JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kal, J. E.
Right arrow Articles by van Wezel, H. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kal, J. E.
Right arrow Articles by van Wezel, H. B.
Anesth Analg 1999;88:271
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Effect of Nitroglycerin on Pacing-Induced Changes in Myocardial Oxygen Consumption and Metabolic Coronary Vasodilation in Patients with Coronary Artery Disease

Jasper E. Kal, MD*, Isabelle Vergroesen, PhD{dagger}, and Harry B. van Wezel, MD, PhD*

Departments of *Anesthesiology and {dagger}Medical Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Address correspondence and reprint requests to H. B. van Wezel, MD, PhD, Department of Anesthesiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
In the present study, we assessed the potential effect of nitroglycerin IV (NTG), a donor of exogenous nitric oxide, on metabolic coronary flow control in patients with coronary artery disease. In 12 patients scheduled for coronary artery surgery, arterial blood pressure, pulmonary capillary wedge pressure, coronary sinus blood flow (continuous thermodilution), myocardial oxygen supply (DVO2), and myocardial oxygen consumption (MVO2) were measured at sinus rhythm and in response to atrial pacing at 30 bpm greater than baseline sinus rate. These measurements were repeated during infusion of NTG 1 and 2 µg · kg-1 · min-1. At control, in the absence of NTG, MVO2 increased from 13.7 ± 3.4 mL O2/min during sinus rhythm to 19.3 ± 5.5 mL O2/min during pacing. NTG 1 and 2 µg · kg-1 · min-1 blunted the pacing-induced increase in MVO2 dose-dependently. During NTG 1 µg · kg-1 · min-1, MVO2 increased from 12.9 ± 3.3 mL O2/min at sinus rhythm to 17.3 ± 4.7 mL O2/min during pacing (P = 0.01 versus control pacing); during NTG 2 µg · kg-1 · min-1, MVO2 increased from 13.4 ± 3.3 mL O2/min to 15.9 ± 3.7 mL O2/min (P = 0.008 versus control pacing). However, the pacing-induced increase in DVO2 per mL O2/min increase in MVO2 ({Delta}DVO2/{Delta}MVO2), was significantly greater during the infusion of NTG 2 µg · kg-1 · min-1 (1.85 ± 0.56; P = 0.023) compared with control (1.51 ± 0.22). This was associated with an increase in coronary sinus hemoglobin oxygen saturation (30% ± 5% at control pacing and 34% ± 6% during pacing with NTG 2 µg · kg-1 · min-1; P = 0.018), which indicates that during the infusion of NTG, there was more metabolic coronary vasodilation than achievable solely on the basis of the metabolic stimulus.

Implications: Our findings suggest that nitroglycerin, a donor of exogenous nitric oxide, reduces pacing-induced increases in myocardial oxygen consumption and enhances metabolic coronary vasodilation in patients with coronary artery disease, in whom endogenous nitric oxide activity may be reduced.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 References
 
Regulation of coronary blood flow is dependent on metabolic, myogenic, neurohumoral, and endothelial responses (1). The overall effect of these combined responses leads to continuous matching of myocardial oxygen supply (DVO2) and consumption (MVO2) (2,3). MVO2 is believed to be the major determinant of coronary blood flow, a process known as metabolic coronary flow regulation (4). Although the precise mechanisms involved in this regulatory process are largely unknown, endothelium-derived nitric oxide (NO) may be one of the important mediators (5–7). However, little is known about the effect of exogenous NO on coronary metabolic flow regulation.

Exogenous NO is released by nitroglycerin (NTG) via a poorly understood enzymatic process, resulting in a number of systemic and coronary hemodynamic changes, which have been studied extensively (8). In patients with coronary artery disease (CAD) who have endothelial dysfunction (9–11), reduced endogenous NO activity (12), and impaired metabolic coronary vasodilation (5,6), exogenous NO may still affect metabolic coronary flow regulation.

