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Circulation. 1995;92:2291-2298

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(Circulation. 1995;92:2291-2298.)
© 1995 American Heart Association, Inc.

Articles

Vagal Modulation of Epicardial Coronary Artery Size in Dogs

A Two-Dimensional Intravascular Ultrasound Study

Presented in part at the 42nd Annual Scientific Session of the American College of Cardiology, Anaheim, Calif, March 14-18, 1993.

Julie A. Kovach, MD; John S. Gottdiener, MD; Richard L. Verrier, PhD

From the Department of Medicine, Division of Cardiology, and the Department of Pharmacology (R.L.V.), Georgetown University Hospital and School of Medicine, Washington, DC, and the Department of Medicine, Cardiovascular Division, New England Deaconess Hospital (R.L.V.), Harvard Medical School, Boston, Mass.

Correspondence to Richard L. Verrier, PhD, Institute for Prevention of Cardiovascular Disease, Deaconess Hospital, Harvard Medical School, 1 Autumn St, Boston, MA 02215.


*    Abstract
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 *Abstract
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Background Because the role of tonic vagus nerve activity in regulating conduit coronary artery size remains undefined, we investigated the response of epicardial coronary artery size to changes in resting vagal tone resulting from vagotomy and muscarinic receptor blockade.

Methods and Results Using intravascular ultrasound to measure left circumflex coronary artery cross-sectional area continuously, we examined the effects of vagotomy on left circumflex cross-sectional area in nine dogs. Lumen area decreased 20% from 8.70±2.81 to 6.92±1.97 mm2 after right vagotomy, 17% to 7.19±2.80 mm2 after left vagotomy (both P<.05 versus baseline), and 38% to 5.42±2.00 mm2 after bilateral vagotomy (P<.05 versus unilateral vagotomy). Vasoconstriction occurred despite increases in heart rate and an unchanged rate-pressure product. In six additional dogs, after acetylcholine (100 µg/kg IV), lumen area increased by 18%, although heart rate, blood pressure, and rate-pressure product were unchanged. Vasodilation was prevented by prior muscarinic blockade with glycopyrrolate. With glycopyrrolate administration and heart rate control by pacing, lumen area decreased by 26% (P=.011). When stellate stimulation was performed in a third group of eight dogs with heart rate, blood pressure, and rate-pressure product controlled by a combination of pacing and exsanguination, there was no change in coronary area, thus precluding reflex sympathetic activation as a contributor to the vasoconstriction produced by vagal withdrawal.

Conclusions Vagus nerve activity maintains tonic dilation of the left circumflex coronary artery by muscarinic receptor activation. Each vagus nerve contributes approximately equally to the tonically dilated state. Vagotomy-induced vasoconstriction occurs independently of local metabolic factors and coronary distending pressure and is a result of cholinergic withdrawal rather than reflex sympathetic activation.


Key Words: ultrasonics • vagus nerve • vasodilation • muscarinic receptors


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowDiscussion
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Although physiological and anatomic evidence of vagal innervation of coronary arteries was described as early as 1939,1 2 3 4 5 6 7 8 9 the role of the vagus nerve in regulating epicardial artery size and motion remains uncertain.

Earlier studies that evaluated the influence of the vagus nerve on coronary size10 11 required dissection of the coronary artery for instrumentation, which may have confounded results by mechanical disruption of pericoronary nerves. Two-dimensional intravascular ultrasound provides direct tomographic imaging of epicardial coronary arteries and accurate measurement of artery cross-sectional area12 13 14 without disruption of pericoronary nerves.

In this study, using intravascular ultrasound to measure epicardial coronary dimensions directly, we first determined the response of the coronary to unilateral and bilateral vagotomy. We then sought to establish the primary role of the cholinergic receptor in mediating this response by investigating the vasodilator response to acetylcholine before and after muscarinic receptor blockade with glycopyrrolate. To differentiate vagal efferent effects from possible reflex adrenergic mechanisms, we then performed unilateral followed by bilateral vagotomy after glycopyrrolate administration. In addition, to distinguish vagotomy-induced vasoconstriction from reflex sympathetic constrictor effects, we stimulated the left stellate ganglion in the baseline state and when the rate-pressure product and coronary distending pressure were controlled by a combination of pacing and exsanguination.


