Download Salutary actionof nicorandil, a new antianginal drug, on myocardial

LABORATORY INVESTIGATION
MYOCARDIAL ISCHEMIA
Salutary action of nicorandil, a new antianginal
drug, on myocardial metabolism during ischemia
and on postischemic function in a canine
preparation of brief, repetitive coronary artery
occlusions: comparison with isosorbide dinitrate
GALEN M. PIEPER, PH.D.,
AND
GARRETT J. GROSS, PH.D.
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ABSTRACT The effects of two antianginal drugs, nicorandil and isosorbide dinitrate (ISDN), on
metabolism and function of the ischemic myocardium were studied in a preparation of multiple coronary
occlusions in barbital-anesthetized dogs. The preparation consisted of three 5 min occlusions of the
left anterior descending coronary artery interspersed by 30 min of reperfusion. An equihypotensive dose
of nicorandil (7.5 ,ug/kg/min) or ISDN (12.5 ,ug/kg/min) was infused 15 min before and during the
second occlusion period. Hemodynamics, myocardial segment shortening (%SS), tissue blood flow,
and myocardial oxygen consumption were determined throughout. Uptake of free fatty acids (FFA),
glucose, and lactate were determined during control and ischemic periods. At the end of the final 30
min reperfusion period, biopsy samples of transmural tissue were taken for analysis of phosphocreatine,
adenine nucleotides, and total tissue water content. No major hemodynamic changes were produced
by either drug except for a 5 to 10 mm Hg decrease in mean aortic pressure. Compared with untreated
and ISDN-treated hearts, hearts of dogs treated with nicorandil exhibited reversal of a significant
increase in FFA uptake during recurrent ischemia. This was accompanied by an attenuation of the
increase in oxygen extraction and CO2 production in the ischemic zone by nicorandil, but not by ISDN.
Nicorandil, but not ISDN, improved %SS during reperfusion. Endocardial ATP and total adenine
nucleotides were preserved in both nicorandil- and ISDN-treated hearts. Tissue edema was also
attenuated by both compounds. Thus, nicorandil improved both function and metabolism during
recurrent myocardial ischemia independent of a hemodynamic effect, whereas ISDN only attenuated
the loss of adenine nucleotides and increase in tissue water.
Circulation 76, No. 4, 916-928, 1987.
REPETITIVE, brief episodes of myocardial ischemia
are common during angina pectoris in patients with
coronary artery disease. Intermittent cross-clamping or
repeated, brief periods of coronary artery occlusion are
also used during cardiac surgery. However, it is not
clear from experimental studies whether recurrent
ischemic episodes of brief duration have a cumulative
effect on the development of regional postischemic
myocardial dysfunction. 1-4
Nicorandil [SG-75; 2-nicotinamidoethyl-nitrate (esFrom the Department of Pharmacology and Toxicology, Medical
College of Wisconsin, Milwaukee.
Supported by Chugai Pharmaceutical Company, Ltd., Tokyo, Japan,
and USPHS grant HL 08311 from the National Institutes of Health.
Address for correspondence: Dr. Galen M. Pieper, Department of
Pharmacology and Toxicology, Medical College of Wisconsin, 8701
Watertown Plank Rd., Milwaukee, WI 53226.
Received Nov. 1 1, 1986; revision accepted July 2. 1987.
916
ter)] has been developed as a new antianginal drug with
potent vasodilating properties. It has recently been
shown to improve postischemic segment dysfunction in
anesthetized5 and conscious6 dogs after a single 10 or
15 min coronary artery occlusion. The improvement in
postischemic myocardial function after nicorandil may
be partially related to a reduction in afterload, but the
improved functional recovery in the presence of nicorandil is significantly greater than that after an equihypotensive dose of nifedipine. Thus suggests that the
beneficial effects of nicorandil on the ischemic myocardium may be independent of peripheral hemodynamics and that other mechanisms must be involved in
its action.
The purpose of this study was to determine whether
there is a metabolic component of the action of nicorandil independent of its hemodynamic effect that
CIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL ISCHEMIA
might explain its salient effect on postischemic myocardial function. Thus, we purposely chose a low dose
of nicorandil that would not significantly alter the ratepressure product or myocardial oxygen consumption to
determine whether the recovery of contractile function
was enhanced after reperfusion. The experimental
preparation of repeated, short periods of coronary
artery occlusion was chosen for these studies to mimic
the recurrent ischemia of anginal attacks observed clinically. Isosorbide dinitrate was chosen for purposes of
comparison because this compound has a similar
hemodynamic profile and plasma half-life to those of
nicorandil.
LAD
FLOW PROBE
TRANSMURAL METABOLISM.
BIOPSY
CORONA&DV
OCCLUDfR
1
SEGMENT LENGTH
ISCHEMIC AREA
%ss= DLtSL X100
DL
Methods
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Surgical preparation and functional analysis. Twenty-four
adult mongrel dogs (15 to 25 kg) of both sexes were used in this
study. Animals were anesthetized with an intravenous combination of 15 mg/kg sodium pentobarbital and 200 mg/kg barbital
sodium. Dogs were ventilated with a Harvard respirator (tidal
volume of 15 ml/kg and 10 to 15 respirations per min) and
supplemented with 100% oxygen. Atelectasis was prevented by
maintaining a trap with an end-expiratory pressure of 5 to 7 cm
of water. Body temperature was maintained at 380 C with a
heating pad. Blood gases were monitored (ABL-2) at various
times throughout the experiment and kept within the normal
physiologic range.
Mean arterial and left ventricular pressures were monitored by
inserting a double pressure transducer-tipped catheter (Millar
PC 771) into the aorta and left ventricle via the left carotid artery.
Left ventricular dP/dt was determined by electronic differentiation of the left ventricular pressure pulse. The right femoral vein
was cannulated for the administration of drugs.
A left thoracotomy was performed at the fifth intercostal
space, the pericardium was incised, and the heart was suspended
in a cradle. A portion of the left anterior descending coronary
artery (LAD) was isolated and an electromagnetic flow probe
(Statham SP 7515) was placed around the vessel. LAD coronary
blood flow was measured with a flowmeter (Statham 2202).
Distal to the flow probe, a micrometer-driven mechanical
occluder was placed to produce a total occlusion of the LAD.
The electrocardiogram was monitored using limb lead II and a
tachograph was used for a continuous measurement of heart rate.
