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Circulation. 1995;91:1560-1567

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(Circulation. 1995;91:1560-1567.)
© 1995 American Heart Association, Inc.

Articles

Effect of ß-Adrenergic Receptor Blockade on Blood Flow to Collateral-Dependent Myocardium During Exercise

Jay H. Traverse, MD; John D. Altman, MD; James Kinn, MD; Dirk J. Duncker, PhD, MD; Robert J. Bache, MD

From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis.

Correspondence to Robert J. Bache, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
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Background ß-Adrenergic receptors have been identified in isolated coronary collateral blood vessels, but their functional significance in the intact heart has not been demonstrated.

Methods and Results We measured myocardial blood flow with radioactive microspheres in normal and collateral-dependent myocardium in eight dogs trained to run on a treadmill before and after ß-adrenergic blockade with propranolol, 200 µg/kg, a dose that effectively inhibited the increase in coronary blood flow produced by selective ß1- and ß2-adrenergic agonists. Collateral vessel growth was stimulated with 2-minute intermittent occlusions of the left anterior descending artery followed by permanent occlusion. During control exercise, blood flow in the collateral zone was 38±5% less than in the normal zone. At identical levels of exercise, with heart rate maintained constant by atrial pacing, propranolol decreased mean blood flow in the collateralized myocardium from 1.93±0.17 to 1.50±0.14 mL · min-1 · g-1 (P<.01), while increasing the subendocardial to subepicardial blood flow ratio from 0.78±0.11 to 0.91±0.10 (P<.05). The decrease in collateral zone blood flow in response to propranolol resulted from an increase in both transcollateral resistance from 25.9±2.3 to 35.2±4.3 mm Hg · mL-1 · min · g (P<.05) and small-vessel resistance in the collateral-dependent myocardium from 30.9±4.7 to 44.0±8.8 mm Hg · mL-1 · min · g (P<.07). Blood flow to the normal zone was also significantly reduced from 3.14±0.21 to 2.23±0.12 mL · min-1 · g-1 (P<.01) after propranolol.

Conclusions ß-Adrenergic blockade decreased blood flow to collateral-dependent myocardium during exercise. These results indicate that ß-adrenergic receptor activation contributes to vasodilation of coronary collateral vessels during exercise.


Key Words: microspheres • occlusions • blood flow


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
When coronary artery occlusion occurs gradually, collateral vessels can grow sufficiently to allow total arterial occlusion with little or no infarction of the dependent myocardium. In this situation, collateral development is adequate to support myocardial needs during resting conditions, but the ability to increase flow is limited, so blood flow may be inadequate to meet myocardial demands during exercise.1 Developed collateral vessels contain a well-organized muscular media and are capable of vasomotor activity.2 Active vasomotion of collateral vessels could be of particular importance during exercise because changes in collateral vessel caliber influence maximum blood flow rates.3 It is possible that sympathetic nervous system activation that occurs during exercise could result in collateral vasomotor activity with subsequent alteration of collateral blood flow.

Feldman et al4 found ß-adrenergic receptors in vascular smooth muscle from well-developed canine coronary collateral vessels by radioligand binding autoradiography and demonstrated that vascular rings from these vessels undergo vasodilation in response to isoproterenol. However, Harrison et al5 were unable to demonstrate {alpha}-adrenergic receptors in well-developed collateral vessels and found that {alpha}-adrenergic agonists did not cause contraction of isolated rings of isolated coronary collateral vessels. These findings suggest that increased activation of the sympathetic nervous system during exercise could cause collateral vasodilation through activation of ß-adrenoceptors. If this is true, then blockade of ß-adrenergic activity could have potential for causing impairment of blood flow to the collateral-dependent region during exercise. Although several previous studies have examined the effect of ß-adrenergic blockade in animal models of exercise-induced myocardial ischemia, no data are available documenting the effect on collateral vessels. Consequently, this study was carried out to test the hypothesis that ß-adrenergic blockade causes vasoconstriction of coronary collateral vessels during exercise. By measuring blood flow to the collateralized region and the pressure drop from the aorta to the collateral-dependent coronary artery, we could determine the effect of ß-adrenergic blockade on both the resistance of the collateral system and the small vessels in the collateral-dependent region.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
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Studies were carried out in 14 adult mongrel dogs weighing 25 to 30 kg that were trained to run on a motor-driven treadmill. All studies were performed in accordance with the "Position of the American Heart Association on Research Animal Use" and were approved by the Animal Care Committee of the University of Minnesota.

