a variety of
indexes. Importantly, in HF dogs, low-dose EMD-57033 yielded comparable
contractile changes to high-dose DOB, whereas higher doses greatly
exceeded a DOB response.
|
|
At the lower dose, EMD-57033 had minimal or slowing effects on HR and
did not significantly alter arterial load or preload (Table 3). At higher doses, EMD-57033 increased
HR in CON and HF hearts (similar to DOB) and reduced
arterial load and preload. These dose-dependent loading and
HR differences are consistent with concomitant PDE3I effects at
the higher dose.
|
EMD-57033 Effects on Diastolic Function
We next tested whether potent inotropic effects from the use of
EMD-57033 were accompanied by compromised diastolic
function as reported in vitro. EMD-57033 had little effect on
relaxation time constants at a low dose, yet significantly improved
early filling rate (comparable to DOB), with even greater effects at
the higher dose. Unlike DOB, these changes were similarly induced in
HF. Similar diastolic changes were observed at a constant
HR (140 bpm; data not shown). EMD-57033 reduced EDP, although this did
not reach statistical significance at a low dose in HF due to a slower
HR and enhanced filling in 2 animals. At a constant HR (140 bpm), EDP
declined in these animals (-5.9±3.6, P<0.05). EMD-57033
did not alter chamber compliance (Figure 3); rather, the EDP reduction was due to
a slight fall in net chamber filling and right heart load (Table 4).
|
|
Force-Frequency Potentiation and Recirculation Fraction
To test whether EMD-57033 augmented inotropic reserve, we studied
its interaction with incremental HR. Both Ees and
dP/dtmax rose with HR in CON and HF animals, but
this rate response was markedly attenuated with HF (P<0.05)
(Figure 4). DOB (10 µg ·
kg-1 · min-1) and
EMD-57033 (0.4 mg · kg-1 ·
min-1) amplified the rate dependence in CON, but
the synergistic effect with EMD-57033 far exceeded that with DOB
(maximal Ees rise 17.6±0.5 versus 7.8±0.0
mm Hg/mm,P<0.01) in HF. Importantly, both drugs
were administered at doses yielding matched basal
contractility before change in HR, so this discrepancy
could not be ascribed to downregulation of ß-receptor signaling.
|
).
EMD-57033 restored rate sensitivity to control levels in HF (
),
markedly enhanced it in CON (
), and, in both conditions, exceeded
responses with DOB.
To further probe mechanisms by which varying doses of EMD-57033
influence in vivo contractility, we measured effects on
beat-to-beat potentiation decay after the abrupt cessation of rapid
pacing. Figure 5A plots
dP/dtmax of the nth beat versus the n+1th beat
after return to normal sinus rhythm after atrial pacing. The slope of
each relation (RF) reflects the relative percentage of
Ca2+ recycled by the SR. DOB increased the slope
at both doses, which is consistent with phospholamban
phosphorylation, whereas it was unchanged by low-dose
EMD-57033. At higher-dose EMD-57033, the slope rose similar to that for
DOB. Summary data support these responses (Figure 5B) and
confirm lower RFs in HF.16 These results also suggest that
low-dose EMD-57033 acts primarily as a Ca2+
sensitizer.
|
Mechanoenergetics
Figure 6 summarizes the
mechanoenergetics results. Contractile augmentation
(
dP/dtmax) in response to 5 µg ·
kg-1 · min-1 DOB
(low dose) was compared with that for low- and higher-dose EMD-57033,
with HR maintained during the interventions. Percent changes in
dP/dtmax were matched for DOB and low-dose
EMD-57033, yet MO2 rose by 144±47%
(mean±SEM) with DOB versus 21.2±7% with EMD-57033
(P<0.001). Thus, the oxygen cost of
contractility declined with EMD, whereas it increased
by >50% with DOB. Mechanical efficiency, estimated as the ratio of
regional stroke work to
MO2, improved 64±32%
with EMD-57033 but declined -29±6% with DOB (P<0.01).
