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Cardiovascular Research 1998 40(1):45-55; doi:10.1016/S0008-6363(98)00122-9
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Vagal nerve stimulation releases vasoactive intestinal peptide which significantly increases coronary artery blood flow

Lillybeth Feliciano and Robert J. Henning*

University of South Florida College of Medicine, Division of Cardiology, Department of Medicine and the James A. Haley Veterans' Administration Hospital, Tampa, FL, USA

* Corresponding author. Tel.: +1 (813) 978 5873; Fax: +1 (813) 978 5884.

Received 9 December 1997; accepted 11 March 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Protocol
 4 Statistical analysis
 5 Results
 6 Discussion
 References
 
Objective: To determine the effects of vasoactive intestinal peptide (VIP), released endogenously from cardiac vagal nerves, on coronary artery blood flow (CBF). Methods: We determined the effects of vagal nerve stimulation (VNS) at frequencies of 10, 15, 20, and 30 Hz on left circumflex coronary artery (LCx) blood flow. The increases in CBF during VNS were compared with the increases in CBF produced by exogenous VIP and also nitroglycerin (NTG). In 18 anesthetized open chest mongrel dogs, we blocked the muscarinic and β-adrenergic receptors with atropine and propranolol. We controlled heart rate and aortic pressure by right atrial pacing and an arterial reservoir. CBF was measured in the LCx with a Doppler flow probe. A 25 gauge catheter was placed in the proximal LCx to inject the VIP receptor antagonist [4Cl-D-Phe6Leu17]VIP, VIP, NTG, or vehicle. CBF, aortic and ventricular pressures, ventricular contractility (+dp/dtmax) and relaxation (–dp/dtmin) and the EKG were measured. Results: VNS (0.5 ms, 20 V, 5 min.) at 20 Hz maximally increased CBF by 62±14% at 5 min from 71±10 to 115±19 ml/min (p<0.01). VNS at 10, 15, and 30 Hz increased CBF by 6±1%, 24±5%, and 24±7%, respectively (all p<0.05 vs control). Following 20 Hz VNS, CBF returned toward the baseline over 30 min. Aortic and left ventricular (LV) pressures, LV +dp/dtmax and LV –dp/dtmin did not significantly change. After the direct administration of [4Cl-D-Phe6Leu17]VIP into the LCx, VNS increased CBF by only 10±4% (p=NS). Exogenous VIP, in doses of 9.0x10–11 to 2.1x10–9 mol, increased CBF by 106±17% to 169±17% (all p<0.01 vs control). NTG, in doses of 2.2x10–8 to 1.7x10–7 mol, increased CBF by 101±15% to 169±20% (all p<0.01 vs control). These increases in CBF persisted during the 1 to 2 min injection period and returned to the baseline within 5 min. Neither VIP nor NTG significantly changed the heart rate, aortic or LV pressures, LV +dp/dtmax or LV –dp/dtmin. VNS at 20 Hz, exogenous VIP, 9.0x10–11 mol, and exogenous NTG, 2.2x10–8 to 4.4x10–8 mol, produced equivalent increases in CBF by analysis of variance determination. Conclusion: The present experiments suggest that VNS releases VIP which directly dilates coronary arteries and significantly increases coronary artery blood flow.

KEYWORDS Coronary artery blood flow; Vasoactive intestinal peptide; Non-cholinergic non-adrenergic nerve stimulation; Neural regulation; Nitroglycerin; Mongrel dog


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Protocol
 4 Statistical analysis
 5 Results
 6 Discussion
 References
 
Vasoactive intestinal peptide (VIP) is present in the post-ganglionic parasympathetic (vagal) and intrinsic nerve fibers in the heart [1, 2]. VIP nerve fibers are found in the coronary arteries, sinoatrial and atrioventricular nodes, atrial myocardium and right ventricle [3–9]. In these fibers, VIP is stored in large dense core vesicles and is released by high frequency (15–20 Hz) vagal nerve stimulation [1, 2, 10, 11]. In contrast, VIP nerve fibers are uncommon or absent in the left ventricle [1, 4, 6].

We have shown that high frequency (20 Hz) vagal nerve stimulation, in the presence of muscarinic and β-adrenergic receptor blockade, releases VIP from cardiac vagal nerves which significantly increases right atrial contractility, right ventricular contractility and relaxation, and the heart rate [12, 13]. In contrast, no significant changes in left ventricular contractility or relaxation occur during vagal nerve stimulation [13]. The increases in right atrial contractility and right ventricular contractility and relaxation during vagal nerve stimulation are independent of changes in the heart rate [12, 13]. However these changes are dependent on the frequency of vagal nerve stimulation [12, 13]. In this regard, the maximum increases in right atrial contractility, right ventricular contractility and relaxation, and heart rate occur during vagal nerve stimulation at a frequency of 20 Hz whereas stimulation with frequencies greater than 20 Hz produce smaller but significant increases in these parameters [12, 13]. Moreover, the vagal induced increases in right heart function and heart rate are significantly reduced by [4Cl-D-Phe6Leu17]VIP, which is a sensitive and selective VIP receptor antagonist [12–19].