Measuring global coronary blood flow at different levels of MVO2 before and during the infusion of the exogenous NO substance donor NTG, offers the possibility to study the interaction between NTG and metabolic coronary flow regulation. Therefore, the aim of the present study was to quantify the effect of NTG on metabolic coronary vasodilation in response to pacing-induced submaximal increases in MVO2 in awake patients scheduled for coronary artery bypass grafting.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 References
 
Twelve patients with stable CAD scheduled for elective coronary artery surgery gave written, informed consent to participate in this study, which was approved by our institutional human investigation committee. Excluded from the study were patients with the following conditions: left ventricular end diastolic pressure >18 mm Hg, left ventricular hypertrophy, ejection fraction <45%, atrioventricular conduction defects, left main stem stenosis, or unstable angina. Patients undergoing additional surgical procedures (e.g., valve replacement or aneurysmectomy) were also excluded.

Calcium channel blockers and long-acting nitrates were administered until the evening before surgery. ß-Adrenoreceptor blocking drugs were continued until the morning of surgery. Lorazepam 4-5 mg PO was given for premedication 2 h before surgery.

On arrival in the operating room, electrocardiogram (ECG) leads were connected. Leads II, III, and V5 were continuously monitored (HP Merlin System; Hewlett-Packard, Palo Alto, CA). A wide-bore peripheral infusion catheter and a 20-gauge radial artery catheter were inserted under local analgesia. Dextrose 5% was infused at a rate of 250 mL/h throughout the study period.

A thermodilution pulmonary artery catheter and a coronary sinus thermodilution catheter (Wilton-Webster Laboratories, Alta Dena, CA) were introduced via the left subclavian vein. The coronary sinus catheter was advanced into the coronary sinus using image intensification fluoroscopy and injection of contrast medium, so that the external thermistor lay 1.5-2 cm from the ostium and there was no major sidebranching vein in the vicinity. The coronary sinus catheter was connected to a Wilton-Webster Wheatstone bridge. Coronary sinus thermodilution signals were recorded by using a multichannel amplifier/recorder system. Catheter calibration factors provided by the manufacturer were used. The absence of right atrial admixture in coronary sinus blood was checked by injecting cold saline into the right atrium while coronary sinus temperature curves were recorded simultaneously (13). Under fluoroscopy, atrial pacing (via coronary sinus catheter) was used for 10–30 s to ascertain the stability of the position of the tip of the coronary sinus catheter in relation to the surrounding anatomical structures and fluoroscopic landmarks. If the stability of the catheter could not be guaranteed, the experiment was discontinued. For the measurement of coronary sinus blood flow (CSBF), room-temperature isotonic sodium chloride solution was used as an indicator and infused into the coronary sinus at a rate of 45 mL/min via a Mark IV infusion pump (Medrad Technology, Pittsburgh, PA) (14). Infusion rates were verified by timed volume collection, and flow calculations reflected the indicator infusion rate that was used.

After adequate instrumentation, patients were allowed to rest for 20 min.

As shown in the flowchart (Fig. 1), three series of measurements were performed both during sinus rhythm and pacing. The first series of measurements was used as control. The second and third series of measurements were performed during the infusion of NTG 1 and 2 µg · kg-1 · min-1, respectively.



View larger version (25K):
[in this window]
[in a new window]
  		Figure 1. The study protocol. Measurements were performed at sinus rhythm (SR) and during pacing at control and during the infusion of nitroglycerin (NTG) 1 and 2 µg · kg-1 · min-1. Pacing values were obtained at a pacing rate of 30 bpm above baseline sinus rate at control. {blacktriangleup} = the measurement of cardiac output, pulmonary capillary wedge pressure, and the simultaneous sampling of blood from the radial artery and coronary sinus. Black segments represent the continuous recording of coronary sinus blood flow, arterial blood pressure, pulmonary artery pressure, right atrial pressure, and electrocardiogram lead II.