*    Methods
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 *Methods
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All animal studies were conducted in accordance with the guidelines of the NIH and the guiding principles of the American Physiological Society. Protocols were approved by the Georgetown University Animal Care and Use Committee. Experiments were conducted in 23 mongrel dogs of either sex (18 males, 5 females) ranging in weight from 25.6 to 34.4 kg. The animals were tranquilized with xylazine (1.1 mg/kg SC) and anesthetized with {alpha}-chloralose (100 mg/kg IV), with additional doses of {alpha}-chloralose as needed. Arterial PO2, PCO2, and pH were maintained in physiological ranges with a volume ventilator, supplemental oxygen, and intravenous sodium bicarbonate. Heart rate was monitored from the surface ECG, and blood pressure was monitored with a 5F Millar catheter placed in the ascending aorta through the left carotid artery and recorded on a strip-chart recorder (Gould, Inc). A left thoracotomy was performed in the fourth intercostal space. Sheaths (8F) were placed in the femoral artery and vein for angiography access and withdrawal of blood or infusion of fluid or medication. Blood losses were replaced with normal saline, and systemic anticoagulation with heparin was initiated (200 IU/kg IV, bolus) and maintained (50 IU/kg IV, hourly). In 9 dogs, both cervical vagi were exposed through bilateral neck incisions in preparation for vagotomy. In 6 additional dogs, the effects of vagotomy and muscarinic blockade were studied under closed-chest conditions with and without fixed-rate pacing by means of a 7F quadripolar catheter placed in the left ventricular outflow tract through a right carotid artery.

The effects of stellate ganglion stimulation on cross-sectional area were studied in the remaining 8 open-chest dogs. The left stellate ganglion and ansae subclavia were isolated and prepared for later stellate stimulation by gentle removal of overlying connective tissue with gauze. In this group of dogs, fixed-rate pacing was accomplished with a pair of stainless steel needle electrodes placed on the left atrial appendage for pacing.

Catheterization Protocol and Imaging System Description
Under fluoroscopic guidance, an 8F guiding catheter was used to engage the ostium of the left main coronary artery from either the right or left femoral artery with a minimum of contrast media. After heparinization, the ultrasound catheter (Interpret, Cardiovascular Imaging Systems) was introduced over the 0.014-in angioplasty guide wire into a stable position in the proximal to midleft circumflex coronary artery, where it remained for the entire protocol. The guiding catheter was withdrawn into the aorta so that flow into the coronary artery was not obstructed. Transducer position was confirmed frequently by fluoroscopy. Axial resolution of the single-element, mechanical intravascular ultrasound system is calculated to be 80 µm; lateral resolution is estimated to be 150 µm on the basis of transducer frequency and wavelength and the speed of sound in tissue. Ultrasound images were displayed on a video monitor and recorded at 30 frames per second on high-resolution super VHS videotape (0.5 in) for later off-line analysis.

Experimental Protocols
Effects of Unilateral and Bilateral Vagotomy
Baseline data of left circumflex cross-sectional area, phasic arterial blood pressure, and heart rate were recorded continuously for 2 minutes in 9 open-chest dogs. Either the left (n=6) or right (n=3) vagus was then divided and tied proximally and distally. To assess the sustained effects of parasympathetic withdrawal by vagotomy and to minimize the initial nonphysiological fluctuations in heart rate and blood pressure that can occur after nerve transection, 10-minute rest periods were allowed for hemodynamic stabilization. Then, intravascular ultrasound images, blood pressure, and heart rate were again recorded for 2 continuous minutes. The contralateral vagus was then divided and tied as described previously. After an additional 10-minute stabilization period, all variables were similarly recorded.

