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Division of Cardiology, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the hypertrophied heart, increased extravascular forces acting to compress the intramural coronary vessels might require augmentation of metabolic vasodilator mechanisms to maintain adequate coronary blood flow. Vascular smooth muscle ATP-sensitive potassium (K+ATP) channel activity is important in metabolic coronary vasodilation, and adenosine contributes to resistance vessel dilation in the hypoperfused heart. Consequently, this study was performed to determine whether K+ATP channels and adenosine have increased importance in exercise-induced coronary vasodilation in the hypertrophied left ventricle. Studies were performed in dogs in which banding of the ascending aorta had resulted in a 66% increase in left ventricular mass in comparison with historic normal animals. Treadmill exercise resulted in increases of coronary blood flow that were linearly related to the increase of heart rate or rate-pressure product. During resting conditions, K+ATP channel blockade with glibenclamide caused a 17 ± 5% decrease in coronary blood flow, similar to that previously observed in normal hearts. Unlike normal hearts, however, glibenclamide blunted the increase in coronary flow that occurred during exercise, causing a significant decrease in the slope of the relationship between coronary flow and the rate-pressure product. Adenosine receptor blockade with 8-phenyltheophylline did not alter coronary blood flow at rest or during exercise. Furthermore, even after K+ATP channel blockade with glibenclamide, the addition of 8-phenyltheophylline had no effect on coronary blood flow. This finding was different from normal hearts, in which the addition of adenosine receptor blockade after glibenclamide impaired exercise-induced coronary vasodilation. The data suggest that, in comparison with normal hearts, hypertrophied hearts have increased reliance on opening of K+ATP channels to augment coronary flow during exercise. Contrary to the initial hypothesis, however, adenosine was not mandatory for exercise-induced coronary vasodilation in the hypertrophied hearts either during control conditions or when K+ATP channel activity was blocked with glibenclamide.
8-phenyltheophylline; glibenclamide; aortic stenosis; myocardium; left ventricular hypertrophy; ATP-sensitive potassium channel
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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LEFT VENTRICULAR hypertrophy (LVH) secondary to chronic pressure overload is associated with increased vulnerability to myocardial hypoperfusion during exercise (2). This abnormality results, at least in part, from an abnormal increase in extravascular forces acting on the intramural coronary vessels in the hypertrophied heart during exercise (11). Consequently, it is likely that metabolic vasodilator mechanisms would be augmented in LVH to compensate for the increased extravascular forces and maintain adequate myocardial perfusion. Metabolic vasodilation occurs in the coronary arterioles and appears to be mediated by opening of ATP-sensitive potassium (K+ATP) channels. Thus, when intravital microscopy was used to directly visualize coronary microvessels in open chest dogs, progressive reductions of perfusion pressure resulted in vasodilation of the arterioles that was abolished by blockade of K+ATP channels with glibenclamide (16). If a heightened state of metabolic vasodilation is required to compensate for the increased extravascular forces during exercise in the hypertrophied left ventricle, then it might be expected that a greater degree of K+ATP channel opening would occur during exercise. The hypothesis that K+ATP channels are activated to a greater degree in hypertrophied than in normal hearts is supported by the report of Numaguchi et al. (20) that K+ATP channel blockade with glibenclamide resulted in a greater decrease of coronary flow in perfused hearts from spontaneously hypertensive rats than from normal rats.
Adenosine produced by myocardial myocytes and endothelial cells can contribute to metabolic coronary vasodilation. Myocardial adenosine production is increased in response to the increased cardiac work during exercise (19). Adenosine production is also increased during myocardial hypoperfusion (22). We have previously observed that, during exercise in the presence of a coronary artery stenosis, adenosine receptor blockade worsens the degree of myocardial hypoperfusion with no change in distal coronary pressure (18). This indicates that adenosine contributes to dilation of the coronary resistance vessels during exercise-induced myocardial ischemia. If hypoperfusion of the hypertrophied left ventricle during exercise results in ischemia, then myocardial adenosine production would be increased. The present study was carried out to determine whether the coronary K+ATP channels are in a greater state of opening in hypertrophied than in normal ventricles at rest or during treadmill exercise. In addition, the effect of adenosine receptor blockade was examined to determine whether there is increased dependence on adenosine for maintenance of coronary vasodilation during exercise in the hypertrophied left ventricle.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies were performed in 12 adult mongrel dogs weighing 22-27 kg (mean = 24 ± 1 kg). All experiments were performed in accordance with the "Guiding Principles in the Care and Use of Laboratory Animals" as approved by the Council of the American Physiological Society and with prior approval of the Animal Care Committee of the University of Minnesota.
