Circulation. 1998;98:58-63
(Circulation. 1998;98:58-63.)
© 1998 American Heart Association, Inc.
Acute Effects of Toborinone on Vascular Capacitance and Conductance in Experimental Heart Failure
Lisa M. Semeniuk, MSc;
Israel Belenkie, MD;
; John V. Tyberg, MD, PhD
From the Departments of Medicine and Physiology and Biophysics, The
University of Calgary, Alberta, Canada.
Correspondence to John V. Tyberg, MD, PhD, Professor of Medicine and Physiology and Biophysics, The University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada. E-mail jtyberg{at}cvr.ucalgary.ca
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Abstract
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Background—Toborinone (OPC-18790), a
phosphodiesterase III inhibitor, enhances cardiac
contractility and is an arterial dilator.
However, its effects on the venous system have not yet been clearly
defined. Because toborinone administration reduces left
ventricular (LV) end-diastolic pressure, it is
probably also a venodilator. Because of the known arterial
effects and the hypothesized venous effects, we compared changes in
systemic vascular conductance (the inverse of resistance) with changes
in venous capacitance.
Methods and Results—In 15 anesthetized, splenectomized
dogs (10 treatment, 5 control), pressures were measured in the right
atrium, aorta, portal vein, and LV. A cuff constrictor was placed
around the portal vein. Cardiac output was measured by thermodilution,
and splanchnic vascular capacitance was measured by blood-pool
scintigraphic methods. Data were collected at baseline, after induction
of heart failure (microsphere embolization into the left
coronary artery), and then after toborinone boluses of 0.1,
0.2, 0.4, and 0.8 mg/kg. Heart failure was associated with decreased
capacitance and conductance (to 87±3% and 64±4% of baseline values,
respectively, P<0.05). After administration of the
lower doses of toborinone, capacitance increased more than conductance;
however, the effects were more balanced at the higher doses. Compared
with nitroglycerin, hydralazine, and
enalaprilat (results of an earlier study) in the same model, toborinone
increased capacitance to a degree similar to that with
nitroglycerin, at higher doses increased conductance
similarly to hydralazine, and increased both capacitance and
conductance considerably more than did enalaprilat.
Conclusions—Toborinone is a potent balanced venous and
arterial dilator in experimental acute heart failure. These
marked effects suggest that it may prove to be a clinically important
alternative to other vasodilators.
Key Words: circulation • vasodilation • heart failure • veins • hemodynamics
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Introduction
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Toborinone
[(±)-6-[3-(3,4-dimethoxy)benzylamino-2-hydroxy]-propyl-2(1H)-quinolinone]
(OPC-18790, Otsuka Pharmaceuticals Co Ltd), a phosphodiesterase III
inhibitor,1 has coronary
vasodilator activity2 and has been shown in both
experimental1 and
clinical3 4 5 6 studies to increase
contractility and cardiac output, with only slight
changes in heart rate and mean blood pressure. In addition, it has no
significant effect on myocardial oxygen consumption and improves
cardiac energetics in ischemic
hearts.7 8 9 Although toborinone is known to be a
vasodilator,3 4 5 previous studies have focused on
arterial dilatation, with little being known about its
venous effects. Our current understanding of its effects on veins is
based on indirect hemodynamic measurements. LV
end-diastolic volume decreased substantially when a low
dose (5 µg · kg-1 ·
min-1) of toborinone was administered to
patients with dilated cardiomyopathy; a higher dose
(10 µg · kg-1 ·
min-1) also reduced systemic vascular resistance
and arterial pressure.3 To the best
of our knowledge, no direct assessment of the effects of toborinone on
vascular capacitance has been reported, although Fujiki et
al10 found a decrease in mean circulatory filling
pressure that was not statistically significant. Because toborinone
decreases LV end-diastolic pressure at lower doses and also
decreases arterial pressure at higher doses in patients
with heart failure, we hypothesized that it would increase vascular
capacitance at lower doses, in addition to increasing systemic
conductance at higher doses.
