Vol. 278, Issue 2, H313-H320, February 2000
Mechanism of preserved positive lusitropy by cAMP-dependent
drugs in heart failure
Taketo
Tanigawa,
Masafumi
Yano,
Michihiro
Kohno,
Takeshi
Yamamoto,
Takayuki
Hisaoka,
Kaoru
Ono,
Takeshi
Ueyama,
Shigeki
Kobayashi,
Yuhji
Hisamatsu,
Tomoko
Ohkusa, and
Masunori
Matsuzaki
Second Department of Internal Medicine, Yamaguchi University School
of Medicine, 1144 Kogushi, Ube, Yamaguchi 755-8505, Japan
 |
ABSTRACT |
In tachycardia-induced
heart failure (HF), positive lusitropic effects of milrinone or
dobutamine were assessed by evaluating the time constant of left
ventricular (LV) pressure decay (
) and Ca2+-ATPase
activity of the sarcoplasmic reticulum (SR). The peak value of the
positive first derivative of LV pressure (+dP/dt) was less
increased, either by dobutamine (2-10
µg · kg
1 · min1)
or by milrinone (4-20 µg/kg), in HF than in control (P < 0.05), whereas was shortened to an extent similar to that in
control with dobutamine [P = not significant (NS)]
and to an even greater extent with milrinone (P < 0.05).
Ca2+-ATPase activity increased similarly in HF and control
with dobutamine (1 µM; +11% in HF vs. +12% in control, P = NS), whereas it increased more with milrinone (1 µM; +19% in HF vs.
+11% in control, P < 0.05). Ca2+-ATPase
activity-cAMP relationships were shifted to the left by milrinone or
dobutamine in HF compared with control. Thus, in HF, the sensitivity of
Ca2+-ATPase activity to cAMP was increased on addition of
cAMP-dependent inotropic agents, contributing to the preservation of
positive lusitropy.
calcium; calcium-adenosinetriphosphatase; dobutamine; milrinone; sarcoplasmic reticulum
| |
INTRODUCTION |
IN HEART FAILURE, the contractile response to
-adrenergic stimulation is attenuated through the mechanism by which
the basal intracellular cAMP level is decreased, i.e., downregulation
of myocardial -adrenoreceptor and increase in inhibitory
guanine-nucleotide binding proteins (Gi) (4, 5, 29). Both
-adrenergic agonists and phosphodiesterase (PDE) inhibitors have the
capability to increase cAMP levels, leading to an enhancement of
cardiac contractility (22). Although the clinical benefits of positive
inotropism by these drugs have been well established in heart failure,
the beneficial role of these cAMP-dependent inotropic agents on left ventricular (LV) relaxation in heart failure remained to be elucidated. In this regard, diastolic dysfunction is a major clinical problem in
cardiac hypertrophy and/or failure as well as systolic dysfunction, and
sometimes cardiac failure can be induced only by diastolic dysfunction
even though systolic function is well preserved (3, 9, 10). Therefore,
for the clinical use of these cAMP-dependent drugs, it is important to
clarify the difference in positive lusitropic effects between the drugs.
Abnormal regulation of intracellular Ca2+ by the
sarcoplasmic reticulum (SR) has been shown to be involved in the
mechanism of contractile and relaxation dysfunction in heart failure
(30, 32). Several investigators demonstrated that Ca2+
uptake by SR is decreased in association with the decreased density of
Ca2+-ATPase in cardiac hypertrophy and/or failure (8, 11,
18, 21, 23, 25, 28). In a previous report (42), we demonstrated that a
low dose of milrinone substantially improved LV relaxation in normal
dogs and that this positive lusitropic effect of milrinone was coupled
with a direct acceleration of Ca2+ uptake by SR, probably
caused by an inhibition of membrane-bound PDE III in SR and hence local
elevation of cAMP.
The goal of this study was to evaluate the effects of two different
cAMP-dependent drugs, milrinone and dobutamine, on LV relaxation in
parallel with the assessment of SR Ca2+-ATPase activity in
tachycardia-induced heart failure. Tachycardia induced by chronic
pacing causes well-defined, predictable, and progressive LV dilatation,
contractile dysfunction, and neurohormonal activation (2, 7, 27, 33,
41), and hence this model may more clearly resemble cardiac failure in
humans than do previous studies of small-animal models of cardiac
hypertrophy and/or failure.