All measurements were monitored on a Grass Model 7 polygraph. A cannula was positioned via the left external jugular vein
in the local anterior intraventricular coronary vein, which
drained the ischemic LAD area to obtain blood samples (figure
1). The cannula tip always lay just distal to the coronary occluder
to ensure sampling primarily from the ischemic-reperfused area.
Roberts et al.8 and others9 have previously shown that blood
sampled by this technique is almost exclusively (95%) draining
the LAD perfusion bed. In three separate dogs, an epicardial
venous catheter was placed directly into the area draining the
ischemic-reperfused region and duplicate blood gas samples
were obtained before and during coronary artery occlusion.
Blood gas values and myocardial oxygen extraction (%02E) and
oxygen consumption (MVO2) were not different when obtained
by the epicardial stick method or by the coronary venous cannula
(preocclusion %O2E = 57.3 + 3.7 vs 54.0 + 3.0 and MVO2
= 10.2 + 0.7 vs 10.0 + 1.3 ml/min/g, respectively; occlusion
%O2E 69.5 + 9.7 vs 64.0 + 2.7 and MVO2 = 2.8 + 0.7
vs 2.6 + 0.7 ml/min/g, respectively). Both aortic and local
coronary venous blood samples were withdrawn for substrate
Vol. 76, No. 4, October 1987
FIGURE 1. Diagram of experimental preparation. Blood samples were
taken from the local coronary vein for the measurement of blood gases,
free fatty acids, glucose, and lactate. Biopsy samples of transmural tissue
were obtained at the end of the third 30 min reperfusion period for the
determination of phosphocreatine, total adenine nucleotides, and tissue
water content. Radioactive microspheres were used to measure coronary
collateral blood flow and piezoelectric crystals to determine %SS by
sonomicrometry. Note that the coronary vein catheter is actually
advanced to a position well within the shaded, ischemic region.
analysis and determination of blood gases and oxygen content.
Blood gases, % oxygen saturation (%O2sat) and hemoglobin
(Hb) values were measured with a Radiometer ABL 2 blood gas
analyzer. Oxygen content (vol%) in arterial and coronary venous
blood samples was determined by multiplying 1.34 x Hb x
%O2sat + 0.003 x Po2. %O2E was calculated as:
A02 CVO2
-
A02
X 100
and MVO2 (in ml/min/100 g) as: A02 - CVO2 X coronary
blood flow (ml/min/100 g), where A02 is arterial oxygen content and CVO2 is coronary venous 02.
Myocardial segment function (% segment shortening, %SS)
was measured in the regions perfused by the left anterior
descending and left circumflex coronary arteries with the use of
two sets of piezoelectric crystals. The crystals were inserted into
the myocardium (approximately 10 to 15 mm apart and 7 to 9
mm deep) parallel to subendocardial fiber orientation.7 The leads
of each crystal were connected to an ultrasonic amplifier that
transformed the sound pulse transmitted between the two crystals into an electrical signal proportional to the distance between
the crystals. The crystals were precalibrated and the tracings
were monitored with an oscilloscope (Soltec 520). By recording
changes in transmission time, the distance between the two
crystals was measured. With left ventricular dP/dt, systolic
length (SL) was determined at maximal negative dP/dt and
diastolic length (DL) was determined just before the onset of
systole. %SS was calculated as:
- SL
-% DLDL
x 100
At the completion of each experiment, the depth of each crystal
was verified. The %SS data were normalized by use of a value
of 10.0 for the control diastolic length.
Myocardial blood flow. Myocardial blood flow was determined by the radioactive microsphere technique. The left atrial
appendage was cannulated for the administration of micro-
917
PIEPER and GROSS
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
spheres while the right femoral artery was cannulated for the
withdrawal of a reference blood flow sample. Carbonized plastic
microspheres (15 ± 3 g.m diameter) labeled with '41Ce, 51Cr,
03 Ru,
or 95Nb were suspended in isotonic saline with 0.01%
Tween 80 added to prevent aggregation. The radioactive microspheres were ultrasonicated for 5 min followed by 5 min of
vortexing. Approximately 2 to 4 x 106 spheres were injected
into the left atrium followed by a 6 ml saline wash. Just before
sphere administration, a reference blood flow sample was withdrawn from the femoral artery at a constant rate of 6.5 mllmin
for 3 min.
At the completion of each experiment, India Ink was injected
into the LAD to delineate the perfusion area. The heart was
removed and stored overnight in 10% formalin. The heart was
sectioned into subepicardium, midmyocardium, and subendocardium of the normal (three pieces) and ischemic regions (five
pieces) and the tissue samples were weighed. All samples were
counted (Searle Analytic 1 195) to determine the activity of each
isotope in each sample. The activity of each isotope was also
determined in the reference blood flow samples. Myocardial
blood flow was calculated by a preprogrammed computer (Apple
lie) to obtain the true activity of each isotope in individual
samples and tissue blood flow was determined with the equation:
Qm = Qr . Cm/Cr
where Qm = myocardial blood flow (ml/min/g tissue); Qr
rate of withdrawal
of the reference blood flow sample (6.5
ml/min); Cr = activity of reference blood flow sample (cpm);
Cm activity of tissue sample (cpmlg). Transmural blood flow
was calculated as the weighted average of the three layers in each
region. Myocardial blood flow distribution (endocardial-epicardial ratio, endo/epi) was calculated by dividing the average
subendocardial flow of each region by the average subepicardial
flow.
Blood chemical analysis. Arterial and local coronary venous
blood samples were collected into ice-chilled tubes containing
sodium fluoride (to prevent glucose metabolism in vitro) and
potassium oxalate (anticoagulant). A 0.5 ml aliquot of the collected blood was immediately added to 1.0 ml of ice-cold, 6%5
perchloric acid for deproteination. Samples were then 2entrifuged and enzymatically analyzed within 3 hr for blood lactate
(Sigma Diagnostics) with the use of a Gilford 250 recording
spectrophotometer.
The remaining blood was centrifuged to obtain plasma for
both glucose and free fatty acid (FFA) determinations. Twenty
microliter aliquots of plasma were taken and analyzed enzymatically for glucose (Sigma Diagnostics) within 3 hr after
termination of the experiment. Plasma FFA was extracted by
adding 100,l of plasma to 6.0 ml of chloroform/heptane/
methanol(200/150/7 volumes) in tightly capped tubes containing 100 mesh-activated silicic acid. Plasma FFA was extracted
by the method of Laurell and Tibbling'0 and stored at-20 C
for analysis at a later date. FFA was analyzed in triplicate by the
analysis outlined by Hron and Menahan."' Plasma FFA and
glucose concentrations were corrected to whole blood and multiplied by regional myocardial blood flow. The arterial-local
coronary venous concentration difference was multiplied by the
regional ischemic myocardial blood flow in milliliters per minute
per 100 g to determine substrate uptake in the ischemic-reperfused zone. Since it was not possible to obtain tissue blood flow
measurements at all periods, the uptakes in control periods 2,
3, and 4 were estimated by the proportional relationship of LAD
blood flow determined by the electromagnetic flow probe
to that assessed by the microsphere method during the control
period 1.