We used a previously described11 experimental
model to study the effects of toborinone on splanchnic vascular
capacitance and systemic vascular conductance (the inverse of systemic
vascular resistance) in acute heart failure. Splanchnic vascular
capacitance was measured by a blood-pool scintigraphic
technique.12 These results were compared with
those in our previous report of the vascular effects of other
vasodilators in the same model.13 Our data
indicate that toborinone has substantial venodilator effects that may
have important clinical implications.
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Methods
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Animal Preparation
Adult mongrel dogs (10 experimental [3 males, 7 females], 5
control [3 males, 2 females]; weight, 13 to 21 kg) were initially
anesthetized with sodium thiopental (25 mg/kg IV) (Abbott
Laboratories) and intubated. Anesthesia was maintained by
ventilation with a mixture of oxygen and nitrous oxide (30:70) and
isoflurane (Anaquest) with a constant-volume respirator (model 607,
Harvard Apparatus). Blood gases and body temperature were
maintained at physiological levels throughout the
experiment. To ensure adequate hydration, a 15-mL/kg infusion of 3.3%
dextrose in 0.3% NaCl was given 2 hours before the experimental
protocol was begun. A splenectomy was performed through a midline
abdominal incision to minimize changes in hematocrit. A pneumatic cuff
was placed around the portal vein. To measure portal venous pressure, a
fluid-filled catheter (OD 1.5 mm, ID 1.00 mm; Dural Plastics
Engineering) was introduced into an arcade branch of the portal vein
and positioned so that the tip lay just upstream from the pneumatic
cuff. To correct for radioactivity from the ventral abdominal wall, a
4x4-cm sheet of radiographic apron material was fixed to
the ventral surface of the liver (Vetbond, 3M Animal Care Products)
just under the ventral abdominal wall.12 The
abdominal wall was reapproximated with towel clips. Fluid-filled
catheters (7F, Abbott) were inserted into the proximal aorta through
the right femoral artery and right atrium through the jugular vein to
measure aortic and right atrial pressures, respectively. LV pressure
was measured with an 8F micromanometer-tipped
catheter (model SPC-485A, Millar Instruments) introduced through the
left carotid artery. Cardiac output was measured by thermodilution with
a triple-lumen balloon thermistor catheter (7F, Abbott) placed in the
pulmonary artery via the right internal jugular vein. A
catheter for removing reference blood samples for radioactivity
analysis was inserted into the right femoral vein. The
fluid-filled catheters were connected to pressure transducers (model
P23Ib, Statham-Gould). The ECG and pressures were recorded
with a multichannel recorder (model VR-16, Electronics
for Medicine–Honeywell). Hemodynamic data were
acquired and analyzed with a custom-designed program (CVSOFT,
Odessa Computer Systems Ltd).
Toborinone was dissolved by use of sonication in a
1.5x10-2 mol/L solution of
D,L-lactate (Sigma Chemical Co) in distilled water to yield
a final concentration of 10-2 mol/L.
Induction of Heart Failure
Heart failure was induced by repeated microsphere
(DuPont; 50-µm diameter, 4 mg/mL) embolizations into the left
coronary artery through a 5F left Judkins coronary
artery catheter as previously described11 until
LV end-diastolic pressure was 
20 mm Hg or cardiac
output was decreased by 50% of the baseline value. Induction of
failure took 100±23 (SD) minutes.
Measurement of SBV
In vivo, red blood cells were labeled by injection of stannous
pyrophosphate 7 mg IV followed by 20 mCi of
[99mTc]pertechnetate.14
This was performed at least 30 minutes before data collection was begun
to minimize the amount of unbound radionuclide. Scintigrams were
recorded from 5 cm above the abdomen for 45 seconds with a gamma
camera (model DYNA-MO 4, Picker) interfaced to a nuclear medicine
computer system (model DPS-3300, ADAC Laboratories). The numbers of
counts per pixel were obtained from manually defined mesenteric regions
of interest (excluding the liver, kidneys, bladder, and large blood
vessels). The regions of interest were computer-duplicated and
redefined only if the camera or the dog was moved. We made corrections
for physical decay (99mTc half-life, 6.02 hours),
"biological decay" (using the count rates of 100 µL reference
blood samples taken every 3 to 5 minutes throughout the experiment),
and the contribution of the ventral abdominal
wall.12
Abdominal scintigrams were obtained at three different portal
pressures, including baseline (7±2 mm Hg), 13±2 mm Hg,
and 18±2 mm Hg, the latter two by inflating the cuff around the
portal vein to raise the pressure to the desired level.
