© 1997 American Heart Association, Inc.
Articles |
Endogenous Nitric Oxide Masks 
2-Adrenergic Coronary Vasoconstriction During Exercise in the Ischemic Heart
the Cardiovascular Division (R.J.B.), Department of Medicine, University of Minnesota Medical School, Minneapolis; 89-1 Enyachou (Y.I.), Izumo City, Shimane Prefecture, Japan; and the Laboratory for Experimental Cardiology (D.J.D.), Thoraxcentre, Erasmus University, Rotterdam, the Netherlands.
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. E-mail Bache001@maroon.tc.umn.edu
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Abstract |
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Previously, we observed that
1- but not 2-adrenergic vasoconstriction restricted blood flow distal to a coronary artery stenosis that resulted in myocardial hypoperfusion during exercise. This study was performed to test the hypothesis that vascular smooth muscle 2-adrenergic vasoconstriction during exercise does exert a flow-limiting effect distal to a coronary artery stenosis but that this action is counterbalanced by simultaneous endothelial 2-adrenergic stimulation of NO production. Eight dogs instrumented with a Doppler velocity probe, hydraulic occluder, and indwelling microcatheter in the left anterior descending coronary artery (LAD) were studied during treadmill exercise in the presence of a coronary artery stenosis before and during infusion of the 2-adrenergic receptor antagonist idazoxan (1.0 µg·kg-1·min-1 IC) before and after NO synthase blockade with NG-monomethyl-L-arginine (LNNA, 1.5 mg/kg IC). Coronary pressure distal to the stenosis was maintained constant during the control period and after administration of idazoxan before and after LNNA. Neither idazoxan nor LNNA altered any of the systemic hemodynamic variables either at rest or during exercise. During exercise in the absence of a stenosis, idazoxan and LNNA had no effect on coronary blood flow. In the presence of a stenosis that decreased distal coronary pressure to 52±3 mm Hg, mean myocardial blood flow measured with microspheres was 0.87±0.17 mL·min-1·g-1 in the LAD-dependent region and 2.52±0.30 mL·min-1·g-1 in the posterior control region, respectively. With no change in distal coronary pressure, idazoxan had no effect on mean myocardial blood flow in the LAD region (0.86±0.17 mL·min-1·g-1), but LNNA decreased mean myocardial blood flow to 0.49±0.09 (P<.01). However, when idazoxan was infused during exercise in the presence of a coronary artery stenosis after LNNA administration, idazoxan increased mean myocardial blood flow to 0.62±0.13 mL·min-1·g-1 (P<.01). These data demonstrate that 2-adrenergic stimulation of endothelial NO production, which occurs during exercise in the presence of a flow-limiting coronary artery stenosis, acts to counterbalance vascular smooth muscle 2-adrenergic vasoconstriction.
Key Words: coronary vasodilation • endothelium • NG-nitro-L-arginine • idazoxan • adrenergic vasoconstriction
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Introduction |
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Studies in open-chest dogs have demonstrated that cardiac sympathetic nerve stimulation produces coronary vasoconstriction, which is mediated by both
1-adrenergic receptors and postjunctional 2-adrenergic receptors on coronary vascular smooth muscle.1 Similarly, coronary vasoconstriction produced by intra-arterial norepinephrine is mediated by both 1- and postjunctional 2-adrenergic receptors, with the contribution of 2-adrenergic receptor activation of equal or greater importance than that of 1-adrenergic receptor activation.2 Despite this evidence that postjunctional 2-adrenergic receptors can contribute to adrenergic coronary vasoconstriction in open-chest animals, studies in chronically instrumented awake animals have demonstrated that coronary vasoconstriction resulting from sympathetic activation during exercise can be fully blocked by the selective 1-adrenergic antagonist prazosin but is not significantly attenuated by selective 2-adrenergic blockade.3 4 Recent studies have suggested that postjunctional 2-adrenergic receptors are located not only on vascular smooth muscle cells, where they produce vasoconstriction, but also on the endothelium,5 where they stimulate release of NO.6 7 Failure to find evidence of a contribution of 2-adrenergic-mediated coronary vasoconstriction could be explained if 2-adrenergic receptor stimulation during exercise caused balanced activation of both constrictor and dilator mechanisms in the normal heart. This possibility is supported by the recent report of Kichuk et al8 that 2-adrenergic receptor stimulation caused dose-dependent increases of NO production by isolated coronary microvessels. This finding suggests that failure of 2-adrenergic blockade to increase coronary blood flow might have occurred not because of lack of a postjunctional vasoconstrictor effect on the coronary vascular smooth muscle but because simultaneous stimulation of NO production by endothelial 2-adrenergic receptors counteracts the vasoconstriction.