| |
MATERIALS AND METHODS |
Heart failure was induced in beagle dogs of either sex by 3 wk of rapid
ventricular pacing at a rate of 250 beats/min using an externally
programmable miniature pacemaker (Medtronic, Minneapolis, MN). The
specific details of the chronic instrumentation were as follows. Beagle
dogs (n = 7 for control; n = 7 for rapid ventricular pacing) were sedated with morphine sulfate (15 mg sc) and thiopental sodium (150 mg iv). They were then anesthetized with isoflurane (2%,
1.5 l/min) and a mixture of nitrous oxide and oxygen (2:1), intubated
with a cuffed endotracheal tube, and ventilated at a tidal volume of 22 ml/kg and a respiratory rate of 15 breaths/min. A bipolar pacing lead
was fixed to the endocardial rapid ventricular pacing surface and the
distal lead was tunneled to a subcutaneous pocket constructed on the
animal's back, and they were connected to a pacemaker (Medtronic).
Cefazolin (1 g iv) was administered before and after surgery. The
control dogs underwent only a sham operation without pacing.
After 1 wk was allowed for animal recovery, the pacemaker was
programmed to 250 beats/min. Dogs were monitored daily for clinical signs and symptoms of heart failure. With the pacing off after 3 wk of
rapid ventricular pacing, the dogs were anesthetized after sedation as
described above. LV pressure was measured by a 7-Fr micromanometer
(Millar) inserted percutaneously via the carotid artery, and
two-dimensional short-axis echocardiograms were obtained at the level
of the head of the papillary muscle. Before insertion, the
catheter was calibrated at 37°C with a mercury manometer. Zero
shift of the pressure transducer was checked by a simultaneous recording of a fluid-filled transducer (model P23 Db, Gould Statham), in which the zero reference point was taken at the level of the right atrium.
Experimental protocol.
After control recording, a stepwise intravenous infusion of dobutamine
(2-10
µg · kg1 · min1)
was started. Five to ten minutes were allowed to obtain a steady state
at each dose, and hemodynamic measurements were made at the end of each
infusion rate. After the dobutamine infusion, pre-milrinone baseline
hemodynamic values were established by waiting at least 3 h, by which
time all measurements returned almost to the initial baseline values.
Milrinone was then intravenously administered by a stepwise cumulative
infusion of 4-20 µg/kg with repeat hemodynamic measurements. The
order of drug administration was not randomized because of the long
duration of milrinone's hemodynamic effects.
All data were recorded at the end of an expiration on a multichannel
recorder (Electronics for Medicine VR12) digitized at intervals of 2 ms
with an on-line analog-to-digital converter. To obtain data for
analysis, we used the average of 10 consecutive cardiac cycles. End
diastole was defined by the peak of the R wave on the
electrocardiogram. The time of the peak value of the negative first
derivative of LV pressure (
dP/dt), obtained from the
digital data of the dP/dt signal, was used to estimate end systole. The time constant of LV pressure decay () was calculated as
the negative inverse slope of the natural log of pressure vs. time
relationship, with the assumption of a pressure asymptote of 0 mmHg and
with use of data from peak dP/dt to 10 mmHg above the
end-diastolic pressure (40).
The care of the animals and the protocols used were in accordance with
guidelines laid down by the Animal Ethics Committee of Yamaguchi
University School of Medicine.
Preparation of LV crude homogenate.
The homogenate was prepared as described previously (12). LV were
homogenized in a solution containing 30 mM Tris-malate, 0.3 M sucrose,
5 mg/l leupeptin, and 0.1 mM phenylmethylsulfonyl fluoride, at pH 7.0. The homogenate was centrifuged at 5,500 g for 10 min, and the
resultant supernatant was filtered through four layers of cheesecloth.
Ca2+-ATPase activity and
cAMP assays.
Ca2+-ATPase activity in LV crude homogenate (control,
n = 6 preparations; heart failure, n = 6 preparations)
was obtained by measuring the amount of Pi released during
the reaction after ATP was added. The assay mixture in a total assay
volume of 500 µl contained 150 mM KCl, 20 mM MES (pH 6.8), 0.3 mM
MgCl2, 10 mM NaN3, 10 mM NaF, 6 µM ionophore
A-23187, 0.32 mM CaCl2, 0.5 mM EGTA (free
[Ca2+] = 1 µM), and crude homogenate (0.125 mg). To start the reaction, 1.0 mM ATP was added to the above priming
solution in the presence or absence of dobutamine (0.1-10 µM) or
milrinone (0.1-10 µM). The amount of Pi reacted was
calculated by converting nanometers (absorbance of 0.1% malachite
green) to nanomoles by means of a standard linear line (13, 24).
The cAMP content in LV crude homogenate (control, n = 6 preparations; heart failure, n = 6 preparations) was determined
with an enzyme immunoassay kit (Biotrak, cAMP enzyme immunoassay
system, Amersham International) according to the kit instructions.