Surgical Preparation
Animals were premedicated with acepromazine (10 mg IM), anesthetized with sodium pentobarbital (30-35 mg/kg IV), intubated, and ventilated with room air supplemented with oxygen. A left thoracotomy was performed in the fifth intercostal space. A heparin-filled polyvinyl chloride catheter, 3.0-mm OD, was introduced into the internal thoracic artery and advanced until the tip was positioned in the ascending aorta. The pericardium was then opened and the heart suspended in a pericardial cradle. A second catheter was placed into the left atrium through the appendage and secured with a purse-string suture. A similar catheter was introduced into the left ventricle at the apical dimple and secured in place. A bipolar pacing electrode was sutured to the right atrial appendage. The proximal left anterior descending coronary artery (LAD) was dissected free, and a Doppler velocity probe (Craig Hartley) was placed around the vessel. A hydraulic occluder and snare-type occluder were positioned around the artery distal to the velocity probe. A heparin-filled silicone rubber catheter (0.3-mm ID) was placed into the artery distal to the occluders.6 The pericardium was then loosely closed, and the catheters and electric leads were tunneled subcutaneously to exit at the base of the neck. The thoracotomy was closed in layers and evacuated of air. Catheters were flushed daily with heparinized saline to maintain patency and were protected with a nylon vest.

Induction of Collateral Vessel Growth
Nine animals in which collateral function was to be studied were returned to the laboratory 1 week after surgery. Collateral vessel development was stimulated with a modification of the repetitive coronary occlusion technique of Franklin et al.7 While distal coronary pressure was measured, the hydraulic occluder was inflated with saline; the flowmeter signal was monitored to ensure total occlusion. Initial distal coronary pressures during occlusion were 10 to 20 mm Hg in all dogs. A protocol of intermittent coronary occlusions of 2-minute duration performed at 15-minute intervals was then begun for 3 hours each day, 5 days per week. When peripheral coronary pressure during occlusion exceeded 35 mm Hg, the artery was permanently occluded by tightening of the snare occluder. The coronary artery velocity signal was monitored to ensure total occlusion. Permanent coronary occlusion was produced within 2 to 3 weeks after the repeated coronary occlusion protocol was begun. Studies were performed 5 to 7 days after permanent coronary occlusion.

Measurement of Myocardial Blood Flow
Myocardial blood flow was measured with 15-µm-diameter microspheres labeled with 141Ce, 51Cr, 85Sr, 95Nb, or 46Sc (NEN Co). Microspheres were obtained as 1.0 mCi in 10 mL low-molecular-weight dextran. For each measurement, 3x106 microspheres were injected into the left atrium and flushed with normal saline. A reference sample of arterial blood was obtained from the aortic catheter at a constant rate of 15 mL/min with a peristaltic pump beginning at the time of microsphere injection and continuing for 90 seconds.

Experimental Protocol
Aortic, left ventricular, and distal coronary pressures were measured with pressure transducers (Spectramed model TNF-R) at midchest level. Left ventricular pressure was recorded both at normal and at high gain for measurement of end-diastolic pressure. Data were recorded on an eight-channel direct writing recorder (Coulbourne Instruments). After all recording instruments were connected, a 5-minute period of warm-up exercise was performed while the exercise intensity was gradually increased to 6.4 km/h at a 15% grade. Heart rate was controlled during the subsequent exercise protocols by atrial pacing at a rate 10 to 20 beats per minute (bpm) faster than the sinus rate recorded during this warm-up exercise. The dogs were then allowed to rest for 1 hour. Control resting hemodynamic measurements were then obtained with the dogs standing quietly on the treadmill. After resting measurements were obtained, exercise was begun at 6.4 km/h at a 15% grade. Hemodynamic measurements were recorded continuously to ensure that steady-state conditions existed. Microspheres were injected into the left atrium for measurement of myocardial blood flow 3 minutes after exercise was begun. The animals continued to exercise for 2 minutes after the microsphere injection.

Animals were then allowed to rest quietly on the treadmill for 1 hour. During this time, isoproterenol (0.4 µg/kg) was administered intravenously, and all hemodynamic measurements were recorded (resting heart rate increased from 142±6 to 223±9 bpm). ß-Adrenergic receptor blockade was then produced with propranolol (200 µg/kg IV) infused over 10 minutes. Isoproterenol was reinfused 10 minutes later to ensure that ß-adrenergic blockade had been achieved (resting heart rate increased from 130±7 to 142±7 bpm). All hemodynamic measurements were again recorded, and the exercise protocol was repeated at the identical exercise level and pacing rate used during control conditions. Hemodynamic measurements and microsphere administration were performed 3 minutes after exercise was begun, and exercise continued for 2 minutes after microsphere injection. One dog developed ventricular fibrillation during the first control exercise period and was excluded from the study. A total of eight dogs completed both protocols and were used for data analysis.