Experimental design. The experimental design consisted of
918
an initial control period followed by three consecutive 5 min
coronary artery occlusions with 30 min of reperfusion allowed
after each occlusion period. Hemodynamics, %SS, MVOI, and
the uptake of various substrates were measured 5 min before each
occlusion (control 1. control 2, and control 3), during each
occlusion (occlusion 1, occlusion 2, and occlusion 3), and 25
min after occlusion 3 (control 4). Regional myocardial blood
flow (radioactive microspheres) was measured 5 min before
occlusion 1 and during each occlusion period. Saline (control
series), nicorandil (7.5 ,ug/kg/min), or isosorbide dinitrate
(ISDN) (12.5 ,tg/kg/min) was infused via a cannula in the right
femoral vein for 15 min before and during the second 5 min
coronary occlusion (total infusion time 20 min). These doses
of nicorandil and ISDN produced only 5 to 10 mm Hg decreases
in systemic arterial blood pressure. The plasma half-life of
nicorandil 12 and ISDN 13 in dogs is 42 and 39 min, respectively.
Tissue biopsy and analysis. At 30 min after release of the
third coronary occlusion, simultaneous transmural drill biopsy
samples were obtained from reperfused and nonischemic zones
of the left ventricle and frozen between liquid nitrogen-chilled
aluminum blocks. 1 Frozen tissue biopsy samples were cleaned
of blood residue and subdivided into epicardial, midmyocardial,
and endocardial layers. Neutralized, perchloric acid extracts of
tissues were analyzed for ATP, ADP, AMP, and phosphocreatine on a Gilford 250 spectrophotometer with the use of coupled
enzymatic assays. 15-- 17
The energy charge potential of the adenylate pool was calculated with the formula:
=
ATP + 0.5 ADP
ATP + ADP + AMP
Additional portions of frozen tissue were weighed and dried
overnight at 950 C to determine tissue water content and to
convert tissue metabolite concentrations to units of micromoles
per gram dry weight. All values are given as the mean + SE
(n = 8, each group). Differences between group means were
compared by a two-way analysis of variance and Fisher's least
significant difference. Values are compared with the preocclusion control by one-way analysis of variance for repeated measures or Dunnett's t test. Paired and unpaired t tests were used
to compare two means within the same animal and between
animals, respectively. Means were considered significantly different if p < .05.
Results
Blood gases and MVO2. During each of the three occlu-
sion periods in untreated hearts, MVO2 and coronary
venous pH and oxygen content decreased while coronary venous Pco2 and %02E increased significantly
(p < .05) compared with the preocclusion control (table
1). %02E was higher during the second occlusion
period as compared with the first occlusion period. The
calculated net changes in these variables for all experimental groups are listed in figure 2. The administration
of nicorandil, but not ISDN, significantly attenuated or
abolished the decrease in coronary venous pH and 02
content and the increase in %02E and venous Pco2
during occlusion 2 (figure 2).
Hemodynamics and blood flow. There were no major
changes in heart rate, mean aortic pressure, left ventricular systolic and end-diastolic pressure, or left ventricular maximum dP/dt between the three experimenCIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL ISCHEMIA
TABLE 1
Oxygen extraction and coronary venous blood gas indexes in untreated hearts
Control,
Occlusion
Control,
Occlusion,
Control3
Occlusion
Control4
CVpH
(units)
(mmn Hg)
cVo,
(vol %)
7.37+0.02
7.30+0.03A
7.35+0.02
7.31 +0,03A
7.33+0.02
7.30 + 0 03A
7.33 + 0.02
40+2
45 3A
40+2
44+ 3A
40+2
43 3A
40 +2
9.5+0.7
8.6 0.6A
9.4+0.6
7.5 0o4A
8.4+0.7
7.5 0.6
9.2+ 07
CVPco,
0, extraction
(A-CV)x 100
A
54.0+3.2
57 7+±29A
55.3+3.7
64,0 2.7A
58.7+4.1
64.0 3.5A
56.8t+3.2
MVO,
(ml/min/g)
10.0-1.3
2.0-0.7'11.7+2.6
2.6 0.7A
11.4 1.0
2.0 0.4A
10.1 +1.2
All values are mean + SEM (n = 8)
A = arterial, CV = local coronary xenous.
ASignificantly different from respective preocclusion control value (p < .05). All control measurements were taken 5 min
before the respective occlusion period. Control measurements 2. 3. and 4 were taken 25 min after reperfusion.
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artery (LAD) blood flow in the hearts of control or
nicorandil-treated dogs during the control period. In
contrast, coronary blood flow decreased in hearts of
dogs treated with ISDN between control 1 and 2 (31 +
4 to 23 + 2 ml/min, p < .05).
During each occlusion period, the rate-pressure
product was equivalent and did not vary between
groups of animals (figure 3). MVO2 tended to be higher
during the second occlusion period in control animals
compared with that in drug-treated animals, but this
difference was not statistically significant. There was
tal groups as a result of coronary artery occlusion. Both
nicorandil and ISDN produced modest decreases in
mean aortic pressure that were not significantly different from the baseline values for each group (table 2).
Mean aortic pressures in the two drug-treated groups
were slightly, but significantly (p < .05), lower than
those observed in control animals. The doses of nitrates
chosen did not produce any changes in left ventricular
pressures, dP/dt, heart rate, rate-pressure product, or
MVO2 (table 2).
There were no significant changes in mean coronary
CORONARY VENOUS BLOOD GASES AND pH
(Control #2 vs. Occlusion #2)
-Tr
0
z
w.
a
0
z
U
w-1
C
NC
ISDN
C
NC
ISDN
P < 0 05 from Control and
Isosorbide Dogs
E
cp
N
occlusion.