Statistics.
Unpaired t-test was used to compare the hemodynamic data
between control and heart failure. Changes within the same group were
analyzed by one-way ANOVA for repeated measures and subsequent Fisher's protected least significant difference (PLSD).
Differences between two groups were analyzed by two-way ANOVA and
subsequent Fisher's PLSD. Data are presented as means ± SE.
Statistical significance was defined by P < 0.05.
| |
RESULTS |
Hemodynamics in the basal condition.
Hemodynamics are summarized in Table
1. After chronic rapid
ventricular pacing, heart rate, LV end-diastolic pressure, and LV
internal diameters were all increased, compared with control. As for
the parameters of LV systolic function, the peak +dP/dt of LV
pressure, cardiac output, and fractional shortening were significantly
decreased. As for the parameters of LV diastolic function, the time
constant of LV pressure decay during isovolumic relaxation period ()
was prolonged after rapid right ventricular pacing.
Hemodynamic changes after administration of milrinone or dobutamine.
Hemodynamics before and after infusion of milrinone or dobutamine are
summarized in Table 2. After the
administration of dobutamine (2-10
µg · kg1 · min1),
LV peak pressure was slightly increased in control conditions and
unchanged in heart failure. LV end-diastolic pressure tended to
increase in control and was unchanged in heart failure. Peak +dP/dt increased and was shortened in both groups. As shown in Fig. 1, peak +dP/dt increased to
a lesser extent in heart failure than in control, whereas was
shortened to a similar extent as in control.
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Fig. 1.
Effect of dobutamine on percent change in peak value of positive 1st
derivative of left ventricular (LV) pressure (+dP/dt;
A) and in time constant of LV pressure decay during isovolumic
relaxation period (; B) from baseline. Values are means ± SE. * P < 0.05 vs. baseline,  P < 0.05 vs. control. In heart failure, peak +dP/dt increased less than
in control after infusion of dobutamine, whereas was shortened to a
similar extent as in control.
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After the administration of milrinone, heart rate was slightly
increased in control and unchanged in heart failure. LV peak pressure
was unchanged in either control or heart failure. LV end-diastolic
pressure decreased in both groups. Peak +dP/dt increased and
was shortened in both groups. As shown in Fig.
2, peak +dP/dt increased to a
lesser extent in heart failure than in control, whereas was
shortened much more than in control by low doses of milrinone
(4-12 µg/kg).
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Fig. 2.
Effect of milrinone on percent change in +dP/dt (A) and
in (B) from baseline. Values are means ± SE.
* P < 0.05 vs. baseline. P < 0.05 vs.
control. In heart failure, peak +dP/dt increased less than in
control after the infusion of low doses of milrinone, whereas was
shortened much more than control.
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Ca2+-ATPase activity and
cAMP level in presence of milrinone or dobutamine.
As summarized in Table 3, both cAMP and
Ca2+-ATPase activity in crude homogenate were significantly
decreased in heart failure compared with control. After the addition of
dobutamine, the cAMP increased in a dose-dependent manner to a lesser
extent in heart failure than in control (Fig.
3A). Ca2+-ATPase
activity was increased in a dose-dependent manner in both groups (Fig.
3B). There was no significant difference in the percent increase of Ca2+-ATPase activity from baseline between
control and heart failure. On the other hand, after milrinone was
added, cAMP increased similarly in both groups (Fig.
4A), whereas
Ca2+-ATPase activity was increased to a greater extent in
heart failure than in control at low doses of milrinone (Fig.
4B).
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Fig. 3.
Effect of dobutamine on cAMP level (A) and
Ca2+-ATPase activity (B) in LV crude homogenates.
Values are means ± SE. * P  0.05 vs. baseline;
P 0.05 vs. control. Dobutamine increased cAMP to a
lesser extent in heart failure than in control. Ca2+-ATPase
activity was increased in a dose-dependent manner, and there was no
significant difference in response between control and heart failure.
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Fig. 4.
Effect of milrinone on cAMP level (A) and
Ca2+-ATPase activity (B) in LV crude homogenate.
Values are means ± SE. * P 0.05 vs. baseline;
P 0.05 vs. control. Milrinone increased cAMP in
heart failure to a similar extent as in control. Low doses of milrinone
exerted more increase in Ca2+-ATPase activity in heart
failure than in control.