Identification of Collateral-Dependent Myocardium
The region of collateral-dependent myocardium was identified by the shadow technique of Patterson and Kirk.8 After completion of the exercise protocol, animals were premedicated with morphine sulfate (2 mg/kg IM), anesthetized with {alpha}-chloralose (100 mg/kg IV), intubated, and ventilated with a respirator. A left thoracotomy was performed in the sixth intercostal space, and the anterior descending artery was carefully dissected free and cannulated with a thin-walled stainless-steel cannula at the site of the snare occluder. A 26-gauge tube incorporated into the cannula allowed measurement of cannula tip pressure. The cannula was then perfused with nonradioactive arterial blood from a reservoir pressurized to maintain cannula tip pressure 10 to 15 mm Hg above mean aortic pressure while radioactive microspheres were injected into the left atrium. With this technique, the collateral-dependent region was perfused with nonradioactive blood while the normal region was perfused with blood containing microspheres. The animals were euthanatized with an overdose of pentobarbital, and the heart and kidneys were removed and placed into 10% buffered formalin. After fixation, the left ventricle was separated from the atrium and right ventricle, and the epicardial vessels and fat were trimmed away. The left ventricle was then sectioned into five transverse rings from base to apex and inspected to ensure the absence of infarct. Each ring was then sectioned into 16 radial segments that were divided into epicardial and endocardial halves, weighed, and placed into vials for counting. Myocardial and blood reference specimens were counted in a gamma spectrometer (model 5912, Packard Instrument Co) at window settings corresponding to the peak energies of each radionuclide. The activity in each energy window was corrected for background, and overlapping counts between isotopes were corrected with a digital computer. Blood flow to each myocardial specimen (Qm) was computed with the formula Qm=Qr · Cm/Cr, where Qr is the reference blood flow rate (milliliters per minute), Cm is counts per minute of the myocardial specimen, and Cr is counts per minute of the reference blood specimen.

Collateral-dependent myocardium was identified as specimens having blood flow rates during the shadow injection more than 3 SDs below the mean value of flow in the samples obtained from the normally perfused region.

Effects of Propranolol on ß-Adrenergic Responses
The degree of ß-adrenergic blockade was assessed by measurement of coronary blood flow responses to ß1- and ß2-adrenergic agonists before and after administration of propranolol in a second group of five chronically instrumented dogs. These dogs underwent the identical surgical procedure as the first group, including placement of an intracoronary catheter and Doppler flow probe on the proximal LAD, but did not undergo the coronary occlusion protocol. Dogs were trained to stand in a sling and were studied during quiet resting conditions. Changes in coronary blood flow were measured in response to administration of the selective ß1-adrenergic agonist dobutamine and the selective ß2-adrenergic agonist albuterol. Dobutamine hydrochloride was dissolved in normal saline and infused into the left atrium at doses of 25, 75, 250, and 750 µg/min at infusion rates of 0.5 and 1.5 mL/min. Coronary blood flow was recorded continuously, and each infusion was continued until blood flow achieved a steady state. The infusion was then discontinued, and blood flow was allowed to return to baseline before each subsequent dose was begun. Albuterol sulfate diluted in normal saline was infused through the LAD catheter at doses of 1, 3, and 10 µg/min. Infusion rates were 0.5 and 1.5 mL/min. After the control coronary blood flow responses to dobutamine and albuterol were obtained, propranolol (200 µg/kg) was infused over 10 minutes through the left atrial catheter. The protocol was repeated 30 minutes later.

Coronary blood flow was calculated from the Doppler frequency shift (kilohertz) using the equation q=2.5xd2xf, where q is coronary blood flow in milliliters per minute, d is the ID of the LAD in millimeters, and f is the Doppler frequency shift measured.9 Because the flow probe is tightly adherent to the coronary artery in the chronically instrumented animal, the external diameter of the artery is fixed and equal to the flow probe ID. From our previous observations, the artery ID was taken as 80% of the flow probe diameter.9