6
10 -
FIGURE 2. Changes in local coronary venous pH,
PC02, 02 content, %O2E between control period 2
and occlusion 2 iti control (C). nicorandil (NC). and
ISDN-treated dogs. All values are the mean + SEM
(n = 8, each group). Nicorandil attenuated the
decrease in coronary venous pH and 02 content and
the increase in Pco2 and %O2E produced by coronary
16
9WUI 12T
86
Z
CY
W
' 1A
° 0C
ID
=
m)
C
NC
ISDN
Vol. 76, No. 4, October 1987
919
PIEPER and GROSS
TABLE 2
Hemodynamic variable before occlusion period 1 or before occlusion period 2 in the presence of nicorandil or ISDN
Untreated
Period 1
96 7
Mean aortic pressure (mm Hg)
109 7
LVSP (mm Hg)
4 1
LVEDP (mm Hg)
140+8
Heart rate (min-')
Rate pressure product
1.57+0.17
(mm Hg min-'x104)
Maximum dP/dt (mm Hg sec) 2400+200
10.0 1.3
MVO, (ml/min /100 g )
31 6
CBF (ml/min -)
ISDN
Nicorandil
Period 2
Period 1
Period 2
Period 1
Period 2
97 5
112 6
3 1
146+9
95 4
107 5
4+1
142+6
89 ± 3A
101 ± 4A
3±1
144±6
96 6
106 6
3 1
155+6
87+ 7
97 7A
2 1
159+4
1.52 0.11
2200+180
8.1 +0.8
31 5
1.46±0.09
2100+120
9.1 + 1.2A
37+6
1.67+0.17
2500+211
11.7 1.4
34±6
All values are the mean - SEM of eight dogs in each group.
LVSP and LVEDP = left ventricular systolic and end-diastolic pressures; CBF
flow.
ASignificantly different from the untreated group (p < .05).
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
no change in MVO2 during subsequent occlusion periods in drug-treated animals. In addition, collateral
blood flow did not change in subsequent occlusion
periods and was not altered by the presence of drug.
Regional myocardial blood flow. Tissue blood flow data
during preocclusion (control) and during each 5 min
occlusion period (occlusions 1, 2, and 3) were determined by the microsphere technique. No significant
changes were observed in the nonischemic (left circumflex-perfused) region throughout the experimental
=
1.65±0.14
2460+215
7.5 ± 0.8A
31 ±4
1.54±0.12
2438±169
7.0 ± 0.9A
23±2A
left anterior descending coronary blood
period in control or nicorandil-treated hearts (data not
shown). However, in the ISDN group, transmural myocardial blood flow in the nonischemic area decreased
from a baseline of 0.93 ± 0.08 ml/min/g in the first
occlusion period to 0.68 + 0.06 and 0.73 ± 0.08
ml/min/g in the second and third occlusion periods. The
endo/epi blood flow ratio was 1.28 ± 0.4 and 1.11 ±
0.08, respectively. In the ischemic region, blood flow
decreased markedly and to a similar extent during all
three occlusion periods in the three groups (figure 3).
CONTROL
io~~~~~~~!
0
I!
OC 1
OCC2
OCC
occ 3
OCC 2
1
OcC 3 occ c
NICORANDIL
30
4
2
0
0
0
OCCGI
OCC
2
OCCC
OCC 3
FIGURE 3. Comparison of the rate-pressure product (HR x LVSP), M'VO2. and collateral blood flow
during each of the three occlusion (OCC) periods. All
values are the mean + SEM (n = 8. each group).
OCC2O
OCC
CCC3
OCC
2
OCC 3
ISOSORBIDE DINITRATE
I
Ccci
X
|
1
occ 1
920
OCC2
S
occ 2
OC
|
OCC 3
OCCi
° E
O2
OC3
o~~~~~~~~~3
2
occ 1
occ 2
OCC 3
i
0N
OCC8
OC
T
1
occ 1
occ 2
occ 3
CIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL ISCHEMIA
" Control
O-0 Nicorandil
A-A Isosorbide
30'
*
a20
z
z
ui
z
v1)
z
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
U
I
U
ening. There were no significant differences between
groups during the occlusion periods (figure 4).
During the first 30 min reperfusion period in the
absence of drugs, the recovery of %SS in the three
groups was similar (figure 4). Immediately after drug
treatment during the second 30 min reperfusion period,
%SS in nicorandil-treated dogs recovered 100% as
compared with the initial control 1 value, whereas %SS
in the saline and ISDN-treated dogs was significantly
decreased (p < .05) compared with their respective
control 1 values (figure 4). When the %SS values
during the second 30 min reperfusion period were compared with their respective control 2 values, %SS in
nicorandil-treated dogs recovered to a greater extent
than those in the saline and ISDN-treated animals and
%SS in the ISDN group was significantly increased
with that in the control group (figure 5). At the end of
the third 30 min reperfusion period, functional recovery
in all three groups was depressed and %SS was approximately 30% to 40% less than the original control 1.
0 Control
O0- Nicorandil
&-* Isosorbide
TIME (Min)
FIGURE 4. %SS (expressed as a percent of control period 1 = 100%)
during the three 5 min occlusion periods and at various times after
reperfusion in the control, nicorandil, and ISDN-treated dogs. All values
are the mean + SEM (n = 8, each group).
In addition, the left ventricular weights, ischemic area
weights, and the percent area at risk for ischemia were
similar in all groups (left ventricular weights: 100.8 ±
9.8, 96.5 + 6.8, and 96.1 ± 5.8 g; ischemic area
weights: 31.0 + 5.7, 30.3 ± 3.4, and 27.4 ± 1.5 g;
% area at risk: 29.8 + 3.2%, 31.2 + 2.4%, and 29.2
± 2.2% for control, nicorandil, and ISDN groups,
respectively). These data indicate that during coronary
occlusion the three groups were subjected to similar
degrees of ischemia.
Myocardial segment function. %SS data at 5 min before
each occlusion period (controls 1, 2, and 3), at the end
of 30 min of reperfusion after occlusion 3 (control 4),
and during occlusion in the various groups are shown
in figures 4 and 5. No significant changes in %SS
occurred in the nonischemic (left circumflex-perfused)
area throughout the experiment in any of the three
groups (data not shown). In the ischemic-reperfused
(LAD-perfused) region, each coronary occlusion
resulted in a reduction in %SS to negative values in all
groups, which is indicative of passive systolic lengthVol. 76, No. 4, October 1987
160
rm
_O
* P<0.05 to Control
t P<0.05 to lsosorbide
*5
z
3 120
40
<80-
~400
z
w
Q0
0
5
C
15
25
Reperfusion (Min)-*
z
::E-40-
-80L
FIGURE 5. %SS (expressed at a percent of control period 2) in control,
nicorandil, and ISDN-treated dogs. All values are the mean + SEM (n
= 8, each group).