The effects of VIP released endogenously from cardiac vagal nerves on coronary blood flow (CBF) are not known. Moreover, the effects of endogenously released VIP on CBF have not been compared with the effects of exogenous VIP or nitroglycerin (NTG). We therefore wished to determine whether VIP produces coronary artery vasodilation that is similar to NTG. Nitroglycerin, which produces significant vasodilation, is commonly used in patients with atherosclerotic coronary artery disease and the mechanisms of action of NTG are known [1, 5, 20–25]. In addition, the effects of NTG on the coronary arteries occur in the absence of any significant increases in myocardial oxygen consumption [1, 5, 21–25]. We wished to determine if VIP acts in the coronary arteries through specific receptors and if blockade of these receptors affects NTG-induced increases in CBF. The absence of any significant effects of VIP-receptor blockade on NTG-induced increases in CBF would suggest that VIP dilates coronary arteries by a mechanism that is different from NTG.

We therefore designed the present study to answer the following questions:

1. Does cardiac vagal nerve stimulation in the presence of muscarinic and β-adrenergic blockade, significantly increase CBF? Are the changes in CBF similar to the changes in CBF produced by exogenous VIP and also NTG?
2. Does cardiac vagal nerve stimulation increase CBF in the absence of any changes in heart rate, aortic and left ventricular pressures, and left ventricular contractility and relaxation?
3. Does [4Cl-D-Phe6Leu17]VIP, a sensitive and selective VIP receptor antagonist, block any changes in CBF produced by vagal nerve stimulation or by NTG?

The results of our experiments are documented in the present report.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Protocol
 4 Statistical analysis
 5 Results
 6 Discussion
 References
 
Experiments were performed on mongrel dogs of either sex with an average weight of 23±1 kg. All experiments conformed to the guidelines established by the National Institutes of Health for animal care and use and were approved by the animal care and use committee of our medical center. Each dog was sedated with morphine sulfate (1.5 mg/kg, i.m.) and anesthetized with alpha-chloralose (100 mg/kg, i.v.). Alpha-chloralose (100 mg/hr) was continuously infused throughout the experiments to insure adequate surgical anesthesia. The depth of anesthesia was verified by the absence of a corneal reflex and by coverage of the eye by the nictitating membrane. Each animal was ventilated through an endotracheal tube connected to a positive pressure ventilator (Harvard Apparatus). Supplemental oxygen was given to maintain the arterial blood oxygen saturation greater than 95%. A femoral vein was isolated and cannulated with polyethylene tubing for fluid administration and sodium bicarbonate was given to maintain the arterial pH between 7.35 and 7.45. Hetastarch in 0.9% sodium chloride was given continuously i.v. to replace fluid losses. The left femoral artery was isolated and cannulated with polyethylene pressure tubing (NAMIC) to continuously monitor aortic pressure and permit blood gas measurements. Arterial blood gas tensions, bicarbonate concentration, and pH were measured at the initiation of each experiment and every one hour thereafter. In addition, a surface electrocardiogram was monitored throughout the experiments. The body temperature was maintained between 37 and 39°C with a heating pad and a heat lamp.

The chest of each animal was opened transversely through the right and left fourth intercostal spaces. The right and left thoracic ansa subclaviae were ligated and transected to interrupt sympathetic nerve transmission to the heart. In addition, the right and left thoracic vagi were transected immediately above the diaphragm. In order to maintain the systemic arterial and coronary perfusion pressures at a constant level during the experiments, a 22-French polyethylene cannula was inserted through the left subclavian artery into the ascending aorta and placed immediately above the aortic valve. The cannula was connected by wide-bore, low resistance Tygon tubing to a 1000 ml reservoir. The reservoir was then adjusted to a height that maintained the mean aortic pressure at a constant level. The LCx was carefully exposed, and a 22 gauge coronary artery cannula (Becton Dickinson) was inserted into the proximal portion of the artery to permit the injection of the VIP antagonist [4Cl-D-Phe6Leu17]VIP, VIP, NTG, or vehicle. The intracoronary injections were performed over 1 to 2 min in order to avoid any coronary artery perturbations. Distal to the coronary artery cannula, a 10 MHz Doppler flow probe (Triton) was carefully placed around the LCx to measure arterial blood flow. Prior to and at the end of each experiment, an electrical calibration of the Doppler flow probe was performed. The pressures in the left and right ventricles (LV and RV) were measured with pressure-tipped transducers (Millar, PC 350) that were inserted through the free walls of each ventricle. The first derivative of LV and RV pressures, dp/dt, was determined by electronic differentiation of the ventricular pressure waveforms (Gould Electronics). The maximum rates of pressure rise, +dp/dtmax, and fall, –dp/dtmin, were used as indices of ventricular contractility and relaxation, respectively. Each Millar catheter was calibrated at 38±0.5°C against a mercury column prior to insertion into the ventricles.

In series 1 and series 2 experiments, a midline cervical incision was performed in each dog and the right and left cervical vagus nerves were isolated and transected. The cardiac ends of the right and left vagus nerves were placed in bipolar electrodes (Harvard) which were connected to an electronic stimulator for subsequent stimulation (Grass, models 44). The distal portions of the electrodes were covered with petrolatum jelly and also mineral oil to provide insulation.

Coronary blood flow, aortic, LV and RV systolic and end-diastolic pressures, LV and RV +dp/dtmax and –dp/dtmin, and the EKG were continuously recorded on a direct writing oscillograph (Gould, TA 5000). A minimum of 20 consecutive waveforms of CBF, aortic and ventricular pressures, dp/dt and EKG were recorded prior to, at the end of each minute of five continuous minutes of vagal nerve stimulation, and at five, ten, twenty and thirty minutes after the cessation of vagal stimulation. In series 2, 3 and 4 experiments, CBF, aortic and ventricular pressures, dp/dt and the EKG were continuously measured prior to, during, and following the administration of the VIP receptor antagonist, VIP, NTG or vehicle.