Data Analysis
Heart rate, pressures, and coronary velocity were measured directly from strip-chart recordings. Transcollateral vessel resistance was calculated as the pressure drop from mean aortic pressure to the pressure at the cannula tip distal to the occlusion divided by mean collateral zone blood flow. Small-vessel resistance in the collateral-dependent region was calculated as (distal coronary pressure–left ventricular end-diastolic pressure)/mean collateral zone blood flow. Total vascular resistance in the normal zone was calculated as (aortic pressure–left ventricular end-diastolic pressure)/mean normal zone blood flow. Resistance calculations were expressed as millimeters of mercury per milliliter per minute per gram. In one animal, measurement of left ventricular end-diastolic pressure could not be obtained and was not included in the calculation of resistance. Data were compared with ANOVA for repeated measures; a value of P<.05 was required for statistical significance. When a statistically significant result was found, individual comparisons were performed with the Wilcoxon signed-rank test. Data are expressed as mean±SEM.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
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Hemodynamic Measurements
Table 1Down shows the hemodynamic data. Mean heart rate with the dogs standing on the treadmill was 127±10 bpm. Propranolol tended to decrease the resting heart rate, although this change did not achieve statistical significance. Propranolol did not alter mean aortic pressure or distal coronary pressure but caused a slight but significant decrease in left ventricular end-diastolic pressure (P<.05) and a significant decrease in left ventricular dP/dtmax (P<.05).


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  		Table 1. Hemodynamic Measurements at Rest and During Treadmill Exercise Before and After Administration of Propranolol

Exercise resulted in similar increases of mean aortic pressure during control conditions and after propranolol. Heart rate during exercise was controlled by atrial pacing and did not vary significantly. The product of heart rate and left ventricular systolic blood pressure was not changed after administration of propranolol. Distal coronary pressure tended to increase after propranolol, but this did not achieve statistical significance. Propranolol resulted in a 23±7% decrease in left ventricular dP/dtmax during exercise.

Myocardial Blood Flow
Left ventricular mass ranged from 101 to 138 g (mean, 122±7 g). The collateral-dependent tissue mass ranged from 7.5 to 30.1 g (mean, 19±3 g), representing 16.6±2.8% of the left ventricle.

Tables 2Down and 3Down show blood flow to normal and collateral-dependent myocardial regions during exercise. During control exercise, mean blood flow in the normal zone was 3.14±0.21 mL · min-1 · g-1 myocardium and was significantly higher in the subendocardium (ENDO) than in the subepicardium (EPI), so the ENDO/EPI blood flow ratio was significantly greater than 1.0 (P<.05). Mean blood flow in the collateral-dependent region was 62±5% of normal zone flow (P<.01), and the ENDO/EPI flow ratio was significantly less than in the normal zone (P<.01).


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  		Table 2. Myocardial Blood Flow to Normal and Collateral-Dependent Myocardium During Exercise


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  		Table 3. Mean Myocardial Blood Flow and Coronary and Transcollateral Vascular Resistances During Exercise

ß-Adrenergic blockade with propranolol resulted in a 27±5% decrease in normal zone mean blood flow (P<.01). This decrease in flow was most marked in the subepicardium, resulting in a slight but significant increase in the ENDO/EPI ratio (P<.05). Propranolol also produced a 22±4% decrease in blood flow to the collateral-dependent region (P<.01). The decrease in blood flow to the subepicardium of the collateral-dependent region was greater than the decrease in subendocardial flow, resulting in a significant increase in the ENDO/EPI ratio in the collateral-dependent region (P<.05).

Collateral Resistance
Table 3Up shows the values for mean aortic and distal coronary pressures, the aorta-to-coronary-artery pressure gradient, and transcollateral resistance. Propranolol tended to increase both mean arterial pressure and distal coronary pressure during exercise, although these differences did not achieve statistical significance. The transcollateral pressure gradient (aorta to distal coronary artery) was not changed by propranolol. As Fig 1Down shows, transcollateral resistance increased 38±13% after propranolol (P<.05). Small-vessel resistance in the collateral region was 30.9±4.7 mm Hg · mL-1 · min · g during control exercise and increased to 44.0±8.8 after propranolol (P<.07). Normal zone resistance was 34.0±2.3 mm Hg · mL-1 · min · g during control exercise and increased to 50.6±4.3 mm Hg · mL-1 · min · g after propranolol (P<.05).



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  		Figure 1. Graphs showing transcollateral vascular resistance, small-vessel resistance in the collateral zone, and normal zone resistance during control exercise and after administration of propranolol in each animal. Transcollateral resistance was calculated as (aortic pressure–distal coronary pressure)/(mean myocardial blood flow in the collateral region). Small-vessel resistance was calculated as (distal coronary pressure–end-diastolic pressure)/(mean myocardial blood flow in the collateral region). Normal zone resistance was calculated as (aortic pressure–end-diastolic pressure)/(mean myocardial blood flow in the normal zone). Mean responses and standard errors are shown to each side. *P<.05, {dagger}P<.07 vs control.