 
Each series of measurements started with the recording of pulmonary capillary wedge pressure (PCWP) and cardiac output (CO). CO was measured in triplicate, averaged (using room-temperature isotonic sodium chloride solution as an indicator), and reported as cardiac index. Blood samples from the radial artery and coronary sinus were simultaneously drawn to determine values for plasma hemoglobin, PO2, PCO2, SO2, and lactate concentrations. Subsequently, continuous recording of CSBF, arterial blood pressure (ABP), right atrial pressure (RAP), pulmonary artery pressure (PAP), and ECG lead II was started. When a constant coronary sinus thermodilution signal had been obtained (after 10–15 s of recording), heart rate (HR) was increased by 30 bpm above baseline sinus rate, by pacing via the coronary sinus catheter. After a recording period of 70 s, during which a new steady state in CSBF had been reached, the coronary sinus indicator infusion was discontinued. Pacing continued at the same rate. Immediately after the indicator infusion, values of PCWP and CO during pacing were recorded, and blood sampling was repeated. Pacing was then stopped.

After this first series of control measurements, the effect of NTG IV on coronary metabolic regulation was studied. Patients received an infusion of NTG at a rate of 1.0 µg · kg-1 · min-1. After an equilibration period of 15 min, the complete protocol was repeated. After the measurements during sinus rhythm had been obtained, HR was increased to the same rate used during pacing at control. The measurements during pacing were again performed as described above. After all measurements during the infusion of NTG 1 µg · kg-1 · min-1, the infusion rate of NTG was increased to 2 µg · kg-1 · min-1, and after 15 min, the protocol was repeated again.

Derived hemodynamic parameters were calculated according to standard formulas. Rate pressure product (RPP) was calculated as systolic blood pressure (SBP) x HR. An index of coronary vascular resistance (CVR) was calculated as (mean ABP - mean RAP)/mean CSBF (15).

SO2 was measured by using an OSM-II hemoxymeter (Radiometer, Copenhagen, Denmark), and PO2 was measured by using an ABL-III analyzer (Radiometer). Lactate concentrations were measured using standard enzymatic techniques (16). Myocardial metabolic indices were calculated according to standard formulas: oxygen content (mL O2/dL) as 1.39 x Hb (g/100 mL) x SaO2 + 2.241 x 0.00136 x PO2 (mm Hg), and MVO2 (mL O2/min) as CSBF x arterio-coronary venous oxygen content difference. DVO2 was calculated as CSBF x SaO2. The myocardial oxygen extraction percentage was calculated as ([SaO2 - ScsO2]/SaO2) x 100, where ScsO2 indicates coronary sinus SO2. The myocardial lactate extraction percentage was calculated as the ([arterial lactate concentration - coronary sinus lactate concentration]/arterial lactate concentration) x 100.

All recordings of continuous signals (ABP, RAP, PAP, CSBF thermodilution curves, and ECG lead II) were digitized online at a sampling rate of 80 Hz by an analog to digital converter (Model RTI 800; Analog Devices Inc., Norwood, MA) incorporated in a personal computer. A signal analysis program (386-Matlab v 3.5j; MathWorks, Natick, MA) was used to average the continuous recordings over periods of 8 s of steady state, before and after the start of pacing, yielding values at sinus rhythm and during pacing, respectively.

The putative effect of NTG on coronary metabolic regulation was analyzed in different ways. First, we used a traditional approach, deducing true vasodilation from changes in ScsO2. This approach is based on the concept that a true coronary vasodilator will directly increase coronary blood flow, leading to an increase in ScsO2. Comparing the ScsO2 values during pacing at control with the values measured during pacing with NTG 1 and 2 µg · kg-1 · min-1 provides information about whether there is coronary vasodilation, in addition to the pacing-induced metabolic vasodilation, which by itself does not influence ScsO2 (17,18).

Second, we analyzed the static aspects of metabolic flow regulation by using a method described by Vergroesen et al. (3,4), by which pacing-induced changes in DVO2 and MVO2 at control and during infusion of NTG (1 and 2 µg · kg-1 · min-1) are compared in each individual patient. This approach allowed us to calculate the mean pacing-induced increase in DVO2 relative to an increase in MVO2 during control and both infusion rates of NTG.