In dogs in which a coronary artery stenosis resulted in hypoperfusion and contractile dysfunction during exercise, intracoronary prazosin but not idazoxan caused an increase in blood flow in the poststenotic region, indicating that coronary resistance vessels are responsive to increases of 1- but not 2-adrenergic vasoconstrictor tone during exercise in the presence of ischemia.9 We recently reported that blockade of NO synthesis aggravated hypoperfusion of myocardium distal to a coronary artery stenosis in exercising dogs, suggesting that NO contributes to coronary vasodilation in hypoperfused myocardium during exercise.10 It is possible that 2-adrenergic receptor activation during exercise results in endothelium-dependent vasodilation, which compensates for the increased coronary vasoconstrictor tone produced by direct smooth muscle constriction. To test this hypothesis, we assessed the effect of selective 2-adrenergic receptor blockade in the absence and presence of NO blockade on coronary blood flow in the normal heart and in hypoperfused myocardium at rest and during exercise. 2-Adrenergic receptors were blocked with idazoxan, and NO production was inhibited with LNNA. Both compounds were administered directly into the coronary artery of chronically instrumented dogs to minimize systemic effects.
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Materials and Methods |
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Studies were performed in 25 adult mongrel dogs weighing 20 to 27 kg and trained to run on a motor-driven treadmill. 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 approved by the Animal Care Committee of the University of Minnesota.
Surgical Preparation
After sedation with fentanyl (0.4 mg IM) and droperidol (20 mg IM), dogs were anesthetized with sodium pentobarbital (30 to 35 mg/kg IV), intubated, and ventilated with a respirator using room air supplemented with oxygen (30%). Respiratory rate and tidal volume were set to keep arterial blood gases within the physiological range. A left thoracotomy was performed in the fifth intercostal space under sterile conditions. A heparin-filled polyvinyl chloride catheter (outer diameter, 3.0 mm) was introduced into the ascending aorta via the left internal thoracic artery. The pericardium was opened, and similar catheters were introduced into the left atrium through the appendage and the left ventricle at the apical dimple. A solid-state micromanometer (model P5, Konigsberg Instrument Co) was also introduced into the left ventricle at the apex. Approximately 1.5 cm of the proximal LAD was dissected free, and a Doppler flow velocity probe (Craig Hartley) was positioned around the artery. Immediately distal to the velocity probe, a hydraulic occluder (outer diameter, 3.0 mm) was placed around the vessel. A heparin-filled silicone catheter (inner diameter, 0.3 mm), bonded to a large silicone catheter (inner diameter, 1.6 mm), was introduced into the LAD immediately distal to the hydraulic occluder for measurement of coronary pressure and infusion of drugs. Miniature 10-MHz Doppler crystals for measurement of myocardial wall thickening were sutured onto the epicardium in the region perfused by the LAD and the left circumflex coronary artery (control region), respectively. 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 were flushed daily with heparinized saline. The catheters, electrical leads, and occluder tubing were protected with a nylon vest.
Hemodynamic Measurements
Studies were performed 10 to 17 days after surgery with the animal exercising on a motor-driven treadmill. Phasic and mean aortic pressure was measured with a Statham P23XL pressure transducer positioned at midchest level. LV pressure was measured with the micromanometer calibrated with the fluid-filled LV catheter. LV dP/dt was obtained via electrical differentiation of the LV pressure signal. Coronary blood flow velocity was measured with a 10-MHz Doppler flowmeter system (Craig Hartley). Data were recorded on an eight-channel direct-writing oscillograph (Coulbourn Instruments).
Regional Myocardial Function
Regional myocardial wall thickening was measured using single epicardial 10-MHz ultrasonic pulsed Doppler crystals (Craig Hartley). The onset of systole was taken as the initiation of the upstroke of LV pressure recorded from the micromanometer; end systole was taken 20 milliseconds before peak negative dP/dt. Maximum systolic excursion (SE) in three myocardial layers (subendocardium [end], midmyocardium [mid], and subepicardium [epi]) was recorded at range-gate depths (R) of 
8, 5, and 3 mm, respectively. Percent myocardial systolic wall thickening (%WT) in each myocardial layer was calculated using the following formulas:
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Myocardial Blood Flow Measurements
Myocardial blood flow was measured with 15-µm-diameter microspheres labeled with 141Ce, 51Cr, 85Sr, 95Nb, or 46Sc (DuPont NEN Co). For each measurement, 3x106 microspheres were injected into the left atrium while a reference sample of arterial blood was withdrawn from the aortic catheter at a rate of 15 mL/min. At the conclusion of the study, 10 mL of Evans blue dye was injected into the coronary artery cannula to stain the region of myocardium perfused by the LAD. Immediately thereafter, a lethal dose of sodium pentobarbital was administered, and hearts were excised and fixed in 10% buffered formalin. After fixation, the left ventricle was sectioned into five transverse rings from base to apex. Each ring was sectioned radially into 12 to 15 sections. Myocardial samples were obtained from the center of the blue-stained region perfused by the LAD and divided into four transmural layers, epicardium to endocardium. The resultant specimens were weighed and placed into vials for counting of radioactivity and computation of blood flow.
Experimental Protocols
Degree of Inhibition of NO Synthase by LNNA
The magnitude and selectivity of LNNA as an NO synthase inhibitor was assessed in 7 dogs standing in a sling. For this purpose, we measured the increases in coronary blood flow produced by intracoronary acetylcholine (0.1, 0.2, 0.4, 1, 2, and 4 µg·kg-1·min-1) and nitroprusside (0.3, 0.6, 1.5, and 3 µg·kg-1·min-1) infused in random order. After completion of these measurements, LNNA was administered in an intracoronary dose of 1.5 mg/kg over a period of 15 minutes at a rate of 0.6 mL/min. Ten minutes after completion of drug administration, coronary blood flow responses to intracoronary infusions of acetylcholine (0.1 to 4 µg·kg-1·min-1) and nitroprusside (0.3 to 3 µg·kg-1·min-1) were repeated.