Adequacy of ß-Adrenergic Blockade
With the dogs resting quietly in a sling, mean LAD blood flow was 44±6 mL/min. Mean aortic pressure was 96±3 mm Hg, heart rate was 98±9 bpm, and left ventricular peak dP/dtmax was 2390±100 mm Hg/s. Infusion of normal saline vehicle had no effect on any measured variables. Administration of propranolol had no significant effect on coronary blood flow (45±9 mL/min), mean aortic pressure (92±6 mm Hg), or heart rate (100±7 bpm) but decreased left ventricular peak dP/dtmax to 1740±190 mm Hg/s (P<.05).

Intravenous administration of dobutamine resulted in dose-dependent increases of heart rate, dP/dtmax, and coronary blood flow. Heart rate increased to a maximum of 138±13 bpm (P<.05), and dP/dtmax increased to 4760±740 mm Hg/s at the highest dose of dobutamine infused (P<.05). As Fig 2Down shows, propranolol caused a rightward shift of the dose-response curve to dobutamine, producing 95% inhibition of the coronary blood flow response to the largest dose of dobutamine used (P<.05).



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  		Figure 2. Graphs showing changes in blood flow in the left anterior descending coronary artery in response to intravenous administration of the selective ß1-adrenergic agonist dobutamine and to intracoronary administration of the selective ß2-adrenergic agonist albuterol before and after propranolol (200 µg/kg IV). Values are mean±SEM. Propranolol significantly blunted the increases in coronary blood flow produced by both dobutamine and albuterol (P<.05 by ANOVA). {bullet} indicates control; {blacktriangledown}, propranolol.

Intracoronary administration of the ß2-adrenergic agonist albuterol caused a dose-dependent increase in coronary blood flow (Fig 2Up) with no significant change in heart rate, mean arterial pressure, or dP/dtmax. Propranolol caused a marked rightward shift of the dose-response curve to albuterol, with 94% inhibition of the coronary vasodilation produced by the largest dose tested (P<.05).


*    Discussion
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 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
In the present study, ß-adrenergic receptor blockade resulted in a significant decrease of myocardial blood flow to the collateral-dependent region during exercise. This decrease in blood flow resulted from vasoconstriction of both the coronary collateral vessels and the small vessels in the collateral-dependent region. The mechanism of this vasoconstrictor response to ß-adrenergic blockade is discussed in detail later.

ß-Adrenergic Receptor Subtypes
In vivo studies of coronary responses to ß-adrenergic agonists are complicated by the resistance vessel dilation that occurs secondary to the increased myocardial metabolic demands produced by these agents. The resultant increase in blood flow activates endothelium-dependent flow-mediated vasodilation, thereby causing vasodilation of proximal coronary arteries.10 Using chronically instrumented dogs in which coronary artery diameter and coronary blood flow were measured simultaneously, Vatner et al11 observed that nonselective ß-adrenergic stimulation with isoproterenol resulted in increases in both myocardial blood flow and coronary arterial diameter. After selective ß1-adrenergic blockade with atenolol, the residual ß2-adrenergic agonist effect of isoproterenol produced a smaller increase in coronary blood flow, with marked attenuation of both resistance vessel and epicardial artery dilation. Studies in calves12 demonstrated that stimulation of both receptor subtypes can cause epicardial coronary artery smooth muscle dilation independent of increases in flow, while ligand binding studies with coronary artery membrane preparations demonstrated both receptor subtypes with ß1 predominance. In studies of isolated perfused canine epicardial coronary artery segments performed in conjunction with radioligand binding assays, Nakane et al13 found both ß1- and ß2-adrenoceptors, although ß1-adrenoceptors predominated, accounting for 74% to 77% of the catecholamine-induced large coronary artery dilation. The findings suggested that in coronary arteries, the ß1 subtype predominates, while in coronary arterioles, the ß2 subtype is the predominant receptor.14

Feldman et al4 examined normal coronary artery segments and well-developed collateral vessels from dogs 6 to 10 months after occlusion of the left circumflex coronary artery with an Ameroid constrictor. With autoradiography, ß-adrenergic receptor–specific [125I]-iodopindolol binding was similar in collateral vessels and normal arteries. Studies with selective antagonists demonstrated a mixed population of ß1 and ß2 receptor subtypes that was similar in collateral and normal arterial vessels. Isolated vessel studies demonstrated that both ß1 and ß2 agonists caused relaxation of preconstricted vessel rings, and analysis according to a two-site model was compatible with a mixed receptor population with ß1 predominance.