Experimental Protocol
In the toborinone-treatment group, hemodynamic
(heart rate, cardiac output, and aortic, right atrial, LV, and portal
venous pressures) and radionuclide data were obtained in duplicate at
baseline, after the induction of heart failure, and at 15 and 30
minutes after each IV bolus (administered over 1 minute) of toborinone
(0.1, 0.2, 0.4, and 0.8 mg/kg). The same protocol was followed in the
control dogs, except that only the toborinone vehicle
(D,L-lactate) was administered, in the same volume as had
been used to dissolve toborinone.
Analysis of Toborinone Plasma Concentrations
Three dogs in the experimental group were used for the
determination of toborinone plasma levels. In these 3 dogs, additional
blood samples (8 mL) were obtained at baseline, after induction of
heart failure, and 1, 15, and 30 minutes after administration of each
dose of toborinone. Samples were collected in heparinized vacuum
containers (sodium heparin glass beads, Becton Dickson Vacutainer
Systems) and centrifuged (HN-SII centrifuge,
International Equipment Co) at 3000 rpm for 10 minutes. The plasma was
transferred into cryogenic vials (Nalge Co) and frozen at -70°C. The
samples were packaged on dry ice and sent by overnight courier for
analysis. Analyses were performed by Kansas City
Analytical Services, Inc. Their reference numbers for the
high-performance liquid chromatography
analysis of toborinone are V0483P1 and B1294P1/B1294P2.
Analysis of Data
Systemic Conductance
Systemic conductance was calculated as the inverse of systemic
vascular resistance (ie, conductance=cardiac output/[mean aortic
pressure-mean right atrial pressure]).
Vascular Capacitance
PP-SBV relations (linear fits of the PP-SBV data points measured
at the 3 portal pressures) were defined for each set of data (duplicate
measurements were taken at baseline and after the induction of heart
failure, and single measurements were taken after the administration of
each dose of toborinone).
By interpolation, vascular capacitance was defined as the SBV at
PP=7.5 mm Hg. One hundred percent capacitance was defined as the
mean of the 2 baseline SBVs, and subsequent values were expressed as
percentages of that value. Rightward or leftward shifts of the PP-SBV
relations reflect increased or decreased capacitance, respectively,
compared with the baseline value. Thus, we measured relative rather
than absolute changes in capacitance. The reported values were
recorded 15 minutes after the administration of the drug.
Statistical Analysis
Mean baseline values were compared with the values obtained
after induction of heart failure by Student's paired t
test. Toborinone values were compared with the control values by
repeated-measures, two-way ANOVA and the Student-Newman-Keuls test.
Because of a slight difference in baseline values of cardiac output
between the treatment and control groups, analysis was
performed using percentage changes from the means of the two baseline
values. Absolute values were used for all other data except for venous
capacitance, which is always expressed relative to the baseline value.
To assess hemodynamic stability after induction of
heart failure in the control group, toborinone-vehicle data were
compared with their heart-failure values by repeated-measures, one-way
ANOVA and the Student-Newman-Keuls test. Student's paired t
test was also used to assess for hemodynamic
differences between the toborinone-treatment group and the group used
for the toborinone plasma level determination. Equalities of slope
coefficients of the PP-SBV relations were compared by use of a partial
F test for a multiple-regression model. Data are expressed as mean±SEM
with statistical significance accepted at the 95% confidence level
(P<0.05).
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Results
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Of 11 dogs originally in the toborinone-treatment group, data from
1 were excluded because they differed from the means by more than 4 SD.
Of the 10 remaining animals, 2 received only 3 of the 4 doses of
toborinone (0.1, 0.2, and 0.4 mg/kg). Of the 5 control dogs, 1 was
given a lidocaine bolus (1 mg/kg IV) during heart-failure induction to
suppress an idioventricular rhythm. The
hemodynamic measurements were not different between
this and the other 4 control dogs.