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Figure 5 shows the relationship between the
percent change of Ca2+-ATPase activity and the percent
change of cAMP in the presence of dobutamine (Fig. 5A) or
milrinone (Fig. 5B). In the presence of either dobutamine or
milrinone, Ca2+-ATPase activity (%)-cAMP (%) relationship
curves were shifted to the left in heart failure compared with control,
indicating higher sensitivity of Ca2+-ATPase activity to
cAMP in heart failure. Compared with dobutamine, low doses of milrinone
exerted a substantial increase in Ca2+-ATPase activity in
heart failure, at a given increase in cAMP.
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Fig. 5.
Relationship between percent change in Ca2+-ATPase activity
and percent change of cAMP in presence of dobutamine (A) or
milrinone (B). Values are means ± SE. Compared with control,
Ca2+-ATPase (%)-cAMP (%) relationship was shifted to left
in heart failure by either dobutamine or milrinone. In particular, low
doses of milrinone produced more increase in Ca2+-ATPase
activity at a given increase in cAMP than dobutamine.
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In the presence of 1 µM thapsigargin (SR Ca2+-ATPase
inhibitor), Ca2+-ATPase activity was decreased by 17.7 ± 3.1% in normal homogenate and by 19.6 ± 1.8% in heart failure
homogenate. There was no significant difference in the percentage of
the thapsigargin-sensitive portion of Ca2+-ATPase activity
between normal and heart failure.
Figure 6 shows the effect of dobutamine or
milrinone on the thapsigargin-insensitive portion of
Ca2+-ATPase activity in normal (Fig. 6A) and heart
failure (Fig. 6B). There was no significant change in the
thapsigargin-insensitive portion of Ca2+-ATPase activity at
various doses of dobutamine or milrinone.
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Fig. 6.
Effect of dobutamine or milrinone on thapsigargin-insensitive portion
of Ca2+-ATPase activity in control conditions (A)
and heart failure (B). Values are means ± SE.
Thapsigargin-insensitive Ca2+-ATPase activity was
influenced neither by dobutamine nor milrinone in control and heart
failure.
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| |
DISCUSSION |
The major findings of this study are as follows. First, in heart
failure, the positive lusitropic effect of either milrinone or
dobutamine was well preserved in association with the increased sensitivity of SR Ca2+-ATPase activity to cAMP. Second, in
particular, the positive lusitropic effect of low doses of milrinone
was more prominent in heart failure than in normal conditions,
associated with a marked stimulation of SR Ca2+-ATPase activity.
Preservation of positive lusitropy in heart failure.
Much evidence has accumulated that in heart failure, the positive
inotropic response to catecholamine is significantly decreased, whereas
positive lusitropy is well preserved (26, 31). The reduction of the
positive inotropic action of dobutamine after heart failure might be
caused by high production of NO (17). Keaney et al. (16) found that
intracoronary infusion of the nitric oxide synthase inhibitor
NG-nitro-L-arginine methyl ester
increased peak ±dP/dt in response to intracoronary infusions
of either dobutamine or isoproterenol in the in situ canine heart.
Consistent with these previous reports, we found that both dobutamine
and milrinone caused less increase in LV contractility in heart failure
than under normal conditions, whereas lusitropic responses to both
drugs were well preserved. Although the underlying mechanism is still
unclear, in heart failure the lusitropic response might be coupled more
efficiently to cAMP than the inotropic responses on stimulation of
either dobutamine or milrinone. Sensitivity of the lusitropic cascade
(i.e., phosphorylation of phospholamban, interaction of phospholamban
to Ca2+-ATPase, etc.) to cAMP may be increased in heart
failure. As a matter of fact, we found that Ca2+-ATPase
activity in heart failure was more enhanced at a given increase in cAMP
either by dobutamine or by milrinone than under normal conditions (Fig.
5). As another possibility, the recently proposed functional
compartmentation of cAMP (1, 6) might partly explain the discordance in
inotropic or lusitropic action to cAMP-dependent drugs in heart
failure. In heart failure, the cAMP produced either by dobutamine or by
milrinone may be better compartmentalized for the elevation of local
cAMP in lusitropic response than in inotropic response.
Mechanisms by which milrinone exerts predominant acceleration of LV
relaxation in heart failure.
Using the model of pacing-induced heart failure, two recent studies
have shown that 1) gene expression and activity of PDE III are
reduced in SR (37) and 2) cAMP and PDE levels are
preferentially reduced in the subendocardium (34). These findings may
account in part for the reduced positive inotropic effect of milrinone and also the predominant positive lusitropy and activation of Ca2+-ATPase by low doses of milrinone.