   3 Protocol
Top
 Abstract
 1 Introduction
 2 Methods
 3 Protocol
4 Statistical analysis
 5 Results
 6 Discussion
 References
 
In each dog, the muscarinic and β-adrenergic receptors were blocked with an initial bolus of i.v. atropine, 0.5 mg/kg, and propranolol, 1 mg/kg, respectively. Subsequently, atropine, 0.2 mg/kg/hr, and propranolol, 0.5 to 1 mg/kg/hr, were continuously infused during the experiments to insure adequate muscarinic and β-adrenergic receptor blockade. The muscarinic receptor blockade was considered to be adequate in each dog if the heart rate did not decrease during vagal nerve stimulation (20 Hz, 0.5 ms, 15 V) for 30 s. The β-adrenergic blockade was considered adequate if ventricular contractility and heart rate did not increase during ansa sublclavia nerve stimulation (1 to 3 Hz, 5 ms, 15 V) for 30 s [12, 13].

In series 1 and in series 2 experiments, each vagal nerve stimulation consisted of 5 min of continuous square-wave pulses (0.5 ms, 20 V). The heart rate in these dogs was controlled by pacing the right atrium with an electronic stimulator (Grass S88). To avoid increases in the heart rate above our pacing rate during vagal stimulation, the sinoatrial node was cooled with liquid nitrogen which was circulated through a 1.5 cm. metallic disk positioned over the sinoatrial node. The efficacy of sinoatrial node cooling was determined by the absence of any significant increase in the heart rate during vagal nerve stimulation in the dogs with muscarinic and β-adrenergic blockade. This procedure has been previously used by other investigators [26]and permitted right atrial pacing at a constant rate and did not affect any other hemodynamic parameter or the electrocardiogram. In these experiments, the right atrium was paced at an average rate of 173±2 beats/min in order to reproduce the heart rates that we had previously observed with vagally released VIP and that other investigators had reported with exogenous VIP administration [12, 13, 27]. We wished to determine if during rapid heart rates, when the metabolic state of the heart is increased and therefore CBF is increased, whether further significant increases in CBF occur in response to vagal nerve stimulation. There were 18 dogs in the series 1 experiments which were randomized to right and left cervical vagus nerve stimulation at frequencies of 10, 15, 20 or 30 Hz for five minutes at each frequency. We used the increases in RV +dp/dtmax and –dp/dtmin during vagal nerve stimulation as a biological measure of VIP release in the heart [13]. To avoid any possible depletion of VIP from cardiac vagal nerves during repetitive vagal stimulations [28], only two vagal nerve stimulations were performed in each animal.

In the series 2 experiments, vagal nerve stimulation was performed after the injection of 8±1 µg/kg [4Cl-D-Phe6Leu17]VIP (Bachem), a sensitive and selective VIP receptor antagonist [12–19]. In the first part of series 2 experiments, the VIP antagonist was directly injected into the LCx of 3 dogs. Direct injection of the VIP antagonist into the LCx does not affect the changes in right ventricular +dp/dtmax and –dp/dtmin during vagal nerve stimulation because the LCx of the dog perfuses primarily the lateral and posterior walls of the left ventricle [29]. In the second part of series 2 experiments, the VIP antagonist was directly injected into the right coronary artery of three separate dogs. The VIP antagonist was dissolved in 0.9% sodium chloride and injected in a total volume of 1 ml. The control injection consisted of 1 ml of 0.9% sodium chloride without the antagonist. Thirty minutes after each injection, we measured mean CBF, aortic and ventricular pressures, LV and RV contractility and relaxation and the EKG during five minutes of continuous 20 Hz vagal nerve stimulation.

In the series 3 experiments, we examined the effects of exogenous VIP administered directly into the LCx. VIP was injected in a randomized manner in doses of 9.0x10–11 mol (n=4), 1.8x10–10 mol (n=4), 2.7x10–10 mol (n=5), 3.3x10–10 mol (n=5), 3.9x10–10 mol (n=6), 6.0x10–10 mol (n=7), 7.5x10–10 mol (n=6), 1.5x10–9 mol (n=4), and 2.1x10–9 mol (n=3) and the changes in CBF were measured. VIP was dissolved in 0.9% sodium chloride and a total volume of 1 ml was injected. The control injection consisted of 1 ml of 0.9% sodium chloride without VIP. In the series 4 experiments, we injected NTG, in doses of 2.2x10–8 mol (n=6), 4.4x10–8 mol (n=13), 8.8x10–8 mol (n=7) and 1.7x10–7 mol (n=6), and measured the changes in CBF. NTG was dissolved in 0.9% saline and a total volume of 1 ml was injected. The control injection consisted of 1 ml of 0.9% sodium chloride without NTG. The doses of VIP and NTG were chosen in order to assess changes in CBF without producing significant peripheral vascular effects. CBF, aortic and ventricular pressures, LV and RV contractility and relaxation and the EKG were continuously measured prior to, during and after the injection of either VIP, NTG or vehicle. We then compared the effects of exogenous VIP and NTG with the effects of vagal nerve stimulation, during muscarinic and β-adrenergic receptor blockade, on CBF.