Effects of Muscarinic Stimulation and Blockade
In 6 closed-chest dogs, intravascular ultrasound images, heart rate, arterial pressure, and right atrial pressure were first recorded continuously for 2 minutes at baseline and then with ventricular pacing at a rate of 200 to 220 beats per minute (bpm). This rate was selected because it was approximately 10 bpm faster than the average rate obtained after glycopyrrolate administration. While pacing was continued, these variables were recorded continuously for an additional 5 minutes as acetylcholine (100 µg/kg IV; Miochol, Johnson & Johnson, IOLAB Pharmaceuticals) was administered as a bolus through the femoral vein. Pacing was then discontinued, and the dog was observed for a minimum of 10 minutes to ensure that all variables returned to their baseline values. Glycopyrrolate (100 µg/kg; Robinul, AH Robins Co) was then given as an intravenous bolus through the femoral vein. Glycopyrrolate was chosen because it has fairly rapid onset with a longer duration of action than atropine and therefore better simulates the sustained effects of vagal transection. Also, the quaternary ammonium structure of the compound limits passage through the blood-brain barrier, thus minimizing possible confounding central nervous system effects. After 20 to 30 minutes for hemodynamic stabilization, coronary images and hemodynamic variables were recorded for 2 minutes without and then with pacing. A second bolus dose of acetylcholine was infused. If a sinus pause, heart block, or vasodilation occurred, suggesting incomplete muscarinic blockade, a second dose of glycopyrrolate was infused. Of 6 dogs, 5 required a second dose of glycopyrrolate to block vasodilation, but only 1 dog had heart block after the first dose. After an additional 20-minute rest period, the variables described were recorded without and with pacing. Five dogs then underwent unilateral vagotomy (right in 2 dogs and left in 3 dogs) followed by bilateral vagotomy. After a 10-minute stabilization period, coronary images and hemodynamic variables were recorded continuously for 2 minutes after each intervention. Heart rate after vagotomy exceeded 200 bpm in every dog; thus, pacing was not performed.

Effects of Left Stellate Ganglion Stimulation
These experiments were performed in 8 open-chest dogs to evaluate the contribution of reflex sympathetic activation to the observed vagotomy-induced coronary vasoconstriction. Intravascular ultrasound images and hemodynamic variables were recorded continuously at baseline for 2 minutes. As described,15 left stellate ganglion and ansae subclavia stimulation with a bipolar electrode using 10-V impulses of 10-millisecond duration at a frequency of 10 Hz (Grass S44 stimulator) was performed until the mean arterial pressure increased by at least 25 mm Hg and was continued for an additional 30 seconds after it reached a plateau. Intravascular ultrasound images and hemodynamic variables were recorded continuously during and after stimulation until all parameters returned to baseline values. Atrial pacing at 180 bpm was then established to approximate the peak heart rate achieved with previous stellate stimulation. When a plateau blood pressure response was attained, controlled exsanguination was accomplished16 by withdrawal of blood through the femoral venous sheath until blood pressure returned to baseline values. Stellate stimulation was terminated after 30 seconds of exsanguination, and the blood was reinfused.

Data and Statistical Analyses
Cross-sectional images of the coronary artery recorded on videotape were reviewed. Timers on the video and strip-chart recorders allowed precise coordination of hemodynamic data with the specific cross-sectional ultrasound image. The single frame depicting the largest lumen of the selected cardiac cycle, representing systole as determined by other investigators, was digitized with software from the intravascular ultrasound system.17 18 Lumen cross-sectional area at the intimal boundary echo was traced with a trackball, and cross-sectional area was calculated by computerized planimetry. Measurements were made by two independent observers. Interobserver and intraobserver reliabilities for lumen area were established previously in our laboratory (r=.96 and r=.97, respectively). Cross-sectional area measurements were made at time 0 and at 10-second intervals for 2 minutes at baseline and after each intervention; thus, 12 values were averaged for each dog and compared. Because no atrial or ventricular premature beats were observed, no beats were eliminated from analysis. Heart rate and arterial and right atrial pressures were determined at the time of measurement of each ultrasound image. The product of heart rate and systolic pressure was calculated to provide an index of metabolic activity. Lumen area, heart rate, and blood pressure were determined at 1-second intervals during and after acetylcholine administration and during stellate stimulation both without and with control of the rate-pressure product and coronary distending pressure.

Statistical analysis was performed by use of STATA software package version 3 (Computer Resource Center). Variables measured before and after unilateral and bilateral vagotomy were analyzed with ANOVA for repeated measures, with post hoc analysis by the Student-Newman-Keuls test. Results from acetylcholine infusion before and after muscarinic blockade were analyzed similarly. Variables measured before and at peak response to stellate stimulation without and with rate-pressure product control were compared by use of Student's t test. Values are presented as mean±SEM. A value of P<.05 was considered statistically significant.


*    Results
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*Results
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Effect of Vagotomy
The effects of unilateral and bilateral vagotomy on coronary artery cross-sectional area and hemodynamic variables are given in Table 1Down. Of note, right and left cervical vagotomy resulted in comparable decreases (20% and 17%, respectively) in left circumflex coronary artery area. Transection of the contralateral vagus resulted in decreases that were additive, a 38% total reduction in cross-sectional area over baseline. Heart rate increased after right and bilateral vagotomy (P<.05), but the rate-pressure product was not significantly changed. An intravascular ultrasound image from one dog is shown in Fig 1Down.