Values at sinus rhythm obtained at control and during both NTG infusion rates were compared by using two-way analysis of variance for repeated measurements. Similarly, data during pacing were compared. Paired standard t-tests were used to compare values at sinus rhythm with values obtained during pacing. A value of P < 0.05 was considered significant. Results are reported as mean ± SD or as percent change ± SD where applicable.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 References
 
In two patients, a stable position of the coronary sinus catheter could not be guaranteed because a shift in catheter position was observed in response to pacing during fluoroscopy for catheter placement. Hence, in these two patients, the study was discontinued prematurely before control measurements were started. In the 12 remaining patients, a stable catheter position could be guaranteed.

Patient characteristics and preoperative chronic medication are shown in Table 1. The patients were all male and comparable with respect to age, weight, and height.


View this table:
[in this window]
[in a new window]
  		Table 1. Patient Characteristics and Clinical Data
 
Six patients were suffering from three-vessel CAD, five from two-vessel CAD, and one patient from single-vessel CAD.

Most patients were using triple therapy for angina, consisting of long-acting nitrates, ß-adrenergic blocking drugs, and calcium entry-blockers. One patient was not using a ß-adrenergic blocking drug, whereas another patient was not using a calcium entry-blocker.

Systemic and coronary hemodynamic variables and myocardial metabolic data are listed in Table 2. Hemodynamic results obtained at control and during the two infusions of NTG are reported at sinus rhythm and during pacing.


View this table:
[in this window]
[in a new window]
  		Table 2. Systemic and Coronary Hemodynamics
 
In our patients who were taking ß-blockers until the morning of surgery, HR increased from 65 bpm at control to 69 bpm during the infusion of NTG 2 µg · kg-1 · min-1. Therefore, pacing-induced changes in HR were smaller during the infusion of NTG 2 µg · kg-1 · min-1 because the same rate of pacing was maintained.

Mean arterial blood pressure (MAP) decreased after the start of the NTG infusion in all patients. A decrease of 6 and 11 mm Hg was observed after the administration of NTG 1 and 2 µg · kg-1 · min-1, respectively. In accordance with the venodilating properties of NTG (8), we further observed a 26% ± 11% decrease in PAP and a 36% ± 35% decrease in PCWP in response to large-dose NTG. Neither NTG 1 µg · kg-1 · min-1 nor 2 µg · kg-1 · min-1 changed systemic vascular resistance (SVR).

MVO2 at sinus rhythm was 13.7 ± 3.4 mL O2/min at control. NTG 1 µg · kg-1 · min-1 decreased MVO2 to 12.9 ± 3.3 (P = 0.016). However, during the infusion of NTG 2 µg · kg-1 · min-1, MVO2 at sinus rhythm was not significantly different from control: 13.4 ± 3.3 mL O2/min (P = 0.310). NTG affected neither CSBF (104, 105, and 111 mL/min during control, NTG 1 µg · kg-1 · min-1, and NTG 2 µg · kg-1 · min-1, respectively) nor ScsO2. Coronary sinus PO2 also remained unchanged throughout the study (20 ± 2 mm Hg at control, 22 ± 3 mm Hg during NTG 1 µg · kg-1 · min-1, and 21 ± 3 mm Hg during NTG 2 µg · kg-1 · min-1).

Thus, changes induced by the NTG infusion per se (in the absence of pacing) mainly concerned MAP, PAP, and PCWP; SVR and coronary hemodynamic and metabolic variables were unaffected.

Pacing the heart at an average rate of 29 bpm above the baseline sinus rate resulted in a significant increase in MVO2. The change in MVO2 from 13.7 ± 3.4 mL O2/min during sinus rhythm to 19.3 ± 5.5 mL O2/min during pacing was matched by an increase in CSBF from 104 ± 30 to 147 ± 44 mL/min. ScsO2 and myocardial oxygen and lactate extraction percentages remained unchanged. In one patient, lactate extraction changed to lactate production only during pacing in the control condition. In this patient, after the start of the infusion of NTG 1 µg · kg-1 · min-1, lactate extraction was found again and continued during all subsequent measurement series. Furthermore, we did not observe ECG signs of myocardial ischemia in any patient at any time during the study period.