   4 Statistical analysis
Top
 Abstract
 1 Introduction
 2 Methods
 3 Protocol
 4 Statistical analysis
5 Results
 6 Discussion
 References
 
Mean values±the standard error of the mean (S.E.M.) are presented. We evaluated the statistical significance of our data by repeated measures analyses of variance (ANOVA) [30]. The maximal changes in mean CBF and RV contractility and relaxation in comparison with the baseline values were evaluated by a paired Student's t test. The Bonferroni modified t test was used to test for differences between specific means [30]. The mean CBF and right ventricular contractility and relaxation during the control periods were normalized to 100% because of some variability among the mongrel dogs in these measurements prior to any intervention. The circumflex mean CBF and right ventricular contractility and relaxation measurements were then expressed as percentage of the control value. Polynomial and linear regression analyses of the changes in CBF during exogenous VIP and also NTG were also performed [30]. In all our experiments, a value of p<0.05 was considered significant.


   5 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Protocol
 4 Statistical analysis
 5 Results
6 Discussion
 References
 
5.1 Series 1. Effects of vagal nerve stimulation on circumflex CBF during controlled heart rate and mean arterial pressure
In the series 1 experiments, we paced the right atrium at a rate that averaged 173±2 beats/min and stimulated the cardiac ends of the right and left cervical vagus nerves at frequencies of 10, 15, 20 or 30 Hz for five minutes at each frequency. Prior to and during vagal nerve stimulation, the mean aortic pressure averaged 102±3 mmHg and did not significantly change due to the arterial reservoir. Left ventricular systolic and end-diastolic pressures averaged 112±3 and 10±2 mmHg, respectively, and did not significantly change during and following vagal nerve stimulation.

Vagal nerve stimulation significantly increased left circumflex CBF (ANOVA, p<0.05) (Fig. 1). The maximum increases in CBF occurred during 20 Hz vagal stimulation. Vagal nerve stimulation at this frequency increased left circumflex CBF from the baseline value of 71±10 ml/min by 55±14% during the first minute and by 62±14% during the fifth minute (both p<0.01) (Fig. 2). The increases in CBF observed during the first and fifth minutes of vagal stimulation were significantly different from the baseline but were not significantly different from each other. Following the termination of vagal nerve stimulation at 20 Hz, CBF declined by 49% over five minutes and then gradually returned toward the baseline during the ensuing 25 min (Fig. 2).


Figure 1
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  		Fig. 1 Effects of vagal nerve stimulation at frequencies of 10 Hz, n=5, 15 Hz, n=4, 20 Hz, n=5 and 30 Hz, n=4 on mean left circumflex CBF during controlled heart rate and mean arterial pressure. CBF increased by 62±14% from the baseline during the fifth minute of 20 Hz vagal nerve stimulation.

 

Figure 2
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  		Fig. 2 Effects of vagal nerve stimulation at 20 Hz on CBF in the absence (dark squares, n=5) and in the presence of (light squares, n=3) intracoronary [4Cl-D-Phe6,Leu17]VIP during controlled heart rate and mean arterial pressure. CBF increased by 62±14% in the absence of the antagonist. However, CBF increased by only 10% (p=NS) during vagal nerve stimulation in the presence of the VIP antagonist. *p<0.05 versus the baseline value, **p<0.01 vs the baseline. In Fig. 2 and Fig. 3, baseline measurements were obtained at –5 and 0 min and the solid bar on the abscissa indicates the 5 min of vagal nerve stimulation. *p<0.05 versus the baseline value, **p<0.01 vs the baseline.

 
Vagal nerve stimulation at frequencies of 10, 15, and 30 Hz also significantly increased CBF. However, the increase was significantly less (p<0.05) than the increase in CBF observed with vagal nerve stimulation at a frequency of 20 Hz (Fig. 1). Vagal nerve stimulation increased CBF by 6±1% at 10 Hz, by 24±5% at 15 Hz and by 24±7% at 30 Hz (all p<0.05 vs baseline). At the end of vagal stimulation at each of these frequencies, CBF returned to the baseline within five minutes and remained at the baseline during the ensuing 25 min.

LV +dp/dtmax and –dp/dtmin at the baseline averaged 1864±56 mmHg/s and 2070±102 mmHg/s, respectively, and did not significantly change during or following vagal nerve stimulation. In contrast, vagal nerve stimulation at a frequency of 20 Hz significantly increased RV +dp/dtmax (p<0.01) and –dp/dtmin (p<0.03) (Fig. 3). RV +dp/dtmax maximally increased by 17±3% (p<0.04) from a baseline value of 578±79 mmHg/sec to 674±91 mmHg/sec during the fourth minute of 20 Hz vagal stimulation (Fig. 3, Top). Following the termination of vagal nerve stimulation, RV +dp/dtmax returned toward the baseline within five minutes and remained slightly, but not significantly, below the baseline during the ensuing 25 min. The increases in right ventricular contractility during 20 Hz vagal nerve stimulation correlated with the increases in coronary artery blood flow by polynomial regression analysis (R2=0.92). RV –dp/dtmin maximally increased by 11±3% (p<0.04) from a baseline value of 434±66 mmHg/sec to 482±71 mmHg/sec during the fourth and fifth minutes of 20 Hz vagal stimulation (Fig. 3, Bottom). Following the termination of vagal nerve stimulation, RV –dp/dtmin returned toward the baseline within five minutes and remained slightly, but not significantly, below the baseline during the ensuing 25 min. During these experiments, RV systolic and end-diastolic pressures averaged 34±1 mmHg and 6±1 mmHg, respectively, and did not significantly change. No myocardial ischemic changes or atrial or ventricular dysrhythmias were recorded on the continuously monitored EKG during these experiments.