Effects of 2-Adrenergic Blockade on the Coronary Pressure-Flow Relation
In 10 dogs, we studied the effect of 2-adrenergic receptor blockade with idazoxan on the coronary pressure-flow relation during exercise. Animals underwent a 5-minute period of warm-up exercise, during which the speed and grade of the treadmill were gradually increased until a heart rate of 180 to 200 bpm was achieved. Dogs were subsequently allowed to rest on the treadmill for 10 to 15 minutes, and exercise was then restarted at the predetermined level. After 2 to 3 minutes of exercise, when hemodynamic variables had reached a steady state, the hydraulic occluder was progressively inflated with saline using a micrometer-driven syringe to provide 10 to 20 separate pressure-flow measurements under conditions varying from no stenosis to total coronary artery occlusion. At each level of inflation, 10 to 15 seconds was allowed for stabilization before measurements were made. After completion of the pressure-flow measurements, the occluder was deflated, exercise was discontinued, and the animals were allowed to rest for 60 minutes.
Sixty minutes after completion of the control measurements, systemic and coronary hemodynamic measurements were made, and an intracoronary infusion of the 2-adrenergic receptor blocker idazoxan (1 µg·kg-1·min-1 over 10 minutes at a rate of 0.6 mL/min) was started. Idazoxan (Reckitt and Colman) was dissolved in normal saline and diluted to the appropriate concentration. We previously observed that this dose of idazoxan completely inhibited the vasoconstrictor response to intracoronary boluses of the selective 2-adrenergic agonist B-HT 933 (Boehringer-Ingelheim) in doses of 0.1, 1.0, and 10 µg/kg).4 Five minutes after beginning the infusion of idazoxan, resting measurements were obtained, and exercise was started at the previous level. After hemodynamic measurements during exercise had reached steady state conditions, coronary-flow measurements were made at 10 to 20 coronary pressure points as described above.
A 3-hour rest period was then allowed to permit the effects of idazoxan to dissipate. This interval was chosen since we previously observed that the 2-adrenergic receptor antagonistic effects of this dose of intracoronary idazoxan subsided within <2 hours.4 After this interval, LNNA was administered into the coronary artery catheter in a dose of 1.5 mg/kg infused over 15 minutes at a rate of 0.6 mL/min. After completion of the LNNA infusion, resting measurements were obtained with the dogs standing on the treadmill, and exercise was then started at the previous level. After steady state exercise was achieved, 10 to 20 coronary pressure-flow measurements were obtained as described above. After a 60-minute rest period, the infusion of idazoxan was restarted (1 µg·kg-1·min-1). Five minutes later, resting hemodynamic measurements were obtained with the dogs standing on the treadmill. Exercise was then begun, and coronary pressure-flow measurements were repeated in the presence of combined NO and 2-adrenergic blockade.
In 7 dogs (including 2 dogs that underwent the pressure-flow protocol during exercise), the effects of idazoxan on coronary pressure-flow relations were examined during resting conditions on a different day. After the dogs had been resting in a sling for 30 minutes, baseline systemic and coronary hemodynamic measurements were obtained. The hydraulic occluder was then inflated to provide 10 to 20 separate pressure-flow measurements under conditions varying from no stenosis to total coronary artery occlusion as described above. Sixty minutes after completion of the control measurements, an intracoronary infusion of idazoxan (1 µg·kg-1·min-1 over 10 minutes) was started. Five minutes after beginning the idazoxan infusion, hemodynamic measurements were obtained, and 10 to 20 coronary pressure-flow measurements were repeated during the infusion of idazoxan. Three hours later, LNNA was infused into the coronary artery catheter in a dose of 1.5 mg/kg. After completion of the LNNA infusion, baseline measurements were obtained, and 10 to 20 coronary pressure-flow measurements were again obtained. After 60 minutes, the infusion of idazoxan was restarted. Five minutes later, hemodynamic measurements were collected, and coronary pressure-flow measurements were repeated.
Effects of 2-Adrenergic Blockade During Exercise With a Coronary Stenosis
In 8 dogs (including 5 dogs that underwent the pressure-flow protocol), we also studied the effects of 2-adrenergic receptor blockade on the distribution of myocardial blood flow and myocardial function during exercise in the presence of a flow-limiting coronary stenosis. Animals were exercised on the treadmill at a level that produced heart rates of 180 to 200 bpm. After steady state hemodynamic conditions had been maintained for 2 to 3 minutes, a LAD stenosis was produced by inflation of the occluder to produce a coronary perfusion pressure distal to the stenosis of 50 mm Hg. After 2 minutes of exercise in the presence of the stenosis, when hemodynamics and myocardial segment shortening had stabilized, microspheres were injected into the left atrium for measurement of myocardial blood flow. When collection of reference blood flow was completed, the coronary stenosis was released, and exercise was discontinued.