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  		Table 1. Effects of Unilateral and Bilateral Vagotomy



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  		Figure 1. Intravascular ultrasound images showing the vasoconstrictor effect of vagotomy on left circumflex lumen cross-sectional area. The catheter and guide-wire artifact are visible within the lumen of the artery in each image. A, The left circumflex coronary artery at baseline with a lumen cross-sectional area of 8.7 mm2. B, The left circumflex coronary artery 10 minutes after left vagotomy (cross-sectional area, 6.1 mm2). C, The left circumflex coronary artery 10 minutes after bilateral vagotomy (cross-sectional area, 4.7 mm2).

Effect of Increases in Heart Rate
Table 2Down summarizes the effect of ventricular pacing on coronary size. Left circumflex coronary artery cross-sectional area did not change with pacing at rates of 200 to 210 bpm. Increases in rate-pressure product caused by increases in heart rate were attenuated by decreases in systolic and diastolic pressures. Pacing increased right atrial pressure, a measure of distending pressure,7 from 5±1 to 8±1 mm Hg.


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  		Table 2. Effects of Ventricular Pacing

Effects of Acetylcholine
Lumen area increased by 18% after acetylcholine administration, from 8.92±0.90 to 10.53±0.70 mm2, with maximum dilation occurring approximately 15 seconds after central venous administration. An ultrasound image illustrating this response is shown in Fig 2Down. At the time of peak vasodilation, heart rate (paced at 200 bpm), systolic pressure (122±17 versus 122±18 mm Hg, P=.96), and rate-pressure product (24 020±4817 versus 23 140±2904, P=.78) were not significantly different from baseline. Vasodilation did not occur with acetylcholine administration after prior administration of glycopyrrolate. Lumen cross-sectional area in response to acetylcholine was 7.05±0.95 mm2 compared with 6.92±0.89 mm2 at baseline (P=.70).



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  		Figure 2. Intravascular ultrasound images showing an increase in left circumflex coronary artery cross-sectional area in response to acetylcholine. Vasodilation did not occur after muscarinic blockade with glycopyrrolate. A, The left circumflex coronary artery at baseline in which cross-sectional area measures 8.8 mm2. B, The left circumflex coronary artery 15 seconds after administration of intravenous acetylcholine (100 µg/kg; cross-sectional area, 10.8 mm2). C, The left circumflex coronary artery 35 seconds after acetylcholine (cross-sectional area, 7.8 mm2). D, E, and F, The same artery after administration of glycopyrrolate at baseline and 15 and 35 seconds after acetylcholine administration in which left circumflex coronary artery cross-sectional area was 6.8, 7.1, and 7.0 mm2, respectively.

Effect of Vagotomy After Glycopyrrolate Administration
The hemodynamic and vasomotor responses to vagotomy after muscarinic blockade, including sample ultrasound images, are presented in Figs 3 through 5DownDownDown. Unpaced heart rate increased from 110±18 to 165±26 bpm after glycopyrrolate administration and increased further to 201±25 bpm after bilateral vagotomy (P<.05 for each). Although systolic pressure decreased with pacing compared with the unpaced state, no significant changes from baseline occurred in blood pressure or rate-pressure product with pacing after glycopyrrolate administration when heart rate was controlled by pacing or after vagotomy. Left circumflex coronary artery cross-sectional area decreased 26% from 8.96±1.18 to 6.62±0.69 mm2 after glycopyrrolate administration (P=.011). There was no further change in lumen cross-sectional area with subsequent unilateral or bilateral vagotomy.



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  		Figure 3. Bar graphs showing the effects of vagotomy and glycopyrrolate on lumen cross-sectional area (CSA) and rate-pressure product (RPP). Results were obtained with and without pacing. Glycopyrrolate decreased coronary artery cross-sectional area by 26%. This occurred while the rate-pressure product was unchanged. There was no significant change in cross-sectional area when vagotomy followed glycopyrrolate. n=6. Values are mean±SEM. *P=.011 vs baseline.