Importantly, these energetic benefits persisted at the higher dose of
EMD-57033, with a -7.8±19.5% change in oxygen cost of
dP/dtmax (P=0.007 versus DOB) and
improved efficiency.
|
P<0.01 versuss MIL+V. P values on top
right of each panel are for ANOVA with all 5 groups. Top left, Percent
change in dP/dtmax, Bottom left, Percent change in
M
Experiments were also conducted with the selective PDE3I milrinone
(Figure 6
), with dP/dtmax matched to
that of DOB and low-dose EMD-57033. Increased systolic function
with milrinone was accompanied by reduced
MO2, lowering the oxygen cost
of dP/dtmax by -29±3.8% and improving
efficiency. However, mechanisms for this response differed from those
with EMD-57033. As shown in Figure 7, milrinone had concomitant potent arterial and venous
dilator effects, with a -30±5% decline in afterload and a -12±2%
decline in preload (both P<0.001). These changes could
themselves reduce MO2 and
improve efficiency.19 To test more comparable
conditions, end-diastolic volume was restored to baseline
with intravenous fluids during milrinone infusion. Although
the inotropic response was similar,
MO2 rose by 75±20%, yielding
an increased oxygen cost of dP/dtmax and no
significant change in efficiency.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The primary new findings of the present study were that in vivo, low-dose EMD-57033 acting principally via Ca2+ sensitization with minimal demonstrable PDE3I action markedly improves inotropy in failing hearts at a substantially reduced energetic cost compared with DOB or with milrinone (with preload restored to baseline). Importantly, EMD-57033 generated these changes with net beneficial effects on diastolic function. These data counter the results of previous studies performed in vitro with this agent that reported adverse changes in diastolic function.8 9 10 They also contrast with studies of other Ca2+ sensitizers with combined PDE3I activity that show much less mechanoenergetic benefit.4 5
Mechanism of Inotropic Effect
A common feature of most agents that enhance
Ca2+ sensitivity of the myofilaments is PDE3I
coactivity. This holds for EMD-57033 as well, although in vitro data
suggest higher selectivity for Ca2+
sensitization, at least at certain doses.7 The
identification of these effects in vivo is important, because primary
PDE3 inhibitors have resulted in increased mortality rates
in chronic HF clinical trials.20 PDE3I elevates cAMP,
increasing contractility and HR, enhancing relaxation,
inducing vasodilation, and accelerating postrest potentiation
decay.14 The current data support minimal PDE3I at a
dosage of 0.4 mg · kg-1 ·
min-1 dose but some activity at the 2-fold
higher dose. Even at the higher dose, however, EMD-57033 remained
equally effective in CON and HF hearts, which is not expected from the
use of pure PDE3I21 and supports primarily
Ca2+ sensitization effects occurring at this dose
as well. The dose dependency of PDE3I effects is consistent
with prior data obtained in conscious swine12 and
dogs.11
The capacity of EMD-57033 to induce quantitatively similar inotropic responses in CON and HF hearts and to restore force-frequency reserve in HF further supports a Ca2+ sensitization mechanism. This contrasts with DOB, which had a blunted basal and rate-enhanced activity in HF. The disparity between DOB and EMD-57033 responses differs from that with levosimendan, another Ca2+ sensitizer and PDE3I that is being tested in clinical trials. In the latter case, contractile responses to isoproterenol and levosimendan were similarly depressed by HF.4
The mechanism of Ca2+ sensitization by EMD 57033 has been postulated to involve direct modification of the actin-myosin interface.6 This prevents inhibition of the actin-myosin interaction by troponin-tropomyosin, promoting cross-bridge formation from weak to strong force-generating states. As a consequence, cross-bridges stay attached longer while generating greater force, leading to more prolonged contraction with less effect on the rising phase of contraction. The present data revealed such disparities at the lower dose. Basal myocardial Ca2+ sensitivity is reportedly enhanced in the pacing-tachycardia model,22 perhaps related to reduced troponin I phosphorylation. Despite this, Ca2+ sensitization effects due to EMD-57033 were similar in HF and CON hearts.