Production of Aortic Stenosis
At 8 wk of age, the dogs were sedated with acepromazine (0.4 mg/kg im), anesthetized with thiamylal sodium (20-25 mg/kg iv), intubated, and ventilated with oxygen-enriched room air. A right thoracotomy was performed in the third intercostal space. The ascending aorta was dissected from the surrounding fat and connective tissue ~1.5 cm above the aortic valve and encircled with a polyethylene band 2.5 mm in width. While measuring left ventricular (LV) and distal aortic pressures, the band was tightened until a 20- to 25-mmHg peak systolic pressure gradient was achieved across the area of constriction. The thoracotomy was then closed, the chest was evacuated of air, and the animals were allowed to recover. Thereafter, the animals were maintained in enclosed runs on a standard laboratory diet until 12-15 mo of age when they were returned to the laboratory for study.Surgical Preparation
Animals were fasted overnight, sedated with acepromazine (0.5 mg/kg im), anesthetized with pentobarbital sodium (30-35 mg/kg iv with supplemental doses as needed to maintain surgical anesthesia), intubated, and ventilated with a mixture of oxygen (30%) and room air (70%). The rate and tidal volume of the ventilator was adjusted to maintain arterial blood gases within physiological limits. A thoracotomy was performed in the fifth left intercostal space, and the heart was suspended in a pericardial cradle. A polyvinyl chloride catheter, 3.0-mm OD, filled with heparinized saline was introduced into the left internal thoracic artery and advanced into the ascending aorta. Similar catheters were introduced into the left atrium through the atrial appendage and into the left ventricle at the apical dimple. A solid-state micromanometer (model P5; Konigsberg Instrument, Pasadena, CA) was also introduced into the left ventricle at the apex. Approximately 1.5 cm of the proximal left anterior descending coronary artery (LAD) was dissected free. A silicone catheter (0.3-mm ID) bonded to a larger silicone catheter (1.6-mm ID) was introduced into the proximal LAD (13). A Doppler flow probe (Craig Hartley, Houston, TX) was positioned around the artery immediately distal to the indwelling catheter. The pericardium was loosely closed, and the catheters and electrical leads were tunneled subcutaneously to exit at the base of the neck. The chest was closed in layers, and the pneumothorax was evacuated. Catheters and electrical leads were protected with a nylon vest. Catheters were flushed daily with heparinized saline.Hemodynamic Measurements
Studies were performed 2-3 wk after surgery. Phasic and mean aortic pressures were recorded with Spectramed fluid-filled transducers positioned at the midchest level. LV pressure was measured with the micromanometer that was calibrated with the fluid-filled LV catheter. The first derivative of LV pressure over time (LV dP/dt) was obtained by electrical differentiation of the LV pressure signal. Phasic and mean coronary blood flow velocity were recorded with a Doppler flowmeter system (Craig Hartley). Data were recorded on an eight-channel direct-writing oscillograph (Coulbourne Instruments, Lehigh Valley, PA).Experimental Protocol
Glibenclamide infusion. The effect of K+ATP channel blockade on systemic and coronary hemodynamics was studied in all 11 dogs. After all recording instruments were connected, the animals were allowed to rest on the treadmill for 30 min. When steady-state conditions had been achieved, baseline resting hemodynamic measurements and coronary blood flow were obtained. A 3-min period of warm-up exercise was then begun at a treadmill speed of 3.2 km/h at 0% grade. Fifteen minutes later, a three-stage treadmill exercise protocol as shown in Table 1 was begun. Each exercise stage was 3 min in duration; LV, aortic, and coronary blood pressure and coronary blood flow were obtained during the last 30 s of each exercise stage when hemodynamic variables had reached a steady state. After a 90-min rest period, an infusion of glibenclamide (50 µg · kg
1 · min1)
was begun into the coronary artery catheter, delivered at a rate of 1.5 ml/min. Five minutes after the infusion began, resting measurements
were obtained, and the three-stage exercise protocol was repeated as
described above. The glibenclamide infusion was then discontinued.