After 60 minutes of rest, an intracoronary infusion of idazoxan (1.0 µg·kg-1·min-1) was begun. Five minutes later, resting measurements were obtained with the dogs standing on the treadmill, and the exercise protocol was repeated during the infusion of idazoxan. When stable exercising hemodynamics were present, the occluder was inflated to produce a coronary pressure equal to that achieved during the first exercise period. After 2 minutes of exercise in the presence of the coronary stenosis, hemodynamics and wall thickening were measured, and a second dose of microspheres was injected into the left atrium. After a 3-hour rest period to allow washout of idazoxan, an intracoronary infusion of LNNA (1.5 mg/kg over 15 minutes) was started. After completion of the LNNA infusion, resting measurements were obtained, and the exercise protocol was repeated. The coronary occluder was partially inflated to produce a coronary pressure equal to that during the first two interventions, and a third microsphere injection was performed as described above. After a 60-minute recovery period, the infusion of idazoxan was again started at a rate of 1 µg·kg-1·min-1 IC, and 5 minutes later, the exercise protocol was repeated. A fourth microsphere injection was performed at a coronary pressure identical to that used during the previous exercise periods. Because of a malfunction of the Doppler system, coronary artery blood flow data were obtained for only 7 of the 8 exercising dogs.
Data Analysis
Heart rate, LV and aortic pressures, and coronary blood velocity were measured from the strip-chart recordings. Mean LV diastolic pressure was determined by planimetry of the pressure signal obtained with the solid-state micromanometer; the interval of diastole, beginning 20 milliseconds before peak LV dP/dt and extending to the onset of the upstroke of LV pressure, was taken. Coronary blood flow was computed from the Doppler shift using the equation Q=2.5xfxD2, where Q is the coronary blood flow (mL/min), f is the Doppler shift (kHz), and D is the internal diameter of the coronary artery within the Doppler probe.11 In chronically instrumented animals, the flow velocity probe is tightly adherent to the coronary artery, so that 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 artery. In this way, any error in computation of the coronary internal diameter affects control and intervention conditions equally.
Optimal curve fitting of the coronary pressure-flow data was obtained with a fourth-order polynomial (y=a+bx+cx2+dx3+ex4), and coronary flows were computed for 11 coronary pressures over the coronary pressure range recorded for each animal. Hemodynamic data were compared using two-way (exercise, treatment) ANOVA for repeated measures. Myocardial blood flow data in the four different layers were analyzed by two-way (treatment, transmural layer) ANOVA for repeated measures. When a significant effect of exercise was observed, comparisons within treatment groups were performed using one-way ANOVA followed by Fisher's exact test. When a significant difference between treatments was observed, comparisons between groups were made with Student's t test for paired data followed by the Bonferroni correction. Statistical significance was accepted at a value of P<.05. All values are presented as mean±SEM.
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Degree of Inhibition of NO Synthase by LNNA
Studies were performed with the dogs standing in a sling, and LNNA was determined to have no effect on mean aortic pressure (90±5 mm Hg) or heart rate (121±7 bpm). The effects of LNNA (1.5 mg/kg IC) on coronary vasodilation produced by the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroprusside are shown in Fig 1
. Intracoronary acetylcholine in doses of 0.1 to 4 µg·kg-1·min-1 had no effect on mean aortic pressure (92±6 mm Hg) or heart rate (118±9 bpm). Coronary blood flow increased from 47±5 mL/min at baseline to 143±15 mL/min during infusion of acetylcholine at a dose of 4 µg·kg-1·min-1. After LNNA administration, this dose of acetylcholine increased coronary blood flow from 44±5 mL/min at baseline to 74±7 mL/min, representing 69±7% inhibition of increase in coronary blood flow produced by the highest dose of acetylcholine (P<.01).
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) conditions and in the presence of LNNA (1.5 mg/kg IC) (
). Data are mean±SEM.
Intracoronary infusion of sodium nitroprusside in doses of 0.3 to 3 µg·kg-1·min-1 decreased mean aortic blood pressure from 96±9 mm Hg at baseline to 86±7 mm Hg during the highest dose (P<.05), with a tendency for heart rate to increase from 113±10 to 128±14 bpm (P=NS). Coronary blood flow increased from 44±4 mL/min at baseline to 117±13 mL/min during infusion of the highest dose of nitroprusside (P<.01). After LNNA administration, nitroprusside infusion caused similar changes in mean aortic pressure and heart rate. The responses of coronary blood flow to nitroprusside were not altered by LNNA (Fig 1
).
Effect of 2-Adrenergic Blockade on the Coronary Pressure-Flow Relation
Coronary Pressure-Flow and Pressure-Function Relations at Rest
Heart rate and mean aortic pressure were 118±6 bpm and 84±5 mm Hg, respectively, during control resting conditions. Heart rate and blood pressure were not altered by infusion of either idazoxan or LNNA. As shown in Fig 2, LNNA caused a rightward shift of the coronary pressure-flow relation, so that coronary blood flow was significantly decreased for coronary pressures below 60 mm Hg. Coronary flow at pressures above 60 mm Hg also tended to decrease after LNNA, but this did not reach statistical significance. Infusion of idazoxan did not alter the coronary pressure-flow relation during control conditions or after infusion of LNNA. The coronary pressure-function relation paralleled the pressure-flow relation; systolic wall thickening remained constant until coronary pressure reached 50 mm Hg before and 70 mm Hg after LNNA and then fell as a function of pressure (Fig 2).