921
PIEPER atid GROSS
TABLE 3
EfFects of repeated ischemic-reperfusion episodes on plasma glucose extraction by the myocardium
Untreated series
A-CV [glucose] (,moles
ml ' plasma)
Glucose uptake (g.moles
minm
00 gg plasma)
Nicorandil series
A-CV [glucose] (,.moles
ml plasma)
Glucose uptake (gmoles
min 100g plasma)
ISDN series
A-CV [glucose] (gmoles
ml plasma)
Glucose uptake (,gmoles
min 100l g ' plasma)
Control
Occlusion
Control,
Occlusion,
Control3
Occlusion.
Control4
0l18 0.06
0.18 0.06
0.42- 0.1
0.43 0. 13
0.35 -- 007
0 24- 0.06
0,28 009
5,88 284
1 57+0.96
14 65 5.21
2.63 0.73B
1554a4 56
0.9880,673
14 425 60
0.16+0 06
028--011
0.37 0.07
0.34+0.07
0.28-0.06
0.33 009
0 30 0.07
7,32±225
368 1,87
28 17+1] 08
3 11+1 17B
1286 226
3 66 lnB
31 .l90 422
0 20 0)08
0 39 0 10
0,35 0.07
0 370 12
042
0.43 0.15
0,620. 10
1.09-367
374+1.19
1341+1.97
3.92+1 3V
872+524
4.621.788
26.27 i7 17
I11
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Each point represents the mean of eight animals ± SEM Glucose concentrations were corrected to whole blood for determination of glucose uptake.
Since microspheres were not used for tissue blood flow determinations at control,, control3, and control4, uptake at these times was calculated with
tissue blood flow estimates based on LAD blood flow measurements by the electromagnetic flowmeter.
Abbreviations are as in table 1
ADifferences compared with control, and occlusion,
BDifferences between control and occlusion values.
%SS in the nicorandil-treated dogs was somewhat
greater than in the saline and ISDN group, but this
difference was not significant (p < 1).
Myocardial glucose extraction. Arterial and coronary
venous glucose concentrations were unaltered by the
repetitive ischemic-reperfusion protocol (not shown).
In contrast, the arterial-coronary venous) glucose concentration difference and glucose uptake (table 3) was
stimulated after the first ischemic and reperfusion episode (control 2). The alteration in the pattern of glucose
extraction was attenuated in the presence of nicorandil
or ISDN.
Myocardial free fatty acid (FFA) extraction. Arterial and
coronary venous FFA concentrations were unaltered by
multiple ischemic-reperfusion episodes (data not
shown). The arterial-coronary venous FFA concentrations and the FFA uptake during each period are
shown in table 4. Baseline FFA uptake values were not
significantly different between experimental groups
before occlusion period 1 based on analysis of variance
(F ratio = 1.96, df - 2 and 19, p > 1 ). It was observed
that there was a progressive increase in FFA arterialcoronary venous differences and FFA uptake in subsequent control periods in untreated dogs (FFA uptake:
6.65 ± 1.85, 13.99 ± 3.02, 14.24 + 3.59, and 18.55
± 5.04 gmoles/min/100 g, respectively). In contrast,
nicorandil produced a progressive decrease in FFA
uptake during control periods (13.35 + 5.02, 10.26 +
1.94, 6.64 + 1.23, and 7.77 -+ 0.84 gmoles/min/100
922
g, respectively). This pattern was significantly different than that observed in untreated hearts. Changes in
FFA uptake during control periods in animals treated
with ISDN were similar to those observed in untreated
animals (5.43 + 1.08, 7.19 ± 1.62, 11.02 + 4.14,
and 14.84 ± 5.67 ,umoles/min/100 g, respectively).
Thus, nicorandil, unlike ISDN, attenuated or reversed
the progressive increase in FFA uptake after recurrent
ischemia.
While the uptake of FFA was reduced during each
period of ischemia in all three groups compared with
the uptake in the respective control period, that in
untreated hearts during both the second control and
second ischemic period was increased relative to that
during the first control and ischemic period. During
ischemic periods in untreated hearts, the uptake of FFA
was twice as high in the second as in the first ischemic
period (figure 6). Nicorandil. but not ISDN. reversed
this increase. When the net change in FFA uptake was
calculated, there was an increase in FFA uptake in both
the ischemic periods (2 and 3) that followed in untreated animals. This was not observed in the ISDN-treated
group. In contrast, a net decrease in FFA uptake was
observed in both ischemic penrods 2 and 3 in the nicorandil-treated group (figure 6).
Myocardial lactate extraction. Uptake of lactate was
reduced in all experimental groups during all three
ischemic periods (table 5). There was no major alterations in the arterial and coronary venous concentraCIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL ISCHEMIA
TABLE 4
Effects of repeated ischemic-reperfusion episodes on plasma FFA extraction by the myocardium
Untreated series
A-CV [FFA] (nmolesml- ' plasma)
FFA uptake (,moles min*100 g )
Nicorandil series
A-CV [FFA] (nmolesml plasma)
FFA uptake (gmoles-min*100 g 1)
ISDN series
A-CV [FFA] (nmolesml 1)
FFA uptake (gmoles-min100 g 1)
Control1
Occlusion,
16
141 44
137
Occlusion2
Control3
Occlusion;
Control
84
235 32A
255 54
166 ± 54
149 + 50
13.99±3.02A
2.26±59AB
14.24+3.59
1.41 40.71B
18.55+5.04
148+30
132+45
138+32
281
1.03±0.32B
6.65 1.85
Control,
150O44
203+78
2.14±0.85B
13.35+5.02
10.26+ 1.94
134+29
95+20
151
1.59±0.55B
5.43 1.08
±
1.40±0.63B
187 46A
179+26
19A
1.92±0.74B
7.19 1.62
6.64+ 1.23
11.02+4.14
138+14
1.53±0.47B
207+58
2.17±0.90B
167±18
7.770.84
279±57A
14.84+5.67
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Each point represents the mean of eight animals + SEM. FFA concentrations were corrected to whole blood for determination of FFA uptake. For
other details see table 3.
Abbreviations are as in table 1.
ADifferences compared with control, and occlusion,.
BDifferences between control and occlusion values.
on lactate metabolism, as determined by comparison
with the control group.
tions of lactate in any of the groups. Generally, there
was an increase in lactate concentration in coronary
venous samples during the ischemic periods (baseline,
1. 19 ± 0.26; occlusion 1, 1.70 + 0.44; occlusion 2,
1.63 + 0.38; occlusion 3, 1.75 + 0.39 mmoles/liter).