Figure 3
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  		Fig. 3 Effects of vagal nerve stimulation at 20 Hz on RV +dp/dtmax and –dp/dtmin in 5 dogs during controlled heart rate and mean arterial pressure. RV +dp/dtmax maximally increased by 17±3% (p<0.04) from the baseline (Top). RV –dp/dtmin maximally increased by 11±3% (p<0.04) from the baseline (Bottom). *p<0.05 versus the baseline value. **p<0.04 versus the baseline value.

 
5.2 Series 2. Effects of the VIP receptor antagonist, [4Cl-D-Phe6Leu17]VIP, on vagal-induced changes in circumflex CBF
In the first part of series 2 experiments, the VIP antagonist, [4Cl-D-Phe6,Leu17]VIP was directly injected into the LCx of three separate dogs. The LCx supplies the lateral and posterior walls of the left ventricle but does not supply any significant amount of arterial blood to the right ventricle [30]. Each dog was paced at a heart rate of 168±2 beats/min which was not significantly different from the heart rate in the series 1 experiments. Prior to and during vagal nerve stimulation, the mean aortic pressure averaged 105±19 mmHg and did not significantly change due to the arterial reservoir. Prior to the injection of the VIP antagonist, the LV systolic and end-diastolic pressures averaged 129±19 and 9±0.5 mmHg, respectively, and LV +dp/dtmax and –dp/dtmin averaged 2050±104 mmHg/sec and 2117±383 mmHg/sec, respectively. Neither the intracoronary injection of [4Cl-D-Phe6,Leu17]VIP nor the water-saline vehicle significantly changed any hemodynamic parameter or the EKG. Prior to vagal nerve stimulation, nitroglycerin at a dose of 10 µg was directly injected into the LCx. We wished to determine if VIP acts in the coronary arteries through specific receptors and if blockade of these receptors affects NTG-induced increases in CBF. The increases in CBF due to nitroglycerin were not affected by the intracoronary injection of the VIP antagonist in these experiments.

Twenty Hertz vagal nerve stimulation performed 30 min after the intracoronary injection of the VIP antagonist, increased the CBF by only 10±4% (p=NS) from the baseline value of 87±4 to 96±4 ml/minute (Fig. 2, open squares). However, the 10% increase in CBF in the presence of the VIP antagonist was significantly different (p<0.005) from the 62% increase in CBF during 20 Hz nerve stimulation in the absence of the VIP antagonist (Fig. 2, dark squares). Following the termination of vagal nerve stimulation, the circumflex CBF returned to the baseline within five minutes and remained at the baseline during the ensuing 25 min (Fig. 2, open squares).

Vagal nerve stimulation, in the presence of the VIP antagonist injected into the LCx did not significantly change LV +dp/dtmax or –dp/dtmin. However, vagal nerve stimulation did significantly increase RV +dp/dtmax and –dp/dtmin (both, p<0.05). RV +dp/dtmax maximally increased by 18±5% (p<0.04) from the baseline value of 430±6 mmHg/sec and RV –dp/dtmin increased by 15±3% (p<0.004) from the baseline value of 300±53 mmHg/sec. Following the termination of vagal nerve stimulation, RV +dp/dtmax and –dp/dtmin returned to the baseline within five minutes and remained at the baseline during the ensuing 25 min.

Vagal nerve stimulation was repeated approximately 80 min after the administration of the VIP antagonist into the left coronary artery. In these dogs, vagal nerve stimulation significantly increased (p<0.05) CBF by 22±5%. Vagal stimulation also increased RV +dp/dtmax by 21±3% and RV –dp/dtmin by 19±4% (both p<0.05).

In the second part of the series 2 experiments, the VIP antagonist was directly injected into the right coronary artery of three separate dogs. Prior to the antagonist, vagal nerve stimulation at 20 Hz increased RV +dp/dtmax by 25±3% and RV –dp/dtmin by 16±4% (both p<0.05). After the intracoronary injection of the VIP antagonist, vagal nerve stimulation increased RV +dp/dtmax and RV –dp/dtmin by only 2±1% (p=NS). Moreover, 20 Hz vagal nerve stimulation following the injection of the VIP antagonist into the right coronary artery significantly increased left circumflex CBF. The vagal induced increases in left circumflex CBF were not affected by the injection of the VIP antagonist into the right coronary artery.

During these experiments, RV systolic and end-diastolic pressures averaged 29±1 and 4.7±1.4 mmHg, respectively and did not significantly change. No myocardial ischemic changes or atrial or ventricular dysrhythmias were recorded on the continuously monitored EKG during these experiments.

5.3 Series 3. Effects of exogenous VIP administered into the circumflex coronary artery on CBF
In series 1 experiments, we demonstrated that vagal nerve stimulation at 20 Hz significantly increased left circumflex CBF. This increase was substantially reduced by the VIP antagonist [4Cl-D-Phe6-Leu17]VIP which was injected into the left circumflex coronary artery. In series 3, we wanted to securely establish that VIP receptors are present in the coronary arteries. We also wanted to compare the changes in CBF during 20 Hz vagal nerve stimulation with the changes in flow produced by exogenous VIP. Accordingly, we injected VIP in doses of 9.0x10–11 mol, 1.8x10–10 mol, 2.7x10–10 mol, 3.3x10–10 mol, 3.9x10–10 mol, 6.0x10–10 mol, 7.5x10–10 mol, 1.5x10–9 mol, and 2.1x10–9 mol or vehicle in a randomized fashion into the LCx and measured changes in CBF. The heart rate, mean aortic pressure, LV and RV systolic and end-diastolic pressures, and LV and RV +dp/dtmax and –dp/dtmin did not significantly change from each respective baseline value at each dose of VIP or following the administration of VIP (Table 1). In addition, the administration of the VIP water–saline vehicle into the circumflex coronary artery of each dog did not significantly change CBF, ventricular pressures or ventricular +dp/dtmax and –dp/dtmin from the baseline values or the continuously monitored EKG.