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Coronary Pressure-Flow and Pressure-Function Relations During Exercise
Heart rate and mean aortic pressure were 190±10 bpm and 113±6 mm Hg, respectively, during control exercise and were not significantly altered by intracoronary infusion of either idazoxan or LNNA. A typical example of the coronary pressure-flow relations during infusion of idazoxan before and after LNNA are shown in Fig 3; the mean data for all 10 dogs are shown in Fig 4. Coronary pressure-flow relations during consecutive control exercise periods were highly reproducible (Fig 3). LNNA caused a rightward shift of the pressure-flow relation so that for coronary pressures <90 mm Hg, blood flow was significantly less than control. Coronary flow for pressures above 90 mm Hg also tended to be lower, but this difference was not significant. Idazoxan did not alter the coronary pressure-flow relation during control conditions. However, after LNNA the pressure-flow relation was shifted leftward by idazoxan so that coronary blood flow at pressures below 80 mm Hg was significantly increased by idazoxan. The coronary pressure-function relation during exercise paralleled the change in the pressure-flow relation; systolic wall thickening remained constant until coronary pressure reached 75 mm Hg before and 90 mm Hg after LNNA and then fell as a function of pressure (Fig 4).
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P<.05 LNNA+idazoxan vs LNNA.
Effect of 2-Adrenergic Blockade During Exercise With a Coronary Stenosis
Systemic and Coronary Hemodynamics
Examples of strip-chart recordings obtained during exercise in the absence and presence of a stenosis of the LAD are shown in Fig 5. Mean hemodynamic data for all animals are presented in Table 1. During control conditions, exercise increased heart rate, LV systolic pressure, LV mean diastolic pressure, and maximum LV dP/dt, whereas mean aortic pressure and LV end-diastolic pressure were not significantly affected. Coronary blood flow increased from 40.5±1.7 mL/min at rest to 70.9±3.6 mL/min during exercise (P<.01). The coronary stenosis caused a significant increase in LV end-diastolic and mean diastolic pressures. Inflation of the occluder to decrease coronary pressure to 52±3 mm Hg resulted in a decrease of coronary blood flow to 24.6±3.5 mL/min (P<.01). Idazoxan did not change any systemic or coronary hemodynamic variable at rest or during exercise. LNNA also did not change hemodynamics at rest or during exercise. With inflation of the occluder, LV mean diastolic and end-diastolic pressure increased significantly after LNNA (P<.05). During exercise in the presence of a stenosis that produced a coronary pressure of 53±3 mm Hg, LNNA decreased coronary blood flow by 45±2% (P<.05 compared with control). The addition of idazoxan increased coronary blood flow during exercise in the presence of the stenosis from 13.4±1.7 to 19.1±2.1 mL/min (P<.05). Mean LV diastolic pressure measured with planimetry was not altered by the addition of idazoxan to LNNA (20±3 mm Hg before compared with 19±2 mm Hg after LNNA), suggesting that the increase in coronary blood flow in response to idazoxan resulted from 2-adrenergic–mediated coronary vasodilation. The addition of idazoxan to LNNA in the presence of the coronary stenosis caused a trend toward an increase in LV dP/dtmax (P=.10).
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Myocardial Blood Flow
Myocardial blood flow data are shown in Table 2 and Fig 6. During exercise, mean myocardial blood flow in the anterior region perfused by the stenotic LAD was 0.87±0.17 mL·min-1·g-1 compared with 2.52±0.30 mL·min-1·g-1 in the posterior control region (P<.01). Hypoperfusion in the anterior region was most pronounced in the subendocardium, reflected by an endocardial-to-epicardial blood flow ratio of 0.37±0.09 compared with 1.29±0.08 in the control region (P<.01). With coronary pressure maintained constant, idazoxan had no effect on blood flow in any myocardial layer. Infusion of LNNA caused a further decrease in blood flow distal to the stenosis in all myocardial layers, with a decrease in mean flow to 0.49±0.09 mL·min-1·g-1 (P<.01 versus control stenosis). The addition of idazoxan to LNNA increased blood flow distal to the stenosis in all myocardial layers, with an increase of mean blood flow to 0.62±0.13 mL·min-1·g-1 (P<.05).
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Myocardial Function
Systolic wall thickening measurements are presented in Table 3. During control conditions, exercise increased systolic thickening of the full wall from 26±1% to 33±1% (P<.01). Inflation of the occluder caused a decrease in wall thickening in all three layers in the anterior ischemic region, with a decrease in full wall thickening to 10±2% (each P<.01). Infusion of idazoxan alone caused no change of regional contractile function. LNNA caused further decreases in systolic wall thickening in the endomyocardial and midmyocardial layers, with a further decrease of full wall thickening to 4±1% (P<.01 versus control stenosis). The subsequent addition of idazoxan increased thickening in the inner and middle layers and resulted in a slight but significant increase in full wall thickening to 7±1% (P<.05 versus LNNA stenosis).
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Discussion |
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The most important finding of the present study is that inhibition of NO synthesis unmasked an
2-adrenergic vasoconstrictor influence distal to a coronary stenosis during exercise but not at rest. As a result, inhibition of NO production exacerbated myocardial hypoperfusion in the region perfused by the stenotic artery during exercise. This represents the first demonstration that 2-adrenergic activation during exercise can cause NO-mediated coronary vasodilation in vivo. In contrast, during normal arterial inflow, inhibition of NO synthesis had no effect on coronary blood flow either at rest or during exercise.