Neither nicorandil nor ISDN had any significant effect
Myocardial tissue energy metabolism and water content.
Repetitive, short periods of myocardial ischemia resulted in a rebound in myocardial phosphocreatine
concentration (table 6). There was no statistically sig-
CONTROL
300.
2~~~~~~~~~~~~~~~~
OCCc 2
occci
01
OCCc
occci
CCc3
0.0
E
~~~~~~~~~~~~~~z
01
2
3CC
ccc
2
OCC3
1
vs. OCC 1
:1
NICORANDIL
0.0
4
300
01~T
I~~~~~~~~~~~~2
280
1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-.
£
01
8
OCC 2
OCCO
OCC 2
Occi
OCC 3
OCC 2
OCC 3
vs. OC
l
OCC 3
v.OCC 1
FIGURE 6. FFA extraction by ischemic-reperfused
areas of hearts during each of three occlusion periods.
Values are the mean + SEM (n = 7 or 8 each group).
Significant difference from occlusion 1 by repeatedmeasures analysis of variance. Significant difference
from untreated hearts.
ISOSOR9IDE DINITRATE
200.~
~
~
~
~
~
~
~
~
~
~
~
~~~~~~0
CLo d 2i
OCC 1
OCC 2
OCC 3
occ i
OCC 2
OCC 3
Vol. 76, No. 4, October 1987
A
OCC 1
c occ
s i.o
OCC 3
v". OCC 1
o2 OCC OC3
OCC 2
OCC 2
w.uOCC1
ts OCC 10
OCC 3
vs.OCCl1
923
PIEPER and GROSS
TABLE 5
Effects of repeated ischemic-reperfusion episodes on blood lactate extraction by the myocardium
Control,
Occlusion,
Control,
Occlusion,
Control3
Occlusion3
Control4
0.30 0.27
0.14 0.43
0.63 +0.20
0.23 +0.08
0.63 +0.24
0.36 ± 0.47
0.71 + 0. 23
59.06 13.98
5.06±5.68A
59.96 17.72
8.28 8.48A
52.78 17.38
5.69±6.56A
42.71 + 13.03
0.73 + 0.09
0.36 + 0.18A
0.67 + 0.09
0.44 ± 0.17
0.78 + 0.05
0.46 ± 0.12
0.77 + 0.05
69.16 13.92
3.71 3.85A
64.43 10.32
4.74±2.49A
58.98+9.98
4.63±2.27A
51.56±7.20
0.81 +0.18
0.77 ±0.35
0.87±0.14
0.66±0.28
0.82+0.16
0.65 0.23
0.87±0.19
70.49 15.78
12.11 + 6.79A
61.49 ± 11.41
11.24 + 8.27A
Untreated series
A-CV [lactate]
(mmoles/liter)
Lactate uptake (,umoles
min '100 g ')
Nicorandil series
A-CV [lactate]
(mmoles/liter)
Lactate uptake (,Lmoles
min -100 g ')
ISDN series
A-CV [lactate]
(mmoles/liter)
Lactate uptake (,umoles
minm1-100 g )
63.07
12.83
13.12 8.03A
59.57
13.57
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Each point represents the mean of eight animals ± SEM. For other details, see table 3.
Abbreviations are as in table 1.
ADifferences between control and occlusion values.
0.911 + 0.006 (untreated), 0.910 + 0.003
(nicorandil), and 0.906 + 0.005 (ISDN).
An increase in tissue water was also evident in the
reperfused region of untreated hearts (figure 8). Both
nicorandil and ISDN attenuated the tissue edema in the
reperfused region after repetitive ischemic-reperfusion
episodes.
nificant reduction in ATP or the various adenine
nucleotide fractions. However, the absolute concentrations of both ATP and total adenine nucleotides
tended to be lower in the endocardial layer of the
reperfused left ventricle, especially when normalized
to the nonischemic region within the same heart (figure
7). This reduction in endocardial ATP and total adenine
nucleotides was prevented by the administration of
either nicorandil or ISDN. There was no significant
difference in the energy (adenylate) charge potential
between layers of nonischemic and reperfused areas.
The values in the endocardial layers of the reperfused
area were
Discussion
The observations in this study suggest that nicorandil
may be an effective therapeutic agent in the treatment
of recurrent myocardial ischemia. The salient effect of
TABLE 6
Effect of multiple, short ischemic-reperfusion episodes on transmural myocardial energy metabolism
Nonischemic zone
Epi
Untreated
Phosphocreatine
ATP
Total adenine nucleotides
Nicorandil
Phosphocreatine
ATP
Total adenine nucleotides
ISDN
Phosphocreatine
ATP
Total adenine nucleotides
Mid
Reperfused zone
Endo
Epi
Mid
Endo
40.77 6.71 39.25 5.15 37.57 3.86
24.67 1.32 26.14 1.07 26.05 1.22
29.08+ 1.57 30.88± 1.55 31.13± 1.62
44.69 3.99
44.69 3.31
23.62 1.30
27.75± 1.46
49.76 1.21 A
24.05 1.09
28.62± 1.07
35.72+3.79 33.86±3.48 31.09+3.02
23.65 0.92 25.25 1.05 23.68 0.77
28.43 1.17 30.26 1.38 28.46±0.85
42.37+3.91
23.21 0.71
36.57 3.13 34.87 3.90 31.41
1.62
24.33±0.51
28.58+0.63
27.85±0.84
48.17 2.26A
23.04±+1.36 23.31 1.24 21.61 0.71
24.42±0.56
27.67 + 1.46 28.37
28.76 0.73
1.19 25.93 0.96
41.07±3.85A 43.33+4.70A
23.34+ 1.13
28.13± 1.35
24.29 0.75
29.15+0.97
42.53 2.59A
23.67 1.08
27.97 1.32
41.91±+ 3.09A
22.47+ 1.34
27.12 + 1.55
Each point represents the mean ± SEM of seven or eight hearts expressed in units of ,umoles per g dry weight.
ASignificantly different from corresponding layer in nonischemic zone.
924
CIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL ISCHEMIA
0
140-
z 0
x
W C)
H- .. 120z .lE
*
0
of single, brief coronary artery occlusions of 10 to 30
min duration. However, many of these effects could be
related, in part, to changes in afterload due to the use
of higher doses of nicorandil. In contrast, the lower
dose of nicorandil used in the present study produced
only a small reduction of mean aortic blood pressure.