Contractile Energetics
The oxygen cost of contractility enhancement in HF
was considerably lower with EMD-57033 than with DOB. The selective use
of PDE3I with milrinone also yielded favorable energetic effects, but
this was found principally due to concomitant loading changes. However,
even after preload restoration, the energetic cost of
contractile improvement with milrinone was still lower than that with
DOB. These results support data from Holubarsch et al,23
who found similar declines in isometric contraction economy from
adrenergic stimulation versus PDE3I but less tension-independent heat
(ie, Ca2+ turnover) with PDE3I. Our study is the
first to demonstrate energetic effects of EMD-57033 in conscious
animals with HF and supports data obtained from studies on isolated rat
cardiomyocytes24 and rabbit and guinea pig
papillary muscles.25 An oxygen-sparing effect is predicted
from Ca2+ sensitization because less ATP
hydrolysis per unit force is required if the cross-bridge cycle favors
longer periods in the force-generating state. However, the combined
PDE3I effects of many sensitizers may limit improved efficiency in
vivo. For example, Tokada et al4 found that the oxygen
cost of enhancing contractility by levosimendan was
similar to that obtained with isoproterenol. Other compounds with
combined sensitization and PDE3I activity have similarly yielded
minimal oxygen-sparing effects.5 The net energetic effect
likely depends on the relative balance between
Ca2+ sensitization and PDE3I. In the case of
EMD-57033, the persistence of favorable energetics and inotropic
responses in HF even at the higher dose supports a balance favoring
sensitization.
Effects on Diastolic Function
In isolated muscle, EMD-57033 shifts leftward the
force-pCa2+ relation, reflecting enhanced
filament sensitization to Ca2+ in both
systolic and lower diastolic ranges.7
This could prolong the time required for strongly bound cross-bridges
to detach, lengthening the duration of tension decay and
increasing diastolic stiffness. Prior studies of isolated
ferret trabeculae or rabbit hearts reported longer
relaxation times and higher diastolic pressure or resting
force after EMD-57033 administration8 9 10 and shorter
diastolic cell length,6 all of which support
myofilament activation. This has led to suggestions that concurrent
PDE3I may be necessary to obviate detrimental diastolic
effects from selective Ca2+ sensitization.
However, we did not observe adverse diastolic influences
even at the lower EMD-57033 dose. At both doses, EMD 57033 improved
peak filling rates, and EDP declined. Shortening of relaxation at the
higher dose likely reflected concurrent PDE3I.
The reduced EDP and improved filling despite little change in relaxation with low-dose EMD-57033 are intriguing and could reflect increased elastic restoring forces due to ejection to lower systolic volumes.26 This mechanism would be relevant to ejecting but not isolated isovolumic or isometric hearts or tissues and could explain the discrepancy with prior studies. This is not the only explanation; Slinker et al27 reported negative lusitropic effects from EMD-57033 in both isovolumic and ejecting isolated rabbit hearts, which highlights the differences between the performance of such compounds in conscious animals versus isolated, crystalloid-perfused hearts.
Force-Frequency Potentiation
The dependence of cardiac contractility on
HR is principally due to an increased Ca2+
transient associated with enhanced SR Ca2+
loading from a calmodulin II–dependent
pathway.28 The force-frequency response is blunted in
human and experimental heart failure and can contribute to impaired
cardiac reserve during stress or exercise.16 29 The
force-frequency dependence can be enhanced by ß-adrenoceptor
stimulation and adenylate cyclase
activation,29 although phosphorylation of
phospholamban is not needed for the rate-dependent acceleration of SR
Ca2+ uptake.28 Conversely, blunted
adrenergic signaling or diminished adenylate
cyclase21 with HF impairs this amplification, as found
in the present study. EMD-57033, in contrast, markedly increased
the force-frequency response in both CON and HF. This is an important
feature of Ca2+ sensitizers, which not only
enhance basal function but also can improve the contractile response to
chronotropic reserve.
Conclusions
Despite the disappointing results of trials with inotropic
agents, HF with depressed systolic function remains a disorder
in which cardiac pumping capacity is often inadequate to meet the
requirements of the organism. Ca2+ sensitizers
potentially offer an important avenue for the enhancement of function,
particularly if they simultaneously provide an
energy-sparing effect.30 The present data are
important in that they provide the first demonstration that
considerable improvement in systolic performance can be
achieved with Ca2+ sensitization in intact
failing hearts at substantial energetic savings and without compromise
of diastolic function. Such agents have the potential to
improve the treatment of HF.
|
Footnotes |
|---|
The first 2 authors contributed equally to this study.
Received July 21, 1999; revision received August 20, 1999; accepted August 26, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Haikala H, Linden I-B. Mechanisms of action of calcium sensitizing drugs. J Cardiovasc Pharmacol. 1995;26(suppl 1):S10–S19.
2.
Kitada Y, Kobayashi M, Narimatsu A, Ohizumi Y.