Methodological Considerations
In the present study, LNNA was used to inhibit NO production. LNNA in a dose of 1.5 mg/kg IC caused 70% inhibition of the vasodilator response to the endothelium-dependent vasodilator acetylcholine. This is consistent with previous studies in anesthetized12 13 and awake14 dogs that LNNA caused 35% to 70% inhibition of the response to acetylcholine and in agreement with the report of Komaru et al15 that LNMMA abolished acetylcholine-induced vasodilation of small coronary arteries (>120 µm) but did not completely inhibit the effect of acetylcholine in coronary arterioles (<120 µm). LNNA did not attenuate the response to the endothelium-independent vasodilator nitroprusside. This is in agreement with previous reports that the effects of LNNA are specific to endothelium-dependent vasodilation.12 14 15 In the present study, dose-response curves examining the effect of LNNA on the vasodilation produced by nitroprusside and acetylcholine were performed in random sequence. These measurements required 60 minutes to complete, so that when acetylcholine was infused second, the results of the largest doses reflect the degree of blockade present 60 minutes after the administration of LNNA. The results at the end of this time were not different from the response when acetylcholine was infused first, with no evidence that the blockade of NO-mediated vasodilation had begun to subside. These findings suggest that even for the longest protocols, NO-mediated vasodilation would have been adequately blocked.
The present study was designed to determine whether 2-adrenergic vasoconstriction during exercise is masked by simultaneous stimulation of NO production. To allow study of the effects of LNNA and idazoxan on vasomotor tone, it is mandatory that extravascular determinants of myocardial blood flow are taken into account. First, under resting conditions and during control exercise, idazoxan and LNNA had no effect on LV dP/dtmax, indicating minimal effects on systolic myocardial compressive forces. Second, heart rates were not different between experimental conditions, so that the diastolic perfusion time was comparable. Finally, LV filling pressure can influence myocardial blood flow distal to a coronary artery stenosis. LNNA increased LV mean diastolic pressure slightly during exercise in the presence of a stenosis. The increase in LV diastolic pressure likely resulted from aggravation of myocardial hypoperfusion by LNNA with consequent further impairment of systolic and diastolic function rather than from a primary effect on LV filling pressure. This is supported by the observation that neither idazoxan nor LNNA had an effect on LV mean or end-diastolic pressure at rest or during exercise with normal arterial inflow, whereas infusion of idazoxan alone (ie, without concomitant NO synthase inhibition) also had no effect on filling pressure during exercise in the presence of a stenosis. Therefore, the observed changes of myocardial blood flow produced by idazoxan and LNNA cannot be explained by changes in extravascular compressive forces.
The effects of LNNA and idazoxan on blood flow were examined over a range of coronary pressures. When pressure-flow relations are examined using measurements of blood flow in a proximal coronary artery, collateral flow can contribute to myocardial tissue flow with resultant underestimation of total blood flow. Messina et al16 have shown that collateral flow can contribute significantly to myocardial tissue blood flow when pressure gradients between coronary arteries exceed 50 to 70 mm Hg. This results in a rightward shift of the pressure-flow relation at low coronary pressures but does not affect the relation at higher pressures, where the interarterial pressure gradient is <50 to 70 mm Hg. In the present study, LNNA without or with idazoxan produced rightward shifts in the pressure-flow relation at both high and lower coronary pressures; the rightward shift at high coronary pressures cannot be attributed to collateral flow. Furthermore, the interventions studied did not cause substantial changes in aortic pressure, which would influence collateral blood flow. Finally, coronary pressure-flow relations were nearly identical when four consecutive control runs were performed sequentially, indicating that there was no detectable recruitment of collateral flow in response to repeated exercise trials. Taken together, these findings imply that the effects of LNNA on the coronary pressure-flow relationship cannot be attributed to collateral flow.
Effect of NO Synthase Inhibition During Normal Arterial Inflow
In the present study, LNNA caused no significant change in coronary flow at rest or during exercise in the presence of normal arterial inflow. Similarly, previous studies in anesthetized12 13 17 and resting14 18 or exercising10 19 awake dogs failed to show a decrease of basal coronary blood flow in response to intracoronary LNNA,10 12 14 19 LNMMA,13 17 or L-NAME.18 Only one study of four awake dogs reported a decrease in coronary flow after intravenous administration of LNMMA.20 In that study, LNMMA resulted in a 30% decrease in heart rate, which may have contributed to the 18% decrease of coronary flow. In contrast to these generally negative results in intact hearts, studies in isolated nonblood-perfused hearts from rabbit,21 22 rat,23 and guinea pig24 25 26 reported an increase in coronary vasomotor tone after the administration of LNNA,23 25 LNMMA,22 24 or L-NAME.22 The discrepancy between in vivo blood-perfused canine hearts and isolated buffer-perfused rodent hearts could be due to differences in species or experimental conditions. In isolated perfused hearts, coronary flow rates are high at baseline (6 mL·min-1·g-1), favoring shear-mediated release of NO. In addition, the absence of blood, and therefore the NO scavenger hemoglobin,27 would likely increase the effect of NO in buffer-perfused hearts.