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8-Phenyltheophylline. On a separate day, the effects of adenosine receptor blockade were studied in seven dogs, all of which were also studied in the glibenclamide group. Control resting measurements were first obtained with the dogs standing on the treadmill. Animals were then exercised using the three-stage protocol described above; each exercise stage was 3 min in duration, and hemodynamic variables were recorded during the last 30 s of each exercise stage. After 90 min of rest, adenosine receptor blockade was produced by infusing 8-phenyltheophylline intravenously in a dose of 5 mg/kg over 5 min. Beginning 10 min after completion of the 8-phenyltheophylline infusion, the exercise protocol was repeated.
Glibenclamide and 8-phenyltheophylline. The
effects of K+ATP channel blockade
combined with adenosine receptor blockade were studied in six animals;
in five of these animals, the effect of glibenclamide alone was also
studied. With the dogs standing on the treadmill, resting measurements
of systemic and coronary hemodynamic variables were obtained. Animals
were then exercised as described above. After 90-min period of rest,
glibenclamide was infused into the coronary artery catheter in a dose
of 50 µg · kg1 · min1
at a rate of 1.5 ml/min. Five minutes after the infusion began, resting
measurements were obtained, and the exercise protocol was repeated.
After completion of the exercise protocol, the glibenclamide infusion
was discontinued, and the animals were allowed to rest for 90 min to
allow coronary flow and systemic hemodynamics to return to control
levels. 8-Phenyltheophylline was then administered intravenously in a
dose of 5 mg/kg infused over 5 min. Ten minutes later, the
intracoronary infusion of glibenclamide (50 µg · kg1 · min1)
was restarted, and 5 min after that resting measurements were obtained,
and the exercise protocol was repeated.
Data analysis. Heart rate, LV, aortic,
and coronary pressures as well as the coronary Doppler shift were
measured from the strip chart recordings. Coronary blood flow was
computed from the Doppler shift using the equation Q = 2.5
f · d2,
where Q is coronary blood flow (ml/min), f is the Doppler
shift (kHz), and d is the internal
diameter of the coronary artery (mm) within the flow probe (14). The
factor 2.5 is a constant derived from the speed of sound in tissue
(C = 1.5 × 105
cm/s), the frequency of the sound beam
(f0 = 10 MHz),
the cosine of the angle of the sound beam relative to the flowing blood
(45°), and the unit conversion factors:
(C · 
/4 · 3)/(2f0 · cos
45°). Because in the chronically instrumented animals the flow
probe is tightly adherent to the coronary artery, the internal diameter of the probe is equal to the external diameter of the artery. To obtain
the inner diameter of the coronary artery, we subtracted the arterial
wall thickness, which in our experience is ~20% of the external
diameter of the coronary artery. In this way, any errors in computation
of the coronary internal diameter would affect control and intervention
conditions equally. Statistical analysis was performed using two-way
(experimental condition and drug treatment) ANOVA for repeated
measures. When a significant effect was observed, comparisons within
drug treatment groups were made using one-way ANOVA followed by
Scheffé's post hoc test. Statistical significance was accepted
at P < 0.05 (2-tailed). All data are
presented as means ± SE.