Hemodynamic Changes Due to Heart Failure
As seen in Table 1
, heart failure
was associated with significant increases in heart rate and right
atrial and LV end-diastolic pressures and significant
decreases in cardiac output, conductance, and capacitance in both the
control and treatment groups. The only difference between the two
groups was that the decrease in aortic pressure from 112±2 to
106±5 mm Hg was not statistically significant in the control
group (P=0.42) and that the decrease from 106±5 to
83±5 mm Hg in the treatment group was significant
(P=0.03).
Hemodynamic Effects of Toborinone
As seen in Table 1
, toborinone increased cardiac output from
2.0±0.2 to 3.3±0.3 L/min and decreased mean aortic pressure from
83±5 to 68±5 mm Hg and LV end-diastolic pressure
from 22.6±1.0 to 18.3±2.1 mm Hg (all P<0.05). The
decreases in right atrial pressure and heart rate were not
statistically significant. In the control group, the only further
statistically significant hemodynamic change after the
induction of heart failure was in right atrial pressure, which
increased from 3.7±0.7 to 5.2±0.7 mm Hg
(P<0.05).
Toborinone increased LV maximum dP/dt from 1160±90 mm Hg/s to
1370±80, 1570±110, 1750±150, and 1930±280 mm Hg/s for the
0.1-, 0.2-, 0.4-, and 0.8-mg/kg doses, respectively (all
P<0.05, one-way ANOVA).
There were no significant differences in any of the
hemodynamic parameters between the subgroup
used for the toborinone plasma level determination and the remainder of
the toborinone-treatment group.
Vascular Capacitance
As illustrated in the top panel of Figure 1, heart failure was associated with a
parallel leftward shift in the PP-SBV relation, reflecting
venoconstriction. Subsequent administration of toborinone was
associated with parallel rightward shifts in the relation
(venodilatation) beyond baseline values. In the control group (bottom
panel of Figure 1), there was a similar leftward shift of the curves
after the induction of heart failure, but the toborinone vehicle had no
significant effects on these relations. There were no significant slope
changes in either the toborinone-treatment (P=0.34) or
control (P=0.99) groups. These data are summarized in Figure 2: after induction of heart failure,
there was a significant decrease in capacitance to 87±3% compared
with baseline (P=0.002). Subsequent toborinone
administration caused significant increases in capacitance to 105±5%,
111±5%, 123±6%, and 118±5% for the 0.1-, 0.2-, 0.4-, and
0.8-mg/kg doses, respectively. In the control animals, there were
similar changes in capacitance after the induction of heart failure
(85±2% versus baseline, P=0.002) but, in contrast to the
treatment group, there were no further significant changes for the
duration of the experiment.
Systemic Conductance
As illustrated in Figure 3, heart
failure was associated with a significant decrease in conductance to
64±4% compared with baseline (P<0.001). After
administration of toborinone, conductance increased to 78±8%,
94±8%, 109±14%, and 128±18% for the 0.1-, 0.2-, 0.4-, and
0.8-mg/kg doses, respectively (P<0.05 for the 0.8 mg/kg
dose). In the control group, heart failure was associated with a
similar decrease in conductance (65±5% versus baseline,
P=0.018), but there were no further significant changes
during the remainder of the experiment.
Comparative Capacitance-Conductance Effects
In Figure 4, the effects of
toborinone on capacitance and conductance from the present study
are compared with the data obtained in our previous study of the
effects of hydralazine, enalaprilat, and
nitroglycerin in the same
model.13 In all groups of animals, heart failure
was associated with a decrease in both capacitance and conductance, and
the drug effects are expressed in relation to the heart failure data
(ie, heart failure capacitance and conductance=100%). Lower doses of
toborinone (0.1 and 0.2 mg/kg) caused a greater increase in capacitance
than conductance. This effect was similar to that obtained with
nitroglycerin. At higher doses (0.4 and 0.8 mg/kg),
there was a pronounced and more balanced effect that was similar to but
considerably greater than that obtained with enalaprilat. At higher
doses, toborinone increased conductance similarly to
hydralazine, which, in contrast to toborinone, had no effect on
capacitance.