Our data fail to support a role for NO in the regulation of coronary vasomotor tone at rest or during exercise in the normal heart. Nevertheless, it is likely that the exercise-induced increase in coronary flow and therefore endothelial shear stress28 caused an increase in NO production during exercise. Flow-mediated vasodilation is most prominent in coronary arteries that are not under metabolic control (>100 µm).29 If LNNA blunted flow-mediated dilation in these segments during exercise, metabolic vasodilation of the coronary arterioles (<100 µm) could normally fully compensate for the resultant increase in vascular resistance.29 30 Alternatively, blockade of NO production in the arterioles could have led to activation of other endothelium-dependent vasodilator mechanisms. This is supported by the finding that LNMMA did not completely inhibit acetylcholine-induced vasodilation of coronary resistance vessels15 and that endothelium-dependent vasodilation in response to bradykinin is only partly blocked by the interruption of NO production.23 31 Other endothelium-derived substances might include prostacyclin31 or endothelium-derived hyperpolarizing factor.32
Effect of 2-Adrenergic Receptor Blockade During Normal Arterial Inflow
In the present study, 2-adrenergic blockade had no effect on coronary blood flow under resting conditions with normal arterial inflow. This is in agreement with previous observations that -adrenergic vasoconstrictor tone is negligible during resting conditions.33 Idazoxan also had no effect on coronary flow during exercise with normal arterial inflow, which is in agreement with previous reports indicating that the 1-adrenergic subtype is the primary mediator of adrenergic coronary vasoconstriction in the normal heart during exercise.3 4 However, recent evidence suggests that the coronary endothelium harbors 2-adrenergic receptors that are capable of mediating NO release.5 6 7 This suggests that the direct vascular smooth muscle constrictor effect of 2-adrenergic activity during exercise might be concealed by a simultaneous endothelium-dependent vasodilator effect. To unmask possible 2-adrenergic vasoconstriction, we blocked NO production with LNNA before the administration of idazoxan. However, even when NO production was blocked, idazoxan did not cause an increase in coronary blood flow, indicating that 2-adrenergic vasoconstriction in the normal heart is negligible both at rest and during exercise.
Response of Coronary Resistance Vessels to Myocardial Hypoperfusion
In unanesthetized animals free from the effects of general anesthesia and acute surgical trauma, Canty and Smith34 demonstrated that myocardial ischemia causes maximal vasodilation of coronary resistance vessels with lack of pharmacologically recruitable vasodilator reserve. In contrast, studies in anesthetized open-chest swine and dogs have documented persistent vasodilator reserve in ischemic myocardium.35 36 37 38 Similarly, myocardial ischemia produced by exercise in the presence of a flow-limiting coronary stenosis does not result in maximal resistance vessel dilation in the hypoperfused region.39 40 Persistent vasomotor tone in coronary resistance vessels during myocardial ischemia is likely due to activation of the adrenergic nervous system, which occurs in response to general anesthesia and acute surgical trauma or during exercise. Coronary resistance vessels in ischemic myocardial regions remain responsive to vasoconstrictor stimuli, since 1-adrenergic receptor39 or 2-adrenergic receptor40 agonists can produce vasoconstriction in ischemic myocardium and aggravate contractile dysfunction. Interestingly, we observed in exercising dogs that the relative increase in coronary flow produced by 1-adrenergic receptor blockade was greater in the presence of myocardial ischemia9 than under conditions of unimpeded arterial blood flow.4 In the present study, inhibition of NO production had no effect on myocardial blood flow during normal coronary inflow but caused vasoconstriction when blood flow was limited by a stenosis. A similar observation was made with the thromboxane A2 mimetic, U46619, which caused a flow reduction during myocardial hypoperfusion but not during normal arterial inflow.41 These observations demonstrate that myocardial hypoperfusion during exercise may actually render the coronary bed more susceptible to vasoconstrictor influences. Augmentation of vasoconstriction by hypoperfusion could be explained by constriction of arterial segments that are not under metabolic control. Chilian et al42 showed that 25% of total coronary resistance resides in small arteries >150 µm in diameter, whereas metabolic vasodilation occurs predominantly in arterioles <100 µm.43 44 Under normal conditions, vasoconstriction of the small arteries can be counterbalanced by vasodilation of the arterioles.30 45 However, when hypoperfusion has already caused metabolic vasodilation of the arterioles, the ability to compensate for vasoconstriction of the small arteries is lost. In this situation, vasoconstriction of the small arteries would aggravate hypoperfusion. Recent evidence suggests that in ischemic myocardium vasomotor tone can also exist in vessels that are under metabolic control. Thus, Chilian and Layne46 observed that even during severe hypoperfusion, exogenous adenosine caused further vasodilation of coronary arterioles. Furthermore, Chilian47 observed that although 1- and 2-adrenergic receptor stimulation had no effect on vessels <100 µm during normal arterial inflow, hypoperfusion unmasked both 1- and 2-adrenergic vasoconstriction in vessels of this size. These findings suggest that the capacity of the resistance vessels to escape from vasoconstrictor influences is impaired at the decreased intravascular pressures that can exist distal to a coronary artery stenosis.