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  		Figure 4. Bar graphs showing the effect of vagotomy and glycopyrrolate on heart rate (HR), right atrial pressure (RAP), and systolic blood pressure (SBP) without and with pacing. Spontaneous heart rate (HR) increased from 110±18 to 165±26 beats per minute (bpm) after glycopyrrolate administration and increased further to 201±25 bpm after bilateral vagotomy. Systolic blood pressure was lower with pacing, whereas right atrial pressure was higher. This resulted in an unchanged rate-pressure product. n=6. Values are mean±SEM. *P<.05 vs baseline unpaced.



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  		Figure 5. Intravascular ultrasound images showing the left circumflex coronary artery in a single animal before and after glycopyrrolate administration followed by vagotomy without and with ventricular pacing. A and B, The left circumflex coronary artery at baseline without and with pacing. Lumen cross-sectional area was unchanged by pacing (15.5 vs 15.1 mm2). C and D, Vasoconstriction after glycopyrrolate administration in both the unpaced (cross-sectional area, 9.2 mm2) and paced (cross-sectional area, 9.4 mm2) condition. E and F, The absence of further vasoconstriction 10 minutes after left cervical vagotomy (cross-sectional area, 8.9 mm2) and bilateral vagotomy (cross-sectional area, 9.1 mm2), respectively.

Effect of Stellate Stimulation
The hemodynamic and ultrasound results of stellate stimulation in the baseline state and when heart rate, rate-pressure product, and distending pressure were controlled are presented in Fig 6Down. During stellate stimulation, lumen area increased 62% from 5.98±0.76 to 9.68±1.21 mm2 (P=.0003), while heart rate increased from 145±12 to 194±11 bpm (P=.00008), systolic pressure increased from 111±7 to 159±11 mm Hg (P=.00001), and rate-pressure product increased from 16 581±2328 to 31 396±3704 bpm · mm Hg (P=.00006). Left circumflex coronary artery cross-sectional area did not change significantly when heart rate, rate-pressure product, and distending pressure were controlled by pacing and exsanguination.



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  		Figure 6. Bar graphs showing the effects of stellate stimulation on left circumflex lumen cross-sectional area (CSA), heart rate (HR), systolic blood pressure (SBP), and rate-pressure product (RPP) before and after control of rate-pressure product (Uncontrolled and Controlled, respectively) by ventricular pacing and graded exsanguination. Stellate stimulation increased coronary artery cross-sectional area by 62%. This increase did not occur when rate-pressure product was controlled. n=8. Values are mean±SEM. *P<.001 vs baseline uncontrolled.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
This study, which used two-dimensional intravascular ultrasound to measure left circumflex coronary artery cross-sectional area directly, provides evidence of tonic vagal modulation of epicardial coronary artery size in anesthetized dogs. This finding is consistent with several lines of evidence from previous investigators who employed various cholinesterase staining techniques to demonstrate that cholinergic fibers form a perivascular network closely applied to the medial-adventitial junction and presumably serve as parasympathetic mediators of vascular smooth muscle tone.2 3 4 Several investigators demonstrated increases in coronary flow in dogs and baboons in response both to acetylcholine19 and to vagal stimulation.5 6 7 8 After dissecting the coronary artery and implanting ultrasonic transducers on the adventitial surfaces of the artery, Cox et al10 demonstrated increases in epicardial artery diameter in response to intravenous acetylcholine in conscious dogs. Acetylcholine-induced vasodilation was confirmed angiographically in normal human coronary arteries.19 20 21 22 However, direct vasodilation of large conduit coronary arteries has not been demonstrated with vagal stimulation. Gerova et al11 demonstrated increases in coronary size with acetylcholine administration but not in response to vagal stimulation in a fibrillating canine heart model with inductive transformers implanted on the epicardial coronary to measure external artery diameter. Because increases in coronary flow in response to vagal stimulation have been observed without increases in conduit artery diameter, it has been thought that the vagally mediated vasodilation occurs primarily in resistance vessels and not in large coronary arteries.9 Using intravascular ultrasound to obviate pericoronary nerve damage, we observed vasoconstriction of large epicardial coronary arteries resulting from vagotomy.