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  		Table 1 Effect of intracoronary vasoactive intestinal peptide on hemodynamics

 
Vasoactive intestinal peptide at each dose caused an immediate and significant increase in left circumflex CBF (ANOVA, p<0.01) (Fig. 4). VIP, at a dose of 9.0x10–11 mol increased CBF by 106±17% and at a dose of 6.0x10–10 mol increased CBF by 167±18% from the baseline measurement (p<0.01). CBF maximally increased by 169±17% with 2.1x10–9 mol of VIP. However the administration of VIP at doses of 7.5x10–10, 1.5x10–9 and 2.1x10–9 mol did not further significantly increase CBF compared to the increase produced by 6.0x10–10 mol VIP (Fig. 4). The CBF increases due to VIP persisted during the 1 to 2 min injection period but then returned to the baseline within 5 min. No myocardial ischemic changes or atrial or ventricular dysrhythmias were present on the continuously recorded EKG during these experiments.


Figure 4
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  		Fig. 4 Exogenous VIP effects on mean circumflex CBF. CBF increased from the baseline in a curvilinear manner (R2=0.86) at doses between 9.0x10–11 and 6.0x10–10 mol and did not significantly increase further at doses between 7.5x10–10 and 2.1x10–9 mol VIP. Each dose of VIP produced a significant (*p<0.01) increase in CBF in comparison with the baseline measurement.

 
We compared the maximum increase in left circumflex CBF due to exogenous VIP with the increases in CBF during 20 Hz vagal nerve stimulation in the series 1 experiments. The increase in CBF due to 9.0x10–11 mol VIP was equivalent to the increase in CBF during vagal nerve stimulation at 20 Hz by analysis of variance.

5.4 Series 4. Effects of NTG administered into the circumflex coronary artery on CBF
In these experiments, we wished to compare the increases in CBF produced by NTG with the increases in CBF that occurred during vagal nerve stimulation in series 1 and also during exogenous VIP in series 3. Accordingly, we administered NTG, in doses of 2.2x10–8 mol, 4.4x10–8 mol, 8.8x10–8 mol and 1.7x10–7 mol directly into the LCx and measured the changes in CBF. The heart rate, mean aortic pressure, LV and RV systolic and end-diastolic pressures, and LV and RV +dp/dtmax and –dp/dtmin did not significantly change from the respective baseline values at each dose of NTG or during the period following the administration of NTG (Table 2). In addition, administration of the NTG water–saline vehicle into the LCx of each dog did not significantly change LV pressures, LV +dp/dtmax or –dp/dtmin or the continuously monitored EKG.


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  		Table 2 Effects of intracoronary nitroglycerin on hemodynamics

 
Nitroglycerin, at each dose, caused an immediate and significant increase in left circumflex CBF (ANOVA, p<0.01) (Fig. 5). The maximum increase in CBF occurred at a dose of 1.7x10–7 mol where CBF increased by 169±20% (p<0.01) from the baseline value of 88±18 ml/min to 237±21 ml/min (Fig. 5). Nitroglycerin increased coronary flow from the baseline value by 101±15% at 2.2x10–8 mol, by 116±9% at 4.4x10–8 mol, and by 149±13% at 8.8x10–8 mol, respectively (all p<0.01 vs. baseline) (Fig. 5). The CBF increases due to NTG persisted during the 1 to 2 min injection period but then returned to the baseline within 5 min. No myocardial ischemic changes or atrial or ventricular dysrhythmias were present on the continuously recorded EKG during these experiments.


Figure 5
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  		Fig. 5 NTG effects on mean circumflex CBF. Following the administration of 2.2x10–8, 4.4x10–8, 8.8x10–8 and 1.7x10–7 mol NTG, CBF increased linearly (R2=0.86) from the baseline. Each dose of NTG produced a significant (*p<0.01) increase in CBF in comparison with the baseline measurement.

 
We compared the maximum increase in left circumflex CBF due to NTG with the increases in flow during 20 Hz vagal nerve stimulation reported in series 1 and with exogenous VIP in series 3. The increase in CBF with NTG at doses of 2.2x10–8 mol and 4.4x10–8 mol was equivalent to the increase in CBF during vagal nerve stimulation at 20 Hz and was also equivalent to the increase in CBF produced by 9.0x10–11 mol of VIP by analysis of variance. In addition, the increases in CBF produced by VIP in doses of 9.0x10–11 to 2.1x10–9 mol in the present experiments were comparable to the increases in flow produced by NTG in doses of 2.2x10–8 to 1.7x10–7 mol.