Effect of NO Synthase Inhibition During Myocardial Hypoperfusion
The present data indicate that NO contributes to coronary vasodilation during myocardial hypoperfusion distal to an arterial stenosis. This finding is in agreement with the report of Smith and Canty18 that inhibition of NO synthesis with L-NAME decreased coronary flow at perfusion pressures below, but not above, the autoregulatory break point. The flow reduction in response to LNNA during hypoperfusion could have resulted from vasoconstriction either in arterial segments that are not under metabolic control but contribute to total coronary resistance (>100 µm in diameter)7 45 or in vessels that are under metabolic control (<100 µm).7 The present study cannot distinguish whether the effect of LNNA was due to the unmasking of normal NO release because other vasodilator mechanisms had been exhausted or whether it was due to an actual increase of NO production in response to myocardial hypoperfusion. An increase in NO production in response to impaired tissue oxygenation has been suggested by Pohl and Busse,48 who observed that hypoxia led to release of an endothelium-derived relaxing factor in feline mesenteric vessels. Similar findings have been reported in the coronary circulation, where myocardial hypoxia resulted in enhanced production of NO in isolated guinea pig hearts.24 25 Coronary arterial oxygen tension is likely to be lower during hypoxia than during limited arterial inflow of well-oxygenated blood, but even during normal arterial inflow, oxygen diffusion occurs so rapidly that in arterioles and even in small arteries, oxygen tensions are lower than in the central aorta.49 This suggests that the vascular endothelium could serve as a tissue oxygen sensor.50
Effect of 2-Adrenergic Receptor Blockade During Myocardial Hypoperfusion
In the present study, 2-adrenergic blockade with idazoxan caused no change in coronary blood flow during exercise either at normal or decreased arterial pressures. In contrast, after blockade of NO synthesis with LNNA, idazoxan caused coronary vasodilation at perfusion pressures below the autoregulatory range. We propose that 2-adrenergic activity augmented endothelial NO production distal to the stenosis during exercise; consequently, inhibition of NO production by LNNA aggravated hypoperfusion by leaving 1- and 2-adrenergic coronary vasoconstriction unopposed.7 47 Failure of idazoxan to increase coronary flow during control exercise suggests that 2-adrenergic receptor–mediated vasoconstriction distal to the stenosis was exactly balanced by 2-mediated stimulation of endothelial NO production. However, after inhibition of NO production, the addition of 2-adrenergic receptor blockade did not fully return coronary flow to the control level. There are several possible explanations for this disparity. First, Jones et al7 observed that inhibition of NO synthase activity potentiated both 1- and 2-adrenergic vasoconstriction, suggesting that 1-adrenergic activation can also mediate endothelial NO release. Since 1-adrenergic receptors were unblocked in the present study, sympathetic activation during exercise might have stimulated 1-adrenergic receptor–mediated NO production, which could account for the residual constriction when idazoxan was administered after LNNA. Second, Schwarz et al51 demonstrated that NO caused prejunctional inhibition of norepinephrine release from sympathetic nerves of perfused rat hearts. This suggests that blockade of NO production in the present study could have caused increased norepinephrine release. As a result, blockade of both NO synthase and 2-adrenergic receptors would not return blood flow to normal, because the increased norepinephrine release could act on unblocked coronary smooth muscle 1-adrenergic receptors to cause vasoconstriction. Finally, it is likely that 2-adrenergic receptor activation is not the only mechanism responsible for NO production. Idazoxan would block only 2-adrenergic receptor–stimulated endothelial NO release but would not alter basal22 or flow-mediated activation of NO synthase.28 Consequently, the combination of idazoxan plus LNNA would not return blood flow to the control level, inasmuch as idazoxan would block only the 2-adrenergic receptor–mediated component of NO release and LNNA would block NO production stimulated by any means. Although 2-adrenergic vasoconstriction was present during exercise (but masked by concomitant NO release), there was no evidence of 2-adrenergic vasoconstrictor activity under resting conditions even after NO synthase blockade. However, LNNA also produced a rightward shift of the coronary pressure-flow relation during resting conditions, demonstrating that inhibition of NO production aggravated hypoperfusion in part via some mechanism other than unopposed 2-adrenergic vasoconstriction.
Clinical Significance
The present findings demonstrate that endothelial NO production acts to oppose adrenergic coronary vasoconstriction during exercise in the presence of a coronary stenosis. Consequently, NO synthase inhibition unmasked an 2-adrenergic coronary vasoconstrictor influence during exercise but not at rest. Impaired NO-dependent vasodilator responses have been observed in patients with atherosclerosis,52 hyperlipidemia,52 or hypertension.53 The present findings suggest that loss of 2-adrenergic receptor–mediated endothelial NO release could render such patients more vulnerable to hypoperfusion distal to a coronary artery stenosis during exercise by leaving postjunctional 2-adrenergic vasoconstriction unopposed.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by US Public Health Service grants HL-20598 and HL-34701 from the National Heart, Lung, and Blood Institute and a Grant in Aid from the Minnesota Affiliate of the American Heart Association. We wish to acknowledge the expert technical assistance of Todd Pavek, Melanie Crampton, Brian Jones, and Paul Lindstrom.
Received August 15, 1996; accepted November 19, 1996.
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