The observation that vagotomy results in coronary vasoconstriction in anesthetized dogs suggests vagal modulation of coronary tone. This finding is supported by the results of recent studies in conscious dogs that implicated parasympathetic modulation of coronary flow during sleep8 and in the presence of cocaine-induced vasoconstriction.23 In our laboratory, Dickerson and colleagues8 demonstrated vagally induced surges in coronary flow associated with pauses in heart rhythm during sleep and further established that these surges were eliminated after disruption of pericoronary nerves produced by gentle crushing followed by formalin. Shannon et al23 showed in conscious dogs that the vasoconstrictor effects of cocaine were attenuated by cholinergic blockade. Tonic vagally induced vasodilation of the coronary artery may have permitted more robust vasoconstriction attributable to {alpha}-adrenergic activation by cocaine, or pretreatment with muscarinic blockers may have produced vasoconstriction, which then attenuated further vasoconstriction by cocaine.

When glycopyrrolate was administered during pacing, right atrial pressure did not increase. Ventricular pacing was shown to result in minor negative inotropic effects that may increase right atrial pressure.24 Glycopyrrolate, by blocking parasympathetic influences on the myocardium and thus allowing unopposed sympathetic myocardial effects, may have attenuated this negative inotropy and prevented the associated rise in right atrial pressure that occurred with ventricular pacing.25

In our study in which heart rate was controlled by pacing and the rate-pressure product was unchanged from baseline, vagotomy induced vasoconstriction. This suggests that tonic vasodilation is the result of parasympathetic influences and not local metabolic factors. This conclusion is supported by studies by Shannon et al23 in which cholinergic blockade attenuated cocaine-induced vasoconstriction in dogs in both the absence and presence of ß-blockade to control metabolic demand.

Right and left vagotomy resulted in a similar degree of constriction of the left circumflex coronary artery, although right vagotomy resulted in more tachycardia than left vagotomy. Bilateral cervical vagal transection produced vasoconstriction that was nearly additive. Although these findings challenge previous assumptions of the unilateral nature of coronary innervation, in which the left vagus serves primarily the left circumflex coronary artery, they are in agreement with the study of Bhagat and colleagues,26 who demonstrated a bilateral effect of vagal stimulation on coronary flow in dogs. Our finding of more lateralized effects of vagal innervation on the sinus node than on coronary size also confirms the anatomic experiments of Denn and Stone,3 who noted that cholinergic fibers do not cross over from the atria, where the right vagus nerve modulates sinus node discharge, to innervate the coronary arteries. They concluded that cholinergic fibers probably arise from intrinsic ganglia located near the base of the aorta and course longitudinally along the coronary arteries.

Our observation of an 18% increase in epicardial coronary artery lumen area in response to central venous administration of acetylcholine is in accord with the findings of Cox and colleagues,10 who measured epicardial coronary diameter response to acetylcholine infusion with ultrasound transducers implanted on the left circumflex coronary artery in conscious dogs and baboons. Our findings that muscarinic blockade completely abolished the vasodilation resulting from acetylcholine establish the muscarinic receptor as the mediator for parasympathetic vasodilation; these findings are also in agreement with those of Cox et al10 and Feigl5 on vagal stimulation in dogs.

An important new observation is that glycopyrrolate administration, like vagotomy, caused significant vasoconstriction when heart rate, metabolic factors, and distending pressure were unchanged, whereas vagotomy performed after glycopyrrolate administration produced no further change in cross-sectional area. This provides evidence that a direct vagal mechanism produces tonic dilation in the anesthetized state. If vasoconstriction were due to reflex sympathetic activation, vagotomy after muscarinic blockade would have resulted in further changes in lumen cross-sectional area. This did not occur. Additional evidence that reflex sympathetic mechanisms did not play a role in vagotomy-induced vasoconstriction is provided by our studies that demonstrate that vasoconstriction did not occur with direct stellate stimulation when metabolic factors and distending pressure were controlled by pacing and exsanguination.

Transection of the vagus nerve may interrupt reflex neural pathways from aortic and carotid baroreceptors, chemoreceptors, and ventricular mechanoreceptors. Activation of these receptors by hypertension, hypoxemia, hypercarbia, or myocardial bulging from ischemia, respectively, results in reflex inhibition of sympathetic tone with parasympathetically mediated increases in coronary flow.27 28 29 30 It is unlikely that any of these receptors were activated significantly in our preparation because vasodilation was not increased over the resting state. Systolic pressure at baseline was only 117±13 mm Hg; hypoxemia and hypercarbia were controlled by appropriate ventilation and administration of bicarbonate; and there was no evidence of ischemia on the ECG. However, if these receptors had been activated before vagotomy, then interrupting these afferents might produce coronary vasoconstriction as a result of loss of parasympathetically mediated vasodilation. This conclusion agrees with our findings that vagotomy results in epicardial vasoconstriction.