An equihypotensive dose of ISDN was only partially
effective in improving postischemic recovery. While
nicorandil has been shown to increase prostacyclin and
decrease thromboxane A2 production,2' it is doubtful
that this has physiologic significance since the concentration of nicorandil (2 mM) was much higher than
that expected in our preparation. The mechanism for
functional improvement by nicorandil is believed to
be related to a metabolic component of its action.
Nicorandil, but not ISDN, prevented or attenuated the
increase in myocardial FFA uptake and %02E within the ischemic zone during a repeated episode of
ischemia.
Substrate utilization in the ischemic zone. It is commonly believed that enhanced FFA uptake is detrimental during ischemia22' 23 and agents that reduce
FFA uptake or oxidation during ischemia are
beneficial.2>28 The reduction in FFA uptake in ischemic regions of nicorandil-treated hearts is assumed to
result in a concomitant reduction in oxidation of FFA.
Although the latter was not directly measured, the
observation that nicorandil attenuated the increase in
%02E and coronary venous CO2 production would be
consistent with a reduction in FFA oxidation. The
corresponding absence of attenuation of the changes in
FFA uptake, %02E, and CO2 production by ISDN
could explain why this agent was not as effective as
nicorandil in preventing postischemic dysfunction.
Since increased FFA oxidation contributes to a relative
TOTAL ADENINE
NUCLEOTIDES
ATP
*
*
*
0
T
0 0
z
100
0 -o
0
0
z
W a)
60
C
NC ISDN
C
NC ISDN
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
FIGURE 7. Left ventricular endocardial concentrations of ATP and
total adenine nucleotides after repeated ischemic-reperfusion episodes.
The values represent the mean + SEM of 7 or 8 animals and are
normalized as a percent of the nonischemic zone perfused by the left
circumflex artery in the same hearts. CON = control; NC = nicorandil,
7.5 ,g/kg/min; ISDN = isosorbide dinitrate, 12.5 ,ug/kg/min.
*Significantly different from control animals as shown by unpaired t
analysis.
nicorandil was manifested by the prevention of regional
postischemic myocardial dysfunction in the following
reperfusion period, preservation of tissue adenine
nucleotides, and attenuation of tissue edema formation.
This was unlike the effects of ISDN, which did not
improve postischemic function. The mechanism for the
functional improvement by nicorandil does not appear
to be related to changes in afterload or increased collateral blood flow, which have been observed previously in this laboratory with higher doses of nicorandil
and in different experimental preparations.5 6, 18 19
Nicorandil has been shown to have a beneficial effect
on postischemic dysfunction5' 7, 18 and the development of ischemic myocardial acidosis20 in preparations
l°
500r
0
u
DN 40.
_
?
1
.J E
bL
h-
J-LM
I
Epi
Endo
UNTREATED
eriseZ
zprfjsdZn|
a
0
a
9
1
1
9
9
a
a
9
a
9
f
a
a
9
a
1
1
1
0
9
e
1
1
A
N.S.51
Nt.S
a
f
Endo
NICORANDIL
Epi
5
1
1
1
a
1
a
N.S.
I
Epi
Endo
ISOSORBIDE
DINITRATE
FIGURE 8. Total tissue water content of transmural sections of dog left ventricle after repeated ischemic-reperfusion episodes.
The values are the mean + SEM of eight hearts. *Significant difference relative to the nonischemic zone value.
Vol. 76, No. 4, October 1987
925
PIEPER and GROSS
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,,oxygen wasting" phenomenon,22 it is possible that this
could also explain why nicorandil prevented the decline
in adenine nucleotides after multiple ischemic episodes. However, this does not appear to explain why
ISDN preserved adenine nucleotides. It is possible that
the preservation of adenine nucleotides by these two
agents may be either unrelated to changes in substrate
uptake during ischemia or arise from different mechanisms than those for improved functional recovery.
Relationiship to previous studies. In an isolated report on
a preparation of recurrent ischemia, Korb et al.29
reported that nicorandil might have a detrimental effect
during myocardial ischemia. They showed that nicorandil increased FFA metabolism and oxygen debt
during a 3 min occlusion interval. The present study
does not confirm these findings. Instead, our study
suggests the opposite conclusion. There are some probable reasons for these discrepancies.
Korb et al.29 used coronary sinus blood for venous
substrate and blood gas concentrations as well as for
blood flow determinations. In contrast, we collected
blood for venous substrates and blood gases from the
local vein draining the ischemic bed. The local vein
samples should be more representative of the ischemic
area and not greatly contaminated from adjacent nonischemic sources, which may dilute blood samples
obtained from the coronary sinus. Furthermore, we
made our blood flow measurements in the ischemic area
by the radioactive microsphere method. Again, this
would be a more precise measure of ischemic myocardial blood flow than that obtained from measurements of coronary sinus blood flow. The flow value
obtained for the determination of coronary sinus blood
flow may have been artificially high due to the contribution of blood flow from adjacent nonischemic
areas, which may contribute significantly to total coronary sinus blood flow. Thus, any calculations of substrate uptake based on measures of coronary sinus
blood flow compound the error in measurement of
coronary sinus substrate concentration and lead to erroneous conclusions.30, 31 Finally, in their preparation of
repetitive occlusion Korb et al.29 used ischemia of
different durations (3 min vs 5 min). It is not known
whether this time differential is of significance. However, it is likely that Korb et al. could not differentiate
a priming effect of repetitive ischemia because they
combined their data from two to three control occlusions or two to three drug-treated occlusions within the
same dog. The averaging of substrate utilization from
multiple periods of occlusion or reperfusion within the
same animal may not be justified based on our results.
Limitations and uniqueness of the preparation. The
926
preparation of recurrent ischemia chosen for these studies was created by ischemic episodes of short duration.
While most experimental protocols consist of ischemic
durations of 10 min or longer, shorter periods may be
relevant to certain clinical situations. The brevity of this
ischemic interval may produce events that are not
entirely characteristic of prolonged ischemia. It is
likely that metabolic events arising during early myocardial ischemia (less than 5 min) are not similar to
those occurring during ischemia of longer duration
(more than 5 min). Thus, there is a progression of
metabolic events that evolve from the transition from
the nonischemic to the overtly ischemic myocardiumi2
It should be emphasized that our preparation is more
representative of the initial transition phase of acute
myocardial ischemia. One manifestation of this phase
is that net lactate production by the heart has not yet
commenced, although coronary venous blood lactate
concentration may be increased. Since we collected
local coronary venous blood samples for substrates
between the third and fourth minute of ischemia, it is
not surprising that not all hearts showed net lactate
production during the ischemic interval. This observation is consistent with other investigators who
observed only marginal lactate production after 5 min9
or significant lactate production after 10 min of
ischemia.3' Alternatively, others have shown net lactate production only on reperfusion after a 2 min occlusion period.33 Unfortunately, we did not measure substrate utilization during early reperfusion. Such
determinations would be complicated by the variability
of the hyperemic blood flow and may not be an accurate
index of lactate production.