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Figure 4. Plots of capacitance versus conductance after
induction of heart failure (HF) (100%) and after subsequent
administration of toborinone (0.1, 0.2, 0.4, and 0.8 mg/kg; 15-minute
values ), nitroglycerin (N), hydralazine (H),
and enalaprilat (E). Toborinone increased capacitance with little
effect on conductance at lower doses and had a more balanced dilator
effect at higher doses, increasing both capacitance and conductance. At
lower doses, toborinone was similar to nitroglycerin
and had a greater effect on capacitance than conductance. At higher
doses, balanced effect of toborinone was similar to but greater than
that of enalaprilat. Also, at higher doses, effect of toborinone on
conductance was similar to that of hydralazine.
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Toborinone Plasma Concentrations
Table 2 lists plasma concentrations
of toborinone. Plasma concentrations doubled with each doubling of the
dose, thus indicating that there was no measurable accumulation of
drug.
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Discussion
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In this study of anesthetized dogs in which acute heart
failure had been induced by coronary artery embolization,
toborinone decreased LV end-diastolic pressure and
increased systemic vascular conductance as expected. However, there was
also substantial venodilatation that was at least as great as that
observed with nitroglycerin and much greater than that
observed with enalaprilat in our previous study in the same model.
Thus, our data clearly demonstrate that the arterial
dilator effects of toborinone are associated with substantial
venodilatation. The parallel rightward displacements of the
pressure-volume curves (top panel, Figure 1) suggest that toborinone
increased splanchnic venous volume by increasing venous unstressed
volume, which implies an active reduction in smooth muscle
tone.12 13 15 The increased conductance that
resulted from toborinone administration clearly reflects reduced
arteriolar tone.
The effects of toborinone on capacitance and conductance are in keeping
with previously reported findings. Thus, the decrease in LV filling
pressure after toborinone administration both in patients with heart
failure3 5 6 16 and in this study is
consistent with venodilatation. Increased capacitance tends to
decrease LV end-diastolic pressure, whereas decreased
systemic vascular resistance tends to increase central venous pressure
(ie, raise it toward mean circulatory pressure) and therefore LV
end-diastolic pressure.17 Thus, the
venodilation was more than sufficient to negate the tendency of
arteriolar dilation to raise filling pressure.
Although toborinone dilates both veins and arterioles after the
development of heart failure, the relative effects appeared to be dose
dependent (see Figure 4). Thus, at lower doses, capacitance increased
more than conductance, whereas at the higher doses, both effects were
prominent. These data are consistent with observations in
patients with heart failure.3 Although
capacitance was not measured directly, decreases in right atrial
pressure, peak pulmonary artery pressure, and LV
end-diastolic volume were also more prominent at a lower
dose, whereas decreased systemic vascular resistance was most evident
with a higher dose. It is possible that the lack of a further increase
in capacitance at higher doses may have been due to maximum or
near-maximum venodilation at the lower dose.18
Another possible explanation is that baroreceptor activity was
decreased by the fall in aortic blood pressure and caused reflex
venoconstriction. This mechanism appears unlikely, however, because
heart rate did not increase, nor did conductance decrease.