Drugs. Glibenclamide was dissolved in deionized water to which sodium bicarbonate was added to bring the pH to 8.5. 8-Phenyltheophylline was dissolved in dimethyl sulfoxide and deionized water, pH 10.0-11.0.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Anatomic Data
LV weight of the animals with supravalvular aortic stenosis was 178 ± 7 g, whereas mean body weight was 24 ± 1 kg. The mean LV weight-to-body weight ratio was 7.47 ± 0.31 g/kg. This value is 66% higher than that in normal animals reported from this laboratory in which a mean LV weight-to-body weight ratio of 4.53 ± 0.15 g/kg was observed (10).K+ATP Channel Blockade
The effects of glibenclamide infusion on systemic and coronary hemodynamics are shown in Table 1. During control conditions, exercise increased the heart rate from 122 ± 6 to 214 ± 8 beats/min (P < 0.01). Mean aortic pressure tended to increase during control exercise, but this did not achieve statistical significance. LV systolic pressure increased from 204 ± 6 mmHg during resting conditions to a maximum of 282 ± 13 mmHg (P < 0.01). Control exercise caused a marked increase in LV end-diastolic pressure from 16 ± 2 mmHg at rest to 37 ± 3 mmHg during exercise stage 3 (P < 0.01). Glibenclamide had no significant effect on heart rate, aortic pressure, maximum LV dP/dt (LV dP/dtmax), or LV end-diastolic pressure. LV systolic pressure during resting conditions tended to be lower during glibenclamide infusion, but this did not achieve statistical significance. However, glibenclamide resulted in an ~7% decrease of LV systolic pressure at each level of exercise, which was significant (P < 0.05).Blood flow in the LAD was 64 ± 6 ml/min at rest and increased to a
maximum of 122 ± 17 ml/min during exercise stage
3. During resting conditions, glibenclamide had no
significant effect on coronary pressure but caused a 17 ± 5%
decrease in coronary flow from 64 ± 6 to 53 ± 6 ml/min
(P < 0.05). During exercise, a
linear relationship was found between coronary blood flow and the heart rate-systolic pressure product (rate-pressure product), both under control conditions and during infusion of glibenclamide (Fig. 1). The regression equations relating
coronary blood flow (y) and the rate-pressure
product (x) were determined under
control conditions (y = 27 + 0.00137x) and during glibenclamide
(y = 23 ± 0.00099x). Analysis of the slopes
for individual animals before and after glibenclamide demonstrated a
significant decrease in the slope of the relationship during
glibenclamide (P < 0.05). In
contrast, in 19 normal animals previously reported (8, 9), glibenclamide caused a parallel rightward shift of the relationship between coronary blood flow and the rate-pressure product, with no
significant change in the slope between control conditions (0.00199 ± 0.00017) and during glibenclamide infusion (0.00194 ± 0.00034). However, comparison of the change in slope caused by
glibenclamide in the previously reported normal animals (8, 9) with the
change in slope in the animals with LV hypertrophy in the present study
did not achieve statistical significance. In the setting of chronic LV
pressure overload, compensated hypertrophy occurs to result in near
normalization of systolic wall stress. Moreover, because the fractional
increase in LV systolic pressure during exercise is comparable between
normal and hypertrophied hearts, the increments in systolic wall stress
should likewise be comparable. Therefore, we also examined the slope of
the relationship when coronary blood flow was plotted against heart
rate. This analysis demonstrated that glibenclamide caused a decrease
in the slope of the relationship in animals with LV hypertrophy (from 0.559 ± 0.130 to 0.365 ± 0.079;
P < 0.05) but did not decrease the
slope in normal animals (from 0.407 ± 0.050 to 0.413 ± 0.108; P = not significant). Furthermore, the
decrease in slope of the relationship between coronary blood flow and
heart rate produced by glibenclamide was significantly different in
animals with LV hypertrophy compared with that previously reported in
normal animals (P < 0.05;
see Refs. 8 and 9).
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Adenosine Receptor Blockade
The effects of 8-phenyltheophylline on systemic and coronary hemodynamics are shown in Table 2. During control conditions, exercise increased the heart rate from 121 ± 8 to a maximum of 207 ± 7 beats/min (P < 0.01), whereas LV systolic pressure increased from 219 ± 13 mmHg during resting conditions to a maximum of 286 ± 18 mmHg (P < 0.01). LV end-diastolic pressure increased from 13 ± 2 mmHg at rest to 30 ± 2 mmHg during exercise stage 3 (P < 0.01). Blood flow in the LAD was 66 ± 8 ml/min at rest and increased to a maximum of 117 ± 18 mmHg during heavy exercise (P < 0.01). Adenosine receptor blockade with 8-phenyltheophylline had no significant effect on the systemic hemodynamic variables at rest and did not alter the response to exercise. Furthermore, 8-phenyltheophylline had no significant effect in coronary blood flow at rest or during exercise (Table 2) and no effect on the relationship between coronary flow and the rate-pressure product (Fig. 2).
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Combined Adenosine Receptor Blockade and K+ATP Channel Inhibition
The systemic and coronary responses to combined 8-phenyltheophylline plus glibenclamide are shown in Table 3. Combined blockade had no significant effect on heart rate or mean aortic pressure either at rest or during exercise. Combined blockade tended to decrease LV systolic pressure during exercise, and this achieved statistical significance during the heaviest level of exercise (P < 0.05). Combined 8-phenyltheophylline plus glibenclamide significantly decreased LV dP/dtmax during the heaviest level of exercise (P < 0.05). LV end-diastolic pressure was not different from control either at rest or during exercise after combined 8-phenyltheophylline plus glibenclamide.