In the present study, both selective ß1- and selective ß2-adrenergic agonists caused dose-dependent increases in coronary artery blood flow in the five dogs studied with noncollateralized hearts. The increases in coronary flow produced by dobutamine in these animals were associated with increases of heart rate and left ventricular dP/dtmax, which is in agreement with the concept that increases in coronary blood flow produced by dobutamine are principally medicated by the increased myocardial oxygen demands that it causes. In contrast, albuterol caused an increase in coronary blood flow that was not associated with significant changes in heart rate or dP/dtmax, indicating primary ß2-adrenergic coronary vasodilation that was not dependent on an increase in myocardial metabolic demands. The dose of propranolol used in the present study resulted in more than 90% inhibition of the coronary vasodilation produced by both dobutamine and albuterol, indicating that the antagonist effectively inhibited both receptor subtypes, thereby allowing study of the influence of ß-adrenergic activation on coronary collateral blood flow during exercise.

Collateral Zone Blood Flow
Using this experimental model, we previously observed that during resting conditions, myocardial blood flow to the collateral zone is approximately 80% of normal zone blood flow.3 Previous studies investigating blood flow to collateral-dependent myocardium in dogs during treadmill exercise demonstrated that the disparity between collateral and normal zone blood flow is related to the extent of collateral development. Lambert et al15 found no differences in blood flow between normally perfused and collateral-dependent myocardium during treadmill exercise in dogs 6 to 10 months after placement of an Ameroid constrictor on the left circumflex. However, because collateral vessels in humans frequently limit flow during exercise,16 we studied animals at an earlier time when the resistance of the collateral vessels was still sufficiently elevated to significantly impair blood flow to the collateral-dependent region during exercise. Thus, mean blood flow to the collateral-dependent region was only 62±5% of normal zone blood flow during control exercise. This is in agreement with histological evidence that the transformation from rudimentary thin-walled channels to well-developed collateral vessels can take up to 6 months.17

Failure of vasodilation of the resistance vessels could also have contributed to the significantly lower blood flow in the collateral zone. This is supported by the relatively high distal coronary artery pressures observed in this study. Pressure in the collateral-dependent coronary artery would be expected to fall during exercise as resistance vessel dilation occurred in the collateral zone and transcollateral flow increased. However, distal coronary pressure during control exercise was 69±5 mm Hg, suggesting the presence of substantial vasomotor tone in the resistance vessels. The finding of a high distal pressure in the presence of subnormal blood flow suggests that the vasodilator capacity of the resistance vessels in the collateral zone is impaired. This is supported by the study of Sellke et al,18 who demonstrated that receptor-mediated endothelium-dependent relaxation was impaired in isolated microvessels from the collateral-dependent region.

Response of Collateral Vessels to ß-Adrenergic Blockade
Propranolol caused a 38±13% increase in resistance across the collateral vascular system. In some vascular beds, vasoconstriction in response to ß-adrenergic blockade has been ascribed to unmasking of {alpha}-adrenoceptor activity. This is unlikely in the coronary collateral vasculature because Harrison et al5 found no evidence for functioning {alpha}-adrenoceptors in isolated collateral vessel rings from dogs with Ameroid occlusion of the left circumflex coronary artery. Similarly, in vitro studies in dogs with chronic coronary artery occlusion demonstrated no decrease in collateral blood flow in response to the {alpha}1-adrenergic agonists methoxamine or phenylephrine5 19 and no or only modest decreases in response to the {alpha}2-adrenergic agonists clonidine or B-HT 920.5 19 20 In contrast, ß-adrenergic agonists have been demonstrated to cause relaxation of preconstricted rings of canine coronary collateral vessels.4 These findings suggest that the increased collateral vascular resistance after administration of propranolol in the present study resulted from interruption of ß-adrenergic vasodilation. These findings are compatible with the concept that adrenergic activation contributes to collateral vessel vasodilation during exercise. Interruption of ß-adrenergic vasodilation would consequently result in increased collateral vascular resistance during exercise.