Does the positive inotropic action of a novel cardiotonic agent,
MCI-154, involve mechanisms other than cyclic AMP? J
Pharmacol Exp Ther. 1987;243:639–645.
3.
Bohm M, Morano I, Pieske B, Ruegg JC, Wankerl M,
Zimmermann R, Erdmann E. Contribution of cAMP-phosphodiesterase
inhibition and sensitization of the contractile proteins for calcium to
the inotropic effect of pimobendan in the failing human
myocardium. Circ Res. 1991;68:689–701.
4.
Tokada K, Wang J, Yi GH, Stennett R, Knecht M,
Packer M, Burkhoff D. Effects of levosimendan on myocardial
contractility and oxygen consumption. J
Pharmacol Exp Ther. 1996;279:120–127.
5. Hata K, Goto Y, Futaki S, Saeki A, Nishioka T, Suga H. Effects of milrinone and sulmazole on left ventricular mechanoenergetics in canine hearts. J Cardiac Fail. 1996;2:203–213.[Medline] [Order article via Infotrieve]
6.
Solaro RJ, Gambassi G, Warshaw DM, Keller MR,
Spurgcon HA, Beier N, Lakatta EG. Stereoselective actions of
thiadiaziones on canine cardiac myocytes and myofilaments. Circ
Res. 1993;73:981–990.
7. White J, Lee JA, Shah N, Orchard CH. Differential effects of the optical isomers of EMD 53998 on contraction and cytoplasmic Ca in isolated ferret cardiac muscle. Circ Res. 1993;73:61–70.[Abstract]
8.
Tobias HA, Slinker BK, Kirkpatrick RD, Campbell
KB. Functional effects of EMD-57033 in isovolumically beating isolated
rabbit hearts. Am J Physiol. 1996;271:H51–H58.
9.
Hajjar RJ, Schmidt U, Helm P, Gwathmey JK.
Ca2+ sensitizers impair cardiac relaxation in
failing human myocardium. J Pharmacol Exp
Ther. 1997;280:247–254.
10.
Hgashiyama A, Watkins M, Chen Z, LeWinter M.
Effects of EMD 57033 on contraction and relaxation in isolated rabbit
hearts. Circulation. 1995;92:3094–3104.
11. Haeusler G, Jonas R, Minck KO, Schliep HJ, Schelling P, Weygandt H, Lues I. In vivo evidence of positive inotropism of EMD 57033 through calcium sensitization. J Cardiovasc Pharmacol. 1997;29:647–655.[Medline] [Order article via Infotrieve]
12. Stubenitsky R, van der Weerd RWP, Haistma DB, Verdouw PD, Duncker DJ. Cardiovascular effects of the novel Ca2+ sensitizer EMD 57033 in pigs at rest and during treadmill exercise. Br J Pharmacol. 1997;122:1257–1270.[Medline] [Order article via Infotrieve]
13.
Drake-Holland AJ, Sitsapesan R,
Herbaczynska-Cedro K, Seed WA, Noble MIM. Effect of adrenaline on
cardiac force-interval relationship. Cardiovasc Res. 1992;26:496–501.
14. Morner SEJN, Arlock P. Mechanical and electrophysiological effects of milrinone on the force-frequency relationship in mammalian myocardium. Acta Physiol Scand. 1994;150:125–132.[Medline] [Order article via Infotrieve]
15.
Urthaler F, Walker AA, Reeves DN, Hefner LL.
Maximal twitch tension in intact length-clamped ferret papillary
muscles evoked by modified post-extrasystolic potentiation.
Circ Res. 1988;62:65–74.
16.
Liu C-P, Ting C-T, Lawrence W, Maughan WL, Chang
M-S, Kass DA. Diminished contractile response to increased heart rate
in intact human left ventricular hypertrophy.
Circulation. 1993;88:1893–1906.
17.
Little WC, Freeman GL, O’Rourke RA.
Simultaneous determination of left ventricular
end-systolic pressure-volume and pressure-dimension
relationships in closed-chest dogs. Circulation. 1985;71:1301–1308.
18. Senzaki H, Chen CH, Kass DA. Greater apparent load sensitivity of ventricular relaxation in human heart failure relates to inadequacy of monoexponential model to define pressure decay. Circulation. 1997;96(suppl I):I-641.
19.
Hasenfuss G, Holubarsch C, Heiss HW, Meinertz T,
Bonzel T, Wais U, Lehmann M, Just H. Myocardial energetics in patients
with dilated cardiomyopathy: influence of
nitroprusside and enoximone. Circulation. 1989;80:51–64.