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In comparison with both control and glibenclamide alone, combined
glibenclamide plus 8-phenyltheophylline did not significantly alter
coronary artery pressure. In comparison with glibenclamide alone,
coronary blood flow was not significantly different at rest and during
the first two exercise stages with combined blockade. However, during
the heaviest level of exercise, coronary flow during combined blockade
was significantly less than during glibenclamide alone (Table 3).
Because of the trend toward decreased LV systolic pressures during
exercise after combined blockade and because of the decrease in heart
rate during the heaviest level of exercise after combined blockade,
coronary blood flow was examined relative to the heart rate-LV systolic
pressure product. As shown in Fig. 3, the
relationship between coronary blood flow and the rate-pressure product
was not different after combined blockade from that during glibenclamide alone. This response was different from normal animals in
which glibenclamide caused a parallel rightward shift of the line with
no significant change in the slope of the relationship (7), whereas the
subsequent addition of 8-phenyltheophylline caused a decrease in the
slope of the relationship (8).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study has yielded several new findings. First, in hearts with pressure-overload hypertrophy, adenosine is not essential for the coronary vasodilation that occurs in response to exercise. In contrast to the lack of effect of adenosine blockade, inhibition of the K+ATP channel opening decreased coronary blood flow both at rest and during exercise. Unlike the findings in normal hearts in which K+ATP channel blockade did not inhibit coronary vasodilation in response to exercise (7), in the hypertrophied hearts, glibenclamide did inhibit the increase in coronary flow that occurred during exercise. Even during coronary hypoperfusion caused by K+ATP channel blockade, adenosine did not exert an additional vasodilator effect on the coronary vasculature. The implications of these findings will be discussed in detail.
Adenosine
Adenosine released into the interstitial space by myocardial myocytes and vascular endothelial cells can engage specific receptors on the coronary smooth muscle cells to cause vasodilation. McKenzie et al. (19) reported that treadmill exercise in dogs caused a fivefold increase in myocardial adenosine content and a doubling of the coronary arteriovenous adenosine content difference. Graded treadmill exercise resulted in progressive increases of pericardial fluid adenosine concentration in proportion to exercise intensity (12). Despite this evidence that myocardial adenosine production increases during exercise and that this is associated with increased overflow into coronary blood, adenosine receptor blockade with 8-phenyltheophylline and/or augmenting adenosine catabolism with intracoronary adenosine deaminase did not decrease basal blood flow and did not interfere with the normal exercise-induced increase in coronary flow (3). These previous findings demonstrated that exercise results in increased adenosine production in normal hearts but that adenosine is not of critical importance for the coronary vasodilation that occurs during exercise.In contrast to the lack of effect of adenosine blockade in the normal heart, adenosine has been shown to contribute to coronary resistance vessel dilation during myocardial hypoperfusion (18). When a coronary stenosis prevented a normal increase in myocardial blood flow during exercise, transmural redistribution of perfusion occurred to result in hypoperfusion that was most severe in the subendocardium (5). This transmural redistribution of blood flow away from the subendocardium is similar to that observed during exercise in the hypertrophied heart (4). When exercise was performed in the presence of a coronary stenosis, interruption of the effect of endogenous adenosine with the adenosine-receptor antagonist 8-phenyltheophylline in conjunction with intracoronary adenosine deaminase to augment adenosine degradation caused a further decrease in blood flow in the hypoperfused myocardial region (18). This decrease in coronary flow in response to adenosine blockade occurred with no change in poststenotic coronary perfusion pressure, indicating that the decrease in flow resulted from constriction of the distal coronary vasculature. The findings indicated that, although adenosine is not essential for the resistance vessel dilation that occurs during exercise in the normal heart, adenosine does contribute to the vasodilation that occurs when the myocardium becomes ischemic. In the present study, adenosine receptor blockade with 8-phenyltheophylline did not decrease coronary blood flow during resting conditions and did not blunt the increase in coronary flow that occurred in response to exercise in the hypertrophied heart. The findings imply that, at the levels of exercise utilized in the present study, adenosine did not make a greater contribution to resistance vessel dilation in the hypertrophied heart than in normal hearts. This suggests that the relative subendocardial underperfusion that has been demonstrated during exercise in the hypertrophied heart (4) does not result in increased adenosine-mediated resistance vessel dilation. It is possible that at heavier levels of exercise a greater contribution of adenosine could occur.