The precise mechanism of action of toborinone has not yet been fully
elucidated, but the increase in capacitance and conductance may be
partially explained by its PDE inhibition, it being somewhat selective
toward the PDE III isoenzyme (cGI-PDE).1 19 The
accumulation of cAMP that results from PDE III inhibition enhances
calcium extrusion across the sarcolemma by two possible mechanisms: (1)
cAMP-dependent protein kinase present in vascular smooth muscle is
known to stimulate the sarcolemmal calcium pump, and (2) cAMP
stimulation of sarcolemmal
Na+,K+-ATPase causes
hyperpolarization and removal of intracellular
sodium. Extracellular sodium then exchanges with intracellular calcium
(Na+/Ca2+ exchanger),
resulting in relaxation of both arterial and venous smooth
muscle.20
Although PDE III inhibition can explain many of the
hemodynamic effects of toborinone, the absence of the
expected reflex-mediated increase in heart
rate3 5 6 9 discriminates toborinone from other
PDE III inhibitors and conventional
ß-agonists.3
Comparison of Toborinone With Other Vasodilators
In this same experimental model of acute heart failure, we
recently described the different effects of 3 vasodilators
(nitroglycerin, enalaprilat, and hydralazine,
each given in a dose that produced approximately the same degree of
hypotension).13 With all toborinone doses, the
degree of venodilation obtained was at least comparable to that caused
by nitroglycerin. At higher toborinone doses, venous
and arterial dilatation were approximately balanced, but
both were greater with toborinone than with enalaprilat. At the highest
toborinone doses, arterial dilatation was comparable to
that of hydralazine. Thus, the substantial venodilating effects
of toborinone suggest that it might be effective in treating patients
with heart failure, and the dose-dependence of the conductance effect
might prove useful in titrating the proportion of venous versus
arterial effects.
Consideration of the Model
The model used in the present study has important
limitations that need to be considered. Clearly, the anesthetic itself
has the potential of substantially altering the vasculature. Because of
the vasodilator effect of the anesthetic, the potential vasoactive
effects of toborinone may be even greater when used in conscious
subjects with heart failure, given that vasoconstriction may be
prominent in heart failure. Brief inflation of the splanchnic
constrictor tended to reduce aortic blood pressure, but as demonstrated
previously, the effect at portal pressures <20 mm Hg is
minimal.12 In addition, acute heart failure
induced by microsphere embolization may be quite different in
some respects from either acute or chronic congestive failure in
patients. Despite these considerations, the vasculature responded to
induction of failure in the expected fashion, and toborinone proved to
be a potent arterial and venous dilator. Thus, although our
findings cannot be assumed to apply to conscious patients with all
forms of heart failure, there are clear and prominent effects in our
model, and some clinical reports suggest that similar effects will be
observed in patients. It therefore appears reasonable to do similar
studies of toborinone in patients with congestive heart failure.
Conclusions
The hemodynamic effects of toborinone were
substantial in our model of acute heart failure and included a large
increase in capacitance (in addition to the expected increase in
conductance) that was considerably greater than that previously
observed with enalaprilat, another balanced vasodilator. These marked
and balanced effects suggest that toborinone has the potential to be
clinically important.
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Selected Abbreviations and Acronyms
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| LV |
= |
left ventricular, left ventricle |
| PDE |
= |
phosphodiesterase |
| PP-SBV |
= |
portal pressure–splanchnic blood volume |
| SBV |
= |
splanchnic blood volume |
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Acknowledgments
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L.M. Semeniuk held a Studentship from and Dr Tyberg is a
Heritage Scientist of the Alberta Heritage Foundation for Medical
Research (Edmonton). The study was supported by a grant-in-aid from the
Medical Research Council of Canada (Ottawa) to Dr Tyberg. We
acknowledge the excellent technical support provided by Cheryl Meek,
Gerald Groves, and Rosa Dani and the statistical advice of Dr Rollin
Brant of the Center for the Advancement of Health. We also thank Drs
T.D. Cowart and N. Chand of Otsuka America Pharmaceutical, Inc, for
supplying the drug and for providing partial support for the
study.
Received November 5, 1997;
revision received January 14, 1998;
accepted January 23, 1998.
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Top
Abstract
Introduction
) was
associated with a significant shift of relations to left compared with
baseline (
). Subsequent administration of toborinone (solid symbols)
produced a significant rightward shift from HF toward and beyond
baseline position. Numbers 0.1, 0.2, 0.4, and 0.8 indicate toborinone
doses (mg/kg). Bottom, Similar plots from
representative control experiment showing effects of HF
and subsequent administration of toborinone vehicle on PP-SBV
relations. HF was associated with a significant shift of relations to
left compared with baseline. Subsequent administration of toborinone
vehicle did not further shift relation. Numbers 0.1, 0.2, 0.4, and 0.8
indicate equivalent toborinone-vehicle doses.
, 15-minute values) or toborinone vehicle (
P<0.05 vs control.