Response of Small Vessels in the Collateral Zone to ß-Adrenergic Blockade
In addition to causing vasoconstriction of the collateral vessels, propranolol administration was associated with a borderline significant increase in small-vessel resistance in the collateral-dependent region. This occurred even though blood flow in the collateral region was substantially less than in the normal region during control exercise. Several factors could have contributed to the tendency for small-vessel constriction after propranolol. First, the increase in small-vessel resistance after propranolol could have occurred secondary to decreased metabolic demands in the collateral region produced by ß-adrenergic blockade. Unfortunately, myocardial oxygen consumption could not be determined because of the inability to obtain uncontaminated venous blood from regions representing the collateral-dependent zone. Second, DiCarlo et al21 reported that in the presence of {alpha}-adrenergic blockade, the addition of ß2-adrenergic blockade caused coronary resistance vessel constriction. It is thus possible that the small-vessel constriction produced by propranolol in the present study resulted in part from loss of a direct ß2-adrenergic vasodilator influence. Finally, small-vessel constriction could have resulted from unopposed {alpha}-adrenergic activity after ß-adrenergic blockade. Adrenergic vasoconstriction has been demonstrated to oppose metabolic vasodilation during exercise in the normal heart.22 In addition, adrenergic vasoconstriction has been shown to exist during exercise in regions of hypoperfused myocardium distal to a coronary artery stenosis.23 It is possible that similar competition between metabolic vasodilator and sympathetic vasoconstrictor influences could also exist at the small-vessel level in the collateral-dependent region.

ß-Adrenergic blockade caused an increase in the ENDO/EPI flow ratio as the result of a greater decrease of blood flow in the subepicardium than in the subendocardium of the collateral-dependent region. This suggests that the metabolic influences that opposed adrenergic vasoconstriction were more potent in the subendocardium. This may be a reflection of the more marked hypoperfusion in the subendocardium of the collateralized region during control exercise and the higher metabolic requirements of the subendocardium.24 Thus, in open-chest dogs, Johannsen et al25 observed that adenosine opposed adrenergic vasoconstriction produced by cardiac sympathetic nerve stimulation in the subendocardium but not in the subepicardium. In the absence of measurements of regional myocardial systolic function, it was not possible to determine whether the improved ENDO/EPI flow ratio after administration of propranolol produced a beneficial effect on contractile performance.

Herzog et al26 examined the effect of nonselective ß-adrenergic blockade with timolol (40 µg/kg IV) on myocardial blood flow during treadmill exercise in dogs 10 to 14 days after acute occlusion of the left circumflex coronary artery. Heart rates were significantly lower at every exercise level after timolol than during control conditions, but when equivalent rate-pressure products were compared, timolol caused a 24% reduction of myocardial blood in the collateral-dependent region and a significant redistribution of flow toward the subendocardium. In that study, the collateral-dependent region contained infarct, so blood flow measurements represented mean values for viable myocardium and scar. The repeated coronary occlusion model used in the present study allowed production of total coronary occlusion without infarct, permitting examination of the effect of ß-adrenergic blockade on blood flow into a totally collateral-dependent region of viable myocardium. Because pressure in the collateral-dependent artery was not measured in the study of Herzog et al,26 it was not possible to distinguish the contribution of vasoconstriction at the resistance-vessel level from collateral vasoconstriction in response to propranolol.

Normal Zone Blood Flow
ß-Adrenergic antagonists typically produce prominent reductions in coronary blood flow during exercise by blocking sympathetic effects on heart rate and contractility.27 In the present study, ß-adrenergic blockade caused a 27% decrease in normal zone blood flow during exercise despite no change in heart rate. In a previous study investigating the effect of ß-adrenergic blockade during exercise, Guth et al28 examined the effects of ß-adrenergic blockade on regional wall motion and perfusion during exercise in animals with single-vessel coronary artery stenosis produced by an Ameroid constrictor. When heart rate was held constant by atrial pacing, regional myocardial blood flow and systolic function in the normal zone decreased after ß-adrenergic blockade, while the ENDO/EPI flow ratio increased as in the present study.