20. Packer M, Carver JR, Rodeheffer RJ. Effects of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991;325:1468–1475.[Abstract]
21.
Feldman MD, Copelas L, Gwathmey JK, Phillips P,
Warren SE, Schoen FJ, Grossman W, Morgan JP. Deficient
production of cyclic AMP: pharmacologic evidence of an
important cause of contractile dysfunction in patients with end-stage
heart failure. Circulation. 1987;75:331–339.
22. Wolff MR, Whitesell LF, Moss RL. Calcium sensitivity of isometric tension is increased in canine experimental heart failure. Circ Res. 1995;736:781–789.
23.
Holubarsch C, Hasenfuss G, Just H, Alpert NR.
Positive inotropism and myocardial energetics: influence of beta
receptor agonist stimulation, phosphodiesterase inhibition, and
ouabain. Cardiovasc Res. 1994;28:994–1002.
24.
Popping S, Fischer SM, Kulsch FD, Ionescu I,
Kammermeier H, Rose H. Economy of contraction of
cardiomyocytes as influenced by different positive
inotropic interventions. Am J Physiol. 1996;271:H357–H364.
25. Hasenfuss G, Pieske B, Kretschmann B, Holubarsch C, Alpert NR, Just H. Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. J Cardiovasc Pharmacol. 1995;26(suppl 1):S45–S51.
26.
Nikolic S, Yellin E, Tamura K, Vetter H, Tamura
T, Meisner JS, Frater RWM. Passive properties of canine left ventricle:
diastolic stiffness and restoring forces. Circ
Res. 1988;62:1210–1222.
27.
Slinker BK, Green HW 3rd, Wu Y, Kirkpatrick RD,
Campbell KB. Relaxation effect of CGP-48506, EMD-57033, and
dobutamine in ejecting and isovolumically beating rabbit
hearts. Am J Physiol. 1997;273:H2708–H2720.
28. Li L, Chu G, Kranias EG, Bers DM. Cardiac myocyte calcium transport in phospholamban knockout mouse: relaxation and endogenous CaMKII effects. Am J Physiol. 1998;274:H1335–H1347.
29.
Mulieri LA, Hasenfuss G, Leavitt BJ, Allen PD,
Alpert NR. Altered myocardial force-frequency relation in human heart
failure. Circulation. 1992;85:1743–1750.
30.
Liao R, Nascimben L, Friedrich J, Gwathmey JK,
Ingwall JS. Decreased energy reserve in an animal model of dilated
cardiomyopathy: relationship to contractile
performance. Circ Res. 1996;78:893–902.
This article has been cited by other articles:
 |
|
 |
|
  K. Chakir, S. K. Daya, R. S. Tunin, R. H. Helm, M. J. Byrne, V. L. Dimaano, A. C. Lardo, T. P. Abraham, G. F. Tomaselli, and D. A. Kass Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization Circulation, March 18, 2008; 117(11): 1369 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Revera, L. van der Merwe, M. Heradien, A. Goosen, V. A. Corfield, P. A. Brink, and J. C. Moolman-Smook Troponin T and {beta}-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy Cardiovasc Res, March 1, 2008; 77(4): 687 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Dai, Y. Tian, C. G. Tocchetti, T. Katori, A. M. Murphy, D. A. Kass, N. Paolocci, and W. D. Gao Nitroxyl increases force development in rat cardiac muscle J. Physiol., May 1, 2007; 580(3): 951 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass and R. J. Solaro Mechanisms and Use of Calcium-Sensitizing Agents in the Failing Heart Circulation, January 17, 2006; 113(2): 305 - 315. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Katori, D. B. Hoover, J. L. Ardell, R. H. Helm, D. F. Belardi, C. G. Tocchetti, P. R. Forfia, D. A. Kass, and N. Paolocci Calcitonin Gene-Related Peptide In Vivo Positive Inotropy Is Attributable to Regional Sympatho-Stimulation and Is Blunted in Congestive Heart Failure Circ. Res., February 4, 2005; 96(2): 234 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Ashley, J. Powers, M. Chen, R. Kundu, T. Finsterbach, A. Caffarelli, A. Deng, J. Eichhorn, R. Mahajan, R. Agrawal, et al. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo Cardiovasc Res, January 1, 2005; 65(1): 73 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass, J. G.F. Bronzwaer, and W. J. Paulus What Mechanisms Underlie Diastolic Dysfunction in Heart Failure? Circ. Res., June 25, 2004; 94(12): 1533 - 1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Soergel, D. Georgakopoulos, L. B. Stull, D. A. Kass, and A. M. Murphy Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1785 - H1792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Takimoto, D. G. Soergel, P. M.L. Janssen, L. B. Stull, D. A. Kass, and A. M. Murphy Frequency- and Afterload-Dependent Cardiac Modulation In Vivo by Troponin I With Constitutively Active Protein Kinase A Phosphorylation Sites Circ. Res., March 5, 2004; 94(4): 496 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Post, C. d'Agostino, V. Lionetti, M. Castellari, E. Y Kang, M. Altarejos, X. Xu, T. H Hintze, and F. A Recchia Reduced Left Ventricular Compliance and Mechanical Efficiency after Prolonged Inhibition of NO Synthesis in Conscious Dogs J. Physiol., October 1, 2003; 552(1): 233 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Paolocci, T. Katori, H. C. Champion, M. E. St. John, K. M. Miranda, J. M. Fukuto, D. A. Wink, and D. A. Kass From the Cover: Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: Independence from beta -adrenergic signaling PNAS, April 29, 2003; 100(9): 5537 - 5542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. F. Saavedra, R. S. Tunin, N. Paolocci, T. Mishima, G. Suzuki, C. W. Emala, P. A. Chaudhry, P. Anagnostopoulos, R. C. Gupta, H. N. Sabbah, et al. Reverse remodeling and enhancedadrenergic reserve from passive externalsupport in experimental dilated heart failure J. Am. Coll. Cardiol., June 19, 2002; 39(12): 2069 - 2076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Senzaki, S. Masutani, J. Kobayashi, T. Kobayashi, N. Sasaki, H. Asano, S. Kyo, Y. Yokote, and A. Ishizawa Ventricular Afterload and Ventricular Work in Fontan Circulation: Comparison With Normal Two-Ventricle Circulation and Single-Ventricle Circulation With Blalock-Taussig Shunts Circulation, June 18, 2002; 105(24): 2885 - 2892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zaugg, M. C. Schaub, T. Pasch, and D. R. Spahn Modulation of {beta}-adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action Br. J. Anaesth., January 1, 2002; 88(1): 101 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Senzaki, C.-H. Chen, S. Masutani, M. Taketazu, J. Kobayashi, T. Kobayashi, N. Sasaki, H. Asano, S. Kyo, and Y. Yokote Assessment of cardiovascular dynamics by pressure-area relations in pediatric patients with congenital heart disease J. Thorac. Cardiovasc. Surg., September 1, 2001; 122(3): 535 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Paolocci, W. F. Saavedra, K. M. Miranda, C. Martignani, T. Isoda, J. M. Hare, M. G. Espey, J. M. Fukuto, M. Feelisch, D. A. Wink, et al. Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling PNAS, August 17, 2001; (2001) 181191198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. SENZAKI, C. J. SMITH1, G. J. JUANG, T. ISODA, S. P. MAYER, A. OHLER, N. PAOLOCCI, G. F. TOMASELLI, J. M. HARE, and D. A. KASS Cardiac phosphodiesterase 5 (cGMP-specific) modulates {beta}-adrenergic signaling in vivo and is down-regulated in heart failure FASEB J, August 1, 2001; 15(10): 1718 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch, H. Post, M. C. Michel, M. Kelm, and R. Schulz Endogenous Nitric Oxide and Myocardial Adaptation to Ischemia Circ. Res., July 21, 2000; 87(2): 146 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, M. X. Li, L. Spyracopoulos, N. Beier, M. Chandra, R. J. Solaro, and B. D. Sykes Structure of the C-domain of Human Cardiac Troponin C in Complex with the Ca2+ Sensitizing Drug EMD 57033 J. Biol. Chem., June 29, 2001; 276(27): 25456 - 25466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Paolocci, W. F. Saavedra, K. M. Miranda, C. Martignani, T. Isoda, J. M. Hare, M. G. Espey, J. M. Fukuto, M. Feelisch, D. A. Wink, et al. Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling PNAS, August 28, 2001; 98(18): 10463 - 10468. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||