K+ATP Channels
In the present study, glibenclamide infusion caused a 17% decrease in coronary blood flow during resting conditions; this value is essentially identical to findings in chronically instrumented normal awake dogs in which intracoronary glibenclamide caused 15-18% decreases of resting coronary flow (7, 9). Although the decrease in coronary blood flow during resting conditions in response to K+ATP channel blockade with glibenclamide was similar to that previously reported in normal hearts, the response to exercise was different. Thus, despite the decrease in resting coronary blood flow, in normal dogs K+ATP channel blockade did not impair coronary vasodilation that occurred in response to exercise so that glibenclamide caused a parallel rightward shift of the line relating coronary blood flow to heart rate or the rate-pressure product, with no significant change in slope (7). In contrast, in the hypertrophied hearts, glibenclamide blunted the increase in coronary flow in response to exercise so that the slope of the line relating coronary blood flow to heart rate or the rate-pressure product was significantly decreased after K+ATP channel blockade. Although glibenclamide caused a significant decrease in the slope of the line relating coronary blood flow and the rate-pressure product, this effect was relatively modest so that comparison of the change in slopes between individual normal and hypertrophied hearts produced by glibenclamide was not statistically significant. Nevertheless, the finding that glibenclamide significantly blunted the increase in coronary blood flow in response to exercise in hypertrophied hearts, but not in normal hearts, supports the hypothesis that K+ATP channel opening is of greater importance in resistance vessel dilation during exercise in hypertrophied than in normal hearts. Furthermore, glibenclamide did cause a decrease in the slope of the relationship between coronary blood flow and heart rate that was significantly different between animals with LV hypertrophy and the previously reported normal animals (8, 9). It should be noted that the dose of glibenclamide in the present study (50 µg · kg1 · min1
intracoronary) likely resulted in a lower concentration of
glibenclamide delivered to the myocardium than in the previous normal
animals because the average LV weight was 66% heavier in the animals
with LVH than in the previous normal animals (7). Despite the fact that
the hypertrophied hearts received a relatively smaller dose of
glibenclamide, they experienced a greater effect on coronary blood
flow. Furthermore, in normal animals, a smaller dose of glibenclamide
(10 µg · kg1 · min1
intracoronary) also did not cause a change in the slope of the relationship between coronary blood flow and the rate-pressure product
(7). Thus the decrease in slope of the relationship caused by
glibenclamide in the hypertrophied hearts cannot be explained by
differences in drug dose between the two groups of animals.
In the model of supravalvular aortic stenosis used in the present study, exercise results in a marked increase in coronary pressure, since the coronary arteries arise proximal to the constricting band. In contrast, in normal hearts, exercise is associated with a more modest increase in coronary perfusion pressure. Because myogenic mechanisms have been demonstrated to participate in coronary autoregulatory responses, it is possible that the higher perfusion pressure in the supravalvular aortic stenosis model might have altered the myogenic set point of the coronary resistance vessels (17, 21). This effect could involve chronic alterations in the responsiveness to adenosine and/or the dependence on K+ATP channel activity. Even without alterations in vascular smooth muscle responsiveness, the increase in coronary flow during exercise would be facilitated by the marked increase in coronary pressure. It is possible that if this increase in coronary pressure during exercise did not occur (e.g., with valvular aortic stenosis), the effect of blocking the opening of K+ATP channels in the hypertrophied hearts would have been greater.
Resistance vessel dilation responsible for metabolic vasoregulation and autoregulation in the coronary circulation occurs principally in arterioles <100 µm in diameter (15). Using intravital microscopy to visualize coronary microvessels in open chest dogs, Komaru et al. (16) observed that progressive reductions of coronary perfusion pressure resulted in dilation of the arterioles, whereas small coronary arteries (>100 µm) tended to decrease in diameter, likely as a passive response to the decrease in intravascular distending pressure. K+ATP channel blockade with glibenclamide abolished the arteriolar vasodilation that occurred in response to reductions of coronary perfusion pressure. In contrast, small artery diameter was not altered by glibenclamide, indicating that K+ATP channel opening occurs predominantly in arterioles. In studies performed during treadmill exercise in chronically instrumented awake dogs, we found that as coronary perfusion pressure was progressively decreased, essentially all of the K+ATP channels had been activated when the lower range of the autoregulatory plateau was reached so that administration of the K+ATP channel opener pinacidil caused no further vasodilation (8). In contrast, at coronary pressures below the autoregulatory plateau, exogenous adenosine was still able to elicit further vasodilation. This finding indicated that myocardial ischemia produced by exercise in the presence of a coronary artery stenosis does not cause maximal vasodilation of the coronary resistance vessels, although it does appear to cause maximal activation of K+ATP channels.