   6 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Protocol
 4 Statistical analysis
 5 Results
 6 Discussion
References
 
The present experiments demonstrate that vagal nerve stimulation, during muscarinic and β-adrenergic receptor blockade, significantly increases CBF to the left ventricle. The maximum increase in CBF occurs during vagal stimulation at a frequency of 20 Hz. No further incremental increases in CBF occur during vagal stimulation at frequencies greater than 20 Hz. The vagal-induced increases in circumflex CBF are independent of any significant changes in LV systolic or end-diastolic pressures, or LV +dp/dtmax or –dp/dtmin, but are significantly reduced or abolished by the intracoronary injection of the VIP receptor antagonist [4Cl-D-Phe6Leu17]VIP into the left coronary artery. This receptor antagonist substantially attenuates the coronary artery vasodilator, inotropic and chronotropic responses elicited by either endogenous or exogenous VIP [12–14, 31, 32]but does not inhibit glucagon, peptide histidine isoleucine, bombesin, cholecystokinin, calcitonin gene related peptide, or substance P [12–18].

In the present experiments, 20 Hz vagal nerve stimulation produced increases in CBF equivalent to the increases in CBF produced by 9.0x10–11 mol of exogenous VIP or 2.2x10–8 to 4.4x10–8 mol of NTG. The diminished CBF response during vagal nerve stimulation in the presence of the VIP antagonist was due to blockade of the VIP receptors in the coronary arteries and was not due to a decrease in vessel reactivity in our preparation because NTG significantly increased coronary artery blood flow.

The present experiments strongly suggest that vagal nerve stimulation releases VIP which combines with VIP receptors in the coronary arteries and significantly increases CBF.

6.1 VIP localization in the heart
VIP is present in post-ganglionic and intrinsic cardiac nerve fibers in all mammals including man [1, 3–9, 33]. These fibers are predominantly found in the coronary arteries, sinoatrial and atrioventricular nodes, the atria and the right ventricle (RV). In contrast, VIP nerve fibers are uncommon or are absent in the left ventricle [1, 4, 6]. Within the coronary arteries, VIP nerve fibers are present in the epicardial coronary arteries and to a lesser extent in the coronary arterioles [1, 8]. In this regard, the concentration of VIP is 7.28±1.65 ng/g in the large epicardial vessels and there is a significant decrease in VIP content to 2.29±0.53 ng/g more distally in the vessel [5]. In addition, exogenous VIP has a more potent effect on the large epicardial vessels than on the resistance vessels [5]. These findings suggest that VIP facilitates flow in the large epicardial vessels.

VIP is stored in large dense core vesicles in post-ganglionic vagal and intrinsic nerve fiber endings and is released by high frequency (15–20 Hz) nerve stimulation [2, 10–13, 28, 33]. In contrast, acetylcholine is primarily stored in small vesicles in post-ganglionic vagal nerve fibers and is released by low frequency (<6 Hz) nerve stimulation [2, 10, 11, 33]. Vasoactive intestinal peptide, after release from vagal nerve terminals, combines with specific VIP receptors which are present in the atria, right ventricle and coronary arteries [34, 35]. However, these VIP receptors do not bind secretin, glucagon, parathyroid hormone, angiotensin II, bradykinin, substance P, neurotensin, or atrial natriuretic peptide [35]. The presence of VIP nerve fibers and VIP receptors in the coronary arteries strongly suggests that VIP is important in the regulation of CBF.

6.2 Effects of VIP on arterial blood flow
The increases in CBF to the left ventricle during vagal nerve stimulation in the present experiments occurred in the absence of any significant changes in the major determinants of myocardial oxygen consumption. These determinants are the mean aortic pressure, LV systolic or end-diastolic pressures, LV contractility, or heart rate [36]. Furthermore, the intracoronary administration of VIP in the present experiments, and also in the experiments by other investigators, substantially increased CBF without significantly increasing any of the major hemodynamic determinants of myocardial oxygen consumption (Table 1) [5, 37]. Therefore, the increase in CBF during vagal nerve stimulation or the intracoronary administration of VIP is not due to increases in myocardial oxygen requirements and cardiac metabolism.

The vagal-induced increases in CBF in the present experiments are also not explained by acetylcholine effects on the coronary arteries for the following reasons. Acetylcholine dilates normal coronary arteries by combining with vascular endothelial muscarinic receptors, releasing nitric oxide, and thereby causing vascular smooth muscle relaxation. However in the present experiments, the muscarinic receptors were blocked by the continuous i.v. administration of atropine as evidenced by the fact that 20 Hz vagal stimulation for five minutes did not significantly decrease the heart rate or left ventricular contractility or relaxation [38]. Finally, catecholamine and prostaglandin effects do not explain the increase in CBF that occurred during vagal nerve stimulation because alpha- and beta-adrenergic receptor blockade and cyclooxygenase inhibition have no effect on VIP-induced arterial dilation [5, 39]. We therefore conclude that VIP has a direct vasodilator effect on the coronary arteries. In this regard, VIP increases intracellular cAMP by as much as three times above basal levels in vascular smooth muscle [40, 41]. The VIP-induced increase in cAMP most likely contributes to coronary vascular smooth muscle relaxation [40, 41].

In animals and humans, exogenous VIP increases the epicardial coronary artery cross-sectional area by as much as 27%, the coronary artery blood flow twofold, and decreases the coronary vascular resistance by as much as 46% [5, 37]. Moreover, vasoactive intestinal peptide's vasodilatory effect is not limited to the coronary arteries. Endogenous or exogenous VIP also produces significant arterial dilation in other body organs. For example, vagal nerve stimulation, in the presence of cholinergic and adrenergic blockade, significantly increases salivary gland and uterine arterial blood flow [42, 43]. In addition, exogenous VIP significantly increases cerebral arterial blood flow as well as blood flow to the eyes, parotid, thyroid and pancreas glands [44, 45].