Although atrial pacing eliminated the effect on heart rate, it did not abolish the negative effect of ß-adrenergic blockade on contractility as assessed from left ventricular dP/dtmax. This is in agreement with the report of Murray and Vatner29 that when heart rates were fixed by atrial pacing, ß-adrenergic blockade resulted in a 23% decrease in left ventricular dP/dtmax during exercise. It is likely that this decrease in contractility caused a reduction of myocardial oxygen requirements and accounted at least in part for the observed decrease in myocardial blood flow. Myocardial oxygen consumption could not be determined in the present study because of the inability to selectively sample venous blood from the collateral-dependent and normally perfused zones. It is not possible to compute myocardial oxygen consumption from coronary arteriovenous oxygen difference in the setting of heterogeneous perfusion because coronary sinus effluent will disproportionately reflect the contributions of the nonischemic myocardium and underrepresent areas of hypoperfused myocardium.30

Limitations
To simplify analysis of the effects of ß-adrenergic blockade on the collateral vasculature and on the resistance vessels in the normal and collateral zones, an experimental model of single coronary artery occlusion without significant stenosis in other vessels was used. In the clinical setting, atherosclerosis is a diffuse process in which significant coronary artery disease commonly coexists in multiple vessels. This can result in complex interactions between vascular beds joined by collateral vessels; thus, a proximal stenosis in a coronary artery from which collateral vessels arise may cause the development of coronary steal, which can impair perfusion of the collateral zone during exercise even without vasomotor changes in the collateral vessels. Use of a single-vessel occlusion model avoided such confounding changes in collateral flow while allowing examination of the direct effects of ß-adrenergic blockade on the collateral vessels. Although the behavior of collateral blood flow in the setting of multivessel coronary artery disease is likely to be more complex than in this experimental model, the effect of ß-adrenergic blockade on the collateral vessels themselves is likely to be similar with either single-vessel or multivessel coronary occlusive disease.

These studies were performed relatively soon after the onset of coronary artery occlusion. Intermittent 2-minute occlusions were performed for 2 to 3 weeks to initiate the development of collateral vessels; permanent coronary occlusion was then produced for 5 to 7 days before studies were performed. Thus, studies were performed within 1 month after the initial ischemic stimulus for collateral development was begun. Previous investigators demonstrated that transient periods of ischemia over 1 hour can stimulate an increase in ß-adrenergic receptor density in the canine left ventricle.31 32 These receptors have been shown to be responsive to ß-adrenergic agonists and are inhibited by propranolol.32 These previous findings are in agreement with those of the present study, which demonstrated that propranolol inhibited ß-adrenergic activity in the collateralized region and in the collateral vessels themselves. It is possible, however, that different results would be obtained after more prolonged periods of coronary artery occlusion.

Clinical Implications
It is paradoxical that ß-adrenergic blockade, which is known to provide beneficial effects in patients with ischemic heart disease, would cause vasoconstriction of coronary collateral vessels. The principal anti-ischemic action of ß-adrenergic blockers results from the decreased myocardial oxygen demand that they produce. In patients with occlusive coronary artery disease undergoing quantitative coronary angiography, Gaglione et al33 found that intracoronary propranolol prevented the worsening of stenosis severity that occurred during supine bicycle exercise. This effect appeared to be related to blunting of the exercise-induced vasodilation of the resistance vessels by propranolol, thereby maintaining a higher distending pressure within the epicardial coronary artery and preventing collapse of the stenosis. Such an effect of propranolol in maintaining a higher pressure in the coronary artery distal to a stenosis would also augment pressure at the origin of the collateral vessels, thereby facilitating collateral blood flow. In addition, it is likely that the decreased metabolic demands resulting from the negative chronotropic and inotropic effects of ß-adrenergic blockade would outweigh the modest constriction of the coronary collateral vessels observed in the present study. Furthermore, the decrease in heart rate, which was prevented in the present study, will increase diastolic perfusion time, thereby improving myocardial blood flow. Nevertheless, the findings suggest that agents such as nitrates that prevent collateral vasoconstriction would have potential for acting synergistically with ß-adrenergic blockers by enhancing blood flow to collateral-dependent regions at the same time that metabolic demands are decreased.

Conclusions
During exercise, propranolol significantly decreased blood flow in collateral-dependent myocardium as the result of vasoconstriction of both the collateral vessels and the coronary resistance vessels. These findings indicate that ß-adrenergic receptors previously demonstrated in coronary collateral vessels in vitro are functional in vivo and can influence blood flow to collateral-dependent myocardium in the intact heart during exercise.


*    Acknowledgments
 
This study was supported by US Public Health Service Grants HL-20598 and HL-32427 from the NHLBI. Dr Altman was supported by a Medical Student Research Fellowship from the American Heart Association. Dr Duncker was supported in part by a NATO Science Fellowship awarded by the Netherlands Organization for Scientific Research. We gratefully acknowledge the expert technical assistance provided by Todd Pavek, Sara Herrlinger, and Melanie Crampton. Andrea Dahl provided secretarial assistance.

Received August 31, 1994; accepted September 28, 1994.


*    References
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*References
 

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