Recently, a particulate, high-affinity type IV cAMP-PDE activity was
shown to exist in cardiac SR (14). In this regard, much evidence has
accumulated that certain cardiotonic agents (milrinone, imazodan, and
amrinone) inhibit this SR membrane-bound "low Km" or
"cGMP-inhibited" PDE type IV isozyme (35, 38, 39) and exert their
contractile effects through subtle alterations in the metabolism of
cAMP (15, 19). With regard to this, functional compartmentation of cAMP
and protein kinases was previously proposed for cardiac muscle (1, 6),
and intracellular Ca2+ mobilization might be affected by
cAMP located in the particulate compartment of canine cardiac myocytes
(6). Because milrinone, at submicromolar concentrations, inhibits
specifically SR membrane-bound PDE III activity (19), the acceleration
of SR Ca2+-ATPase activity by low doses of milrinone might
be caused by an inhibition of membrane-bound PDE III in SR, followed by
a local elevation of cAMP, not the global cytosolic elevation of cAMP. Indeed, we previously demonstrated (42) that a low dose of milrinone significantly enhanced LV relaxation in association with the
substantial increase in the rate of Ca2+ uptake by cardiac
SR. This effect of milrinone might also explain why, in this study
using LV homogenate, milrinone exerted more increase in the
Ca2+-ATPase activity in heart failure than dobutamine at a
given increase in cAMP (Fig. 5).
Limitations.
Milrinone exerts a vasodilating effect as well as positive inotropic
and lusitropic effects. Therefore, afterload reduction by this drug may
possibly induce acceleration of LV relaxation. With regard to this,
when LV pressure was increased by ~25% (mean 30 mmHg) by addition of
phenylephrine together with milrinone, was not significantly
influenced in normal dogs (unpublished data). Furthermore, in the
present study, the low dose of milrinone (4 µg/ml) did not change
peak LV pressure and LV end-diastolic pressure, whereas was
shortened by 16% in heart failure. Therefore, the
PDE-inhibitory effect of milrinone might be predominantly involved in
the positive lusitropic effect, particularly at a low dose. At higher
doses of milrinone, the mixed effects of PDE III inhibition and
vasodilatation may play important roles in the improvement of LV relaxation.
In the present study, we measured whole Ca2+-ATPase
activities in myocardium. However, the SR Ca2+-ATPase
activity alone comprises ~25% of the total muscle homogenate activity, and ~75% of total Ca2+-ATPase activity in
muscle homogenate is provided by intracellular organs other than SR,
i.e., Ca2+-Mg2+-ATPase of the plasmalemma and
myofibrils (36). Therefore, we should address the reaction of these
other Ca2+-ATPase activities to milrinone or dobutamine in
this study. As shown in Fig. 6 , thapsigargin-insensitive
Ca2+-ATPase activity, which comprises ~80% of total
Ca2+-ATPase activity, was influenced by neither dobutamine
nor milrinone. Only the thapsigargin-sensitive portion of
Ca2+-ATPase activity was changed by these drugs, indicating
that these positive inotropic agents indeed affect SR
Ca2+-ATPase activity.
In the present study, the degree of heart failure appears moderate
(heart rate ~100 beats/min, no change in LV systolic pressure, LV
end-diastolic pressure <25 mmHg) compared with the hemodynamic values
reported in the literature (20, 26, 37). In severe heart failure, the
cytosolic level of cAMP and the protein expression of
Ca2+-ATPase might substantially decrease, and hence the
positive lusitropic responses to cAMP-dependent drugs may deteriorate
no matter how SR Ca2+-ATPase activity is hypersensitized to
cAMP. Also, it is likely that the sensitivity of SR
Ca2+-ATPase activity to cAMP may change depending on the
severity of heart failure. Clearly, more work is needed.
In conclusion, 1) positive lusitropic effects by cAMP-dependent
drugs were well preserved, probably because of the higher sensitivity
of SR Ca2+-ATPase activity to cAMP in heart failure, and
2) a low dose of milrinone substantially improved LV relaxation
in association with stimulation of SR Ca2+-ATPase activity
in heart failure much more than under normal conditions.
| |
ACKNOWLEDGEMENTS |
The authors thank Dr. Kenichi Yoshida, Department of Legal
Medicine, Yamaguchi University School of Medicine, for helpful technical advice.
| |
FOOTNOTES |
This work was supported by a grant-in-aid for scientific research in
Japan (Grants C 09670722 and C 11670684) and by a Health Sciences
Research Grant for Comprehensive Research on Aging and Health from the
Ministry of Health and Welfare, Japan.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. Yano, Second
Dept. of Internal Medicine, Yamaguchi Univ. School of Medicine, 1144 Kogushi, Ube, Yamaguchi 755-8505, Japan.
Received 3 May 1999; accepted in final form 18 August 1999.
| |
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