Several investigators recently demonstrated that activation of muscarinic receptors by both acetylcholine and vagal stimulation results in increases in coronary flow that are mediated by the endothelium-derived relaxing factor (EDRF) nitric oxide and attenuated or abolished by its antagonists.31 32 33 Chu et al34 found evidence for tonic vasodilation of conduit coronary arteries mediated by nitric oxide in conscious dogs and showed a reduction in epicardial coronary artery diameter of 5.5% with blockade of EDRF synthesis. This reduction in coronary diameter agrees with the reductions in left circumflex coronary area we found when tonic influences of vagal activity were removed by vagotomy. The possibility that parasympathetic withdrawal induces reductions in EDRF that then produce vasoconstriction deserves further study.

Although sympathetic cholinergic dilation, such as occurs in vessels in the skeletal muscle of some animals,35 remains a possible explanation for vagally mediated tonic dilation of the coronaries, no evidence for sympathetic cholinergic dilation of coronary arteries has been found in studies using stellate stimulation after depletion of catecholamines with reserpine or adrenergic receptor blockade in dogs36 or after atropine administration in cats.37

Study Limitations
Changes in cross-sectional area observed in response to autonomic stimulation and blockade may result in part from an influence of chloralose anesthesia on the tonic activity of the vagus nerve. This is unlikely to be a significant factor because there was no indication of excess vagal tone, ie, bradycardia, PR prolongation, or AV block, in any dog when baseline measurements were made. Also, Cox38 observed that chloralose anesthesia, unlike pentobarbital, does not disrupt baseline hemodynamic variables.

Coronary flow was not measured in the present study. Rather, we focused on cross-sectional area changes and used intravascular ultrasound to avoid potential disruption of the pericoronary nerves, which can occur when devices are attached to vascular adventitia. To the best of our knowledge, this is the first study to describe the tonic effects of the autonomic nervous system on the cross-sectional area of conduit arteries. Previous studies of vascular diameter relied exclusively on intravenous administration of autonomic agonists and antagonists to stimulate the coronary vasculature. Accordingly, we deemed it essential to maximize the conditions for detecting a change in cross-sectional area without the risk of blunting the response by pericoronary nerve damage. With recent advances in intracoronary Doppler ultrasound guide wires used with intravascular two-dimensional ultrasound, it is possible to measure simultaneous effects of neurogenic intervention on both conduit artery size and total coronary flow.39 40 41 This will aid in evaluating autonomic control of coronary tone, eg, in differentiating effects on epicardial coronary arteries from those on resistance vessels as demonstrated with adenosine by Sudhir et al.39 40

Clinical Implications
Vagal modulation of conduit coronary artery tone may play an important role in the maintenance of myocardial perfusion in health and disease. The potential improvement in coronary flow during myocardial ischemia could contribute to the antifibrillatory influence of vagal stimulation observed in conscious and anesthetized animals during myocardial ischemia with and without a prior healed infarction.42 43 Acetylcholine was shown to dilate normal human coronary artery segments but to produce vasoconstriction in atherosclerotic segments.19 20 21 This is presumably due to an impairment in release of EDRF from the damaged endothelium. Thus, whether tonic vagal activity exerts a salutary influence on myocardial perfusion and arrhythmogenesis during acute myocardial ischemia may depend in part on the extent of atherosclerotic disease in the vessel wall.

Conclusions
Our results indicate that the vagus nerves modulate epicardial coronary artery size in anesthetized dogs, with each contributing approximately equally to the maintenance of tonically dilated tone. Dilation occurs independently of local metabolic factors and distending pressure and is mediated by cholinergic receptors. Because epicardial coronary artery constriction also occurred in response to muscarinic blockade, did not worsen after subsequent vagotomy, and was not reproduced by direct neural sympathetic stimulation, it appears that this vasodilation is directly mediated by the vagus and not by reflex sympathetic mechanisms.


*    Acknowledgments
 
This work was supported by grants HL-33567 and HL-50078 from the NHLBI, NIH, Bethesda, Md. We thank Marian M. Thurnher for her technical and surgical expertise and Sandra S. Verrier for her editorial contributions.

Received June 24, 1994; revision received April 25, 1995; accepted May 3, 1995.


*    References
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*References
 

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