Instead of focusing on the reperfusion phase for
substrate utilization, we chose as one of our primary
foci a comparison of events occurring during each
ischemic interval since this might influence the functional recovery of the succeeding reperfusion period.
Between the first and second occlusion cycles, we
observed a priming effect on substrate utilization before
and during the ischemic period. We know of no other
study that has detected such a priming phenomenon.
This is most likely because investigators who use a
preparation of recurrent ischemia measure functional
indexes rather than metabolic variables. Thus, our studies are unique in that regional myocardial blood flow,
regional contractile function, regional MVO2, transmyocardial substrate uptake, and regional myocardial
energy metabolism were all measured within the same
hearts. It is not yet known whether the substrate priming after the first occlusion cycle is a compensatory
mechanism to regenerate chemical energy stores and to
CIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL ISCHEMIA
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
protect the myocardium from further ischemic insult.
Alternatively, when the substrate priming (i.e.,
enhanced FFA extraction) carries over into the second
occlusion cycle, it may have deleterious consequences,
as indicated by the observation of postischemic
dysfunction.
Adenine nucleotides in recurrent ischemia. Repetitive
ischemic episodes of short duration do not apparently
produce a cumulative effect on adenine nucleotide loss
from myocardial tissue. It has been suggested that the
largest decline in myocardial ATP occurs after the first
occlusion (10 or 15 min duration), with a slower rate
of depletion in subsequent episodes.4 34 3 It is not yet
known whether this difference in ATP hydrolysis
between first and subsequent ischemic episodes occurs
in preparations of shorter duration such as that used in
our study. We assume that the reduction in myocardial
adenine nucleotides should be the same in all groups
after the first occlusion period since collateral blood
flow and MVO2 in the ischemic zone was similar in all
groups in the absence of drug infusions. Despite this,
both nicorandil and ISDN were effective in preserving
myocardial adenine nucleotides when given before and
during the second occlusion period. This suggests that
while a single 5 min episode of myocardial ischemia
may cause hydrolysis of ATP stores, there may not be
a concomitant efflux of nucleosides and bases. In such
a case, rephosphorylation to normal ATP levels would
still be possible on reperfusion. However, in the
absence of pharmacologic intervention between the
first and second occlusion periods, a progressive loss
in tissue energy metabolites probably occurs. Therefore, the largest loss of myocardial adenine nucleotides
may well occur after the second ischemic episode in our
preparation of repetitive ischemia, in contrast to the
preparation of Reimer et al.34
It was not ascertained in either the preparation of
Reimer et al. or in our preparation whether a reduced
rate of ATP depletion in subsequent ischemic cycles is
related to the degree of functional impairment during
the reperfusion period immediately after a previous
ischemic interval. Thus, it could be argued that postischemic hypofunction may result in decreased demand
for ATP utilization. However, such a scenario would
predict that since nicorandil improves contractile function it should result in a greater utilization of myocardial ATP. However, both nicorandil and ISDN attenuated the loss of myocardial adenine nucleotides,
despite different levels of postischemic function. This
suggests that the preservation of myocardial adenine
nucleotides by these drugs proceeds by mechanisms
other that preservation of contractile function.
Vol. 76, No. 4, October 1987
Postischemic contractile function after recurrent ische-
mia. Some controversy also exists as to whether repetitive occlusions produce a progressive decrease in
regional contractile function. A number of
studies," ' 4 including the present one, suggest that
%SS progressively decreases after each succeeding
ischemic episode. In contrast, Lange et al .2 reported an
initial decrease in' contractile function that was not
decreased further after a second or third occlusion.
Some of this controversy may be related to the variation
in experimental protocol including: the duration of the
occlusion period, the duration of reperfusion, and the
number of occlusion periods. It is also difficult to
compare various studies on contractile function since
collateral blood flow and area at risk were not provided
in all cases. While the occlusion and reperfusion periods in the study by Lange et al.2 are similar to those
of the present study, they did not find a progressive
deterioration in myocardial contractile function with
repeated ischemic episodes. This may be related to the
higher2 and more variable36 blood flow values reported
by Lange et al. compared with those observed in the
present study during ischemia. Higher collateral blood
flow during ischemia would be conducive to better
recovery of function during reperfusion. While we did
show a progressive deterioration in contractile function
during subsequent ischemic episodes in untreated
hearts, we were also able to demonstrate that our preparation was still sensitive to therapeutic improvement
in wall function, despite an initial decline in %SS.
Implications of the study. Our preparation of repeated,
brief coronary artery occlusions was used to test the
efficacy of nicorandil and ISDN during myocardial
ischemia and reperfusion. Our observations may have
potential clinical applications for drug testing. In this
regard, the choice of cycle for drug intervention may
influence the results obtained. The preparation chosen
for these studies appears to be ideal since drug intervention occurred at the point of the substrate priming
effect. Therefore, interventions at this point may be
useful in determining whether a drug will have a beneficial effect on postischemic myocardial dysfunction.
Finally, the low doses of nitrates chosen for this
study were well within the range of those that would
be used clinically. The results of the study indicate that
nicorandil significantly improves postischemic contractile dysfunction independent of hemodynamic
changes. The metabolic data suggest that nicorandil
may prove to be a more desirable clinical agent than
ISDN in the treatment of angina pectoris.
We gratefully acknowledge the technical assistance of Ms.
Anna Hsu, Ms. Jeannine Moore, and Ms. Bernadette Giddings.
927
PIEPER anid GROSS
We also thank Dr. Kazushige Sakai and Chugai Pharmaceutical
Co., Ltd., for the gift of nicorandil.
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Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
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CIRCULATION
Salutary action of nicorandil, a new antianginal drug, on myocardial metabolism during
ischemia and on postischemic function in a canine preparation of brief, repetitive
coronary artery occlusions: comparison with isosorbide dinitrate.
G M Pieper and G J Gross
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Circulation. 1987;76:916-928
doi: 10.1161/01.CIR.76.4.916
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