Previous studies have demonstrated that K+ATP channels contribute to ischemic coronary vasodilation. Thus K+ATP channel blockade decreased the reactive hyperemia that followed a brief coronary artery occlusion in both anesthetized and awake dogs (1, 7). Adenosine has also been found to participate in coronary reactive hyperemia so that adenosine receptor blockade results in a decrease in reactive hyperemic blood flow (3). The contributions of K+ATP channels and adenosine to coronary reactive hyperemia are additive so that the combination of K+ATP channel blockade and adenosine inhibition causes greater reduction of reactive hyperemia than either intervention alone (9).
Interaction Between K+ATP Channels and Adenosine
In normal hearts, blockade of K+ATP channels with glibenclamide caused a decrease of blood flow during resting conditions but did not impair the increase in flow that occurred during exercise (7). The resistance vessel dilation that occurred in response to exercise after K+ATP channel blockade was mediated in part by adenosine, since adenosine receptor blockade blunted the increase in coronary flow during exercise after glibenclamide by ~70% (9). Interestingly, in the hypertrophied hearts in the present study, adenosine blockade did not blunt resistance vessel dilation in response to exercise after K+ATP channel blockade. Resistance vessel dilation produced by adenosine is in part mediated by opening of K+ATP channels (9). Adenosine appears to have an additional vasodilating effect that is not blocked by inhibition of K+ATP channels and that may be mediated by a separate adenylyl cyclase pathway (23). In the hypertrophied hearts in the present study, glibenclamide alone caused blunting of exercise-induced coronary vasodilation that was comparable to the combined effects of glibenclamide plus 8-phenyltheophylline in normal dogs (9). Thus it appears that progressive K+ATP activation occurs during exercise-induced coronary vasodilation in the hypertrophied heart and that, when this is blocked, alternative mechanisms are unable to maintain the increase in coronary blood flow during exercise. This finding is in agreement with the previous report of Numaguchi et al. (20) that K+ATP channel activity played a greater role in maintaining coronary vasodilation in isolated perfused hearts from spontaneously hypertensive rats with LV hypertrophy than in normal rats.The reason that adenosine blockade failed to further impair the increase in coronary blood flow in response to exercise after K+ATP channel blockade in the hypertrophied hearts in the present study is unclear. The increased adenosine production during ischemia or during increased myocardial metabolic activity is derived from the intracellular store of ATP. When ATP hydrolysis exceeds the rate of ATP production, intracellular ADP levels rise. ADP is acted upon by adenylate kinase to produce one molecule each of ATP and AMP. AMP can then be converted to adenosine by the ectoenzyme 5'-nucleotidase and can escape into the extracellular fluid to produce coronary vasodilation. In the severely hypertrophied hearts in the present study, myocardial ATP content is decreased by ~40% (24). Furthermore, there is evidence that 5'-nucleotide phosphorylase activity is decreased in the hypertrophied rat left ventricle (6). It is thus possible that, in an effort to conserve ATP, adenosine production is decreased in the hypertrophied heart. Unfortunately, it was not possible to obtain measurements of coronary venous adenosine in the present study.
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ACKNOWLEDGEMENTS |
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We acknowledge the expert technical assistance provided by Melanie Crampton and Paul Lindstrom. Secretarial support was provided by Carol Quirt.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-21872 and HL-20598. P. J. Melchert was supported by a Medical Student Research Fellowship from the American Heart Association. D. J. Duncker was supported by a Fellowship of the Royal Netherlands Academy of Arts and Sciences.
Present address of D. Duncker: Laboratory for Experimental Cardiology, Thoraxcenter, Erasmus University, 3000 DR Rotterdam, The Netherlands.
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: R. J. Bache, Div. of Cardiology, Dept. of Medicine, Univ. of Minnesota Medical School, Box 508 UMHC, 420 Delaware St. SE, Minneapolis, MN 55455 (E-mail: bache001{at}tc.umn.edu).
Received 30 December 1998; accepted in final form 31 March 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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