In the present experiments, 20 Hz vagal nerve stimulation increased CBF by as much as 62% from the baseline. In contrast, 30 Hz vagal nerve stimulation increased CBF by only 24% from the baseline. Similarly, 20 Hz vagal nerve stimulation maximally increases right atrial contractility, right ventricular contractility and relaxation, and heart rate and further significant incremental increases do not occur during vagal nerve stimulation at frequencies greater than 20 Hz [12, 13]. The decrease in CBF, right heart and heart rate responses at stimulation frequencies greater than 20 Hz may be due to pre-synaptic receptors that limit VIP release [13, 19, 46, 47]. In this regard, autoreceptors mediate the release of norepinephrine, dopamine, acetylcholine, serotonin, gamma-aminobutyric acid, glutamine, and neuropeptide Y [47, 48]. Therefore, autoreceptors most likely mediate the release of VIP. Alternatively, high frequency (>20 Hz) vagal nerve stimulation may not result in one to one neural transmission. In this instance, VIP may be released only with alternate impulses [19].

6.3 Comparison of the effects of exogenous VIP and NTG with the effects of vagal nerve stimulation at 20 Hz
In the present experiments, exogenous VIP substantially increased CBF without significantly changing the major determinants of myocardial oxygen consumption and thereby confirmed the presence of VIP receptors in the left coronary artery. Moreover, the increase in CBF produced by 9.0x10–11 mol of VIP was equivalent to the increase in CBF during 20 Hz vagal nerve stimulation as determined by an analysis of variance. This suggests that 20 Hz vagal nerve stimulation for periods of five minutes releases VIP in the coronary artery in concentrations comparable to 9.0x10–11 mol of exogenous VIP. Similarly, the increase in CBF produced by 2.2x10–8 to 4.4x10–8 mol of intracoronary NTG was equivalent to the increase in CBF produced by 20 Hz vagal nerve stimulation. Moreover, comparison of the vasodilator effects of exogenous VIP with the effects of exogenous NTG indicates that the smaller doses of VIP produce equivalent increases in CBF.

6.4 Effects of VIP on right ventricular contractility and relaxation
In our previous work we demonstrated that vagal nerve stimulation at 20 Hz releases VIP which significantly increases right ventricular contraction and relaxation by 28 and 23%, respectively [13]. Moreover these changes were decreased by as much as 85% by [4Cl-D-Phe6Leu17]VIP, a VIP antagonist that was directly injected into the right coronary artery. Therefore, we used the increases in RV dp/dt during vagal nerve stimulation as a biological measure of VIP release in the heart.

In the present experiments, vagal nerve stimulation significantly increased RV +dp/dtmax and –dp/dtmin. Moreover, the increases in right ventricular dp/dt during vagal nerve stimulation correlated with the increases in coronary blood flow. The increases in RV +dp/dtmax and –dp/dtmin were abolished by direct injection of [4Cl-D-Phe6Leu17]VIP into the right coronary artery. However, direct injection of the VIP antagonist into the LCx, did not significantly decrease the vagal-induced increases in right ventricular +dp/dtmax and –dp/dtmin because the LCx of the dog perfuses primarily the lateral and posterior walls of the left ventricle [29]. Consequently, no significant amount of the VIP antagonist injected into the circumflex coronary artery reached the right ventricular myocardium.

6.5 Potential cardiovascular application
There is very little information about the role of VIP in cardiovascular regulation. However, intense transient increases in vagal efferent activity occur in individuals who experience abrupt and substantial increases in arterial blood pressure in response to emotional stimuli or to a vasoconstrictor drug such as occurs with activation of the carotid sinus reflex. In this regard, D.L. Kunze has demonstrated that physiologic firing frequency of vagal fibers maximally increases to 40 Hz with the carotid sinus reflex due to blood pressures ranging from 180 to 230 mmHg [49]. Therefore, VIP can be released with intense vagal stimulation due to carotid sinus reflex activation in order to assist the heart in compensating for the increased myocardial oxygen demands. Moreover, following intense vagal stimulation, tachycardia (‘post-vagal tachycardia’) frequently occurs [50]. This ‘post-vagal tachycardia’ is not abolished by β-adrenergic blockade but is blocked by VIP antagonists [14, 50]. This ‘post-vagal tachycardia’ is believed to be due to release of VIP from cardiac vagal nerves [12, 14].

6.6 Conclusion
The present experiments suggest that vasoactive intestinal peptide is released during vagal nerve stimulation and significantly increases CBF. Twenty Hz vagal nerve stimulation produces increases in CBF that are equivalent to the increases in CBF produced by 9.0x10–11 mol of exogenous VIP or 2.2x10–8 to 4.4x10–8 mol of NTG. We propose that endogenous VIP is important in the regulation of coronary artery blood flow.

Time for primary review 30 days


   Acknowledgements
 
This work was supported, in part by the National American Heart Association, the Florida Affiliate of the American Heart Association, the University of South Florida, the National Emergency Medicine Association, and the Robert O. Law Foundation. We wish to thank Paul Leaverton, Ph.D., Director of Biostatistics and Epidemiology Department of the University of South Florida and Nick Coblio, R.Ph. of the James A. Haley VA Hospital, for their assistance with the statistical analyses of our data. We also wish to thank Dr. Norman N. Yoshimura of McGaw Incorporated for his generous contribution of Hetastarch and Wilda Rivera, B.S., John Soto and Marghoob Khan, M.D. for their technical assistance.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Protocol
 4 Statistical analysis
 5 Results
 6 Discussion
 References
 

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