NTG significantly blunted the pacing-induced increases in MVO2 in a dose-dependent manner (Fig. 2). MVO2 increased by 40% ± 15% during control, 33% ± 20% during the administration of NTG 1 µg · kg-1 · min-1 (P = 0.39 compared with the increase at control), and only 19% ± 10% during the administration of NTG 2 µg · kg-1 · min-1 (P = 0.004 compared with the increase at control). As a result, absolute MVO2 during pacing was significantly reduced during the administration of NTG 1 and 2 µg · kg-1 · min-1 (Table 2).



View larger version (21K):
[in this window]
[in a new window]
  		Figure 2. Effects of IV nitroglycerin (NTG) on rate pressure product (RPP) and myocardial oxygen consumption (MVO2), during sinus rhythm (SR) and atrial pacing. Shown are the values (mean ± SEM) at control and during the infusion of NTG 1 and 2 µg · kg-1 · min-1, which demonstrates the attenuated pacing-induced increase in MVO2 during the large-dose NTG infusion. *P < 0.05 compared with corresponding value at control.

 
During pacing, the infusion of NTG 1 and 2 µg · kg-1 · min-1 did not change CSBF compared with values obtained at control (P = 0.162), despite the significant reduction in MVO2 (Table 2). The constant CSBF with pacing, associated with the NTG-induced reduction in MVO2 during pacing, led to an increase in ScsO2 from 30% ± 5% at control to 34% ± 6% during the infusion of NTG 2 µg · kg-1 · min-1 (P = 0.01). There was a concomitant significant reduction in myocardial oxygen extraction percentage (Table 2). This suggests that, during infusion of NTG 2 µg · kg-1 · min-1, there was more coronary vasodilation in response to pacing than was expected on the basis of the primary change in MVO2.

This is illustrated in Figure 3, in which the average pacing-induced increase in DVO2 relative to an increase in MVO2 is shown. Before NTG infusion, atrial pacing resulted in an increase of 1.51 ± 0.22 mL O2/min in oxygen supply for each increase of 1 mL O2/min in MVO2, an index of normal metabolic coronary flow regulation (3,18). During the infusion of NTG 2 µg · kg-1 · min-1, the change in DVO2 per mL O2/min increase in MVO2 was significantly increased to 1.85 ± 0.56 mL O2/min (P = 0.023).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 3. Effect of IV nitroglycerin (NTG) on coronary metabolic flow regulation, i.e., the change in myocardial oxygen supply (DVO2) in relation to the pacing-induced change in myocardial oxygen demand (MVO2). Shown are the values (mean ± SEM) at control and during the infusion of NTG 1 and 2 µg · kg-1 · min-1. NTG increased the change in DVO2 in relation to the change in MVO2. *P = 0.01 compared with value at control.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 References
 
This study in awake patients with CAD showed that an infusion of NTG 2 µg · kg-1 · min-1 did not change CSBF or MVO2 during sinus rhythm but did attenuate pacing-induced increases in myocardial metabolic activity. Furthermore, the pacing-induced average increase in DVO2 per mL O2/min increase in MVO2 was significantly greater during the infusion of NTG 2 µg · kg-1 · min-1 than at control. This suggests that NTG caused more coronary vasodilation than was required on the basis of the increase in MVO2 induced by pacing.

We studied NTG at infusion rates of 1 and 2 µg · kg-1 · min-1 to deal with the potential variation in individual sensitivity to NTG (19). The small dose of 1 µg · kg-1 · min-1 used in the present study resulted in significant hemodynamic changes, including reductions in MAP, PAP, and PCWP (Table 2). This dose corresponds with the largest dose used by Ihlen et al. (20) in a comparable study. The high infusion rate of 2 µg · kg-1 · min-1 was chosen to ascertain an effect in patients possibly desensitized to NTG by long-acting oral nitrates. It is unlikely that the absence of changes in MVO2 and coronary blood flow during the infusion of NTG 2 µg · kg-1 · min-1 and sinus rhythm was due to NTG being given in too small a dose.

The effect of NTG on metabolic coronary flow regulation has only been studied in conditions of pacing- or exercise-induced myocardial ischemia (21–23). This makes interpretation of these studies difficult because mechanisms other than metabolic coronary flow regulation may prevail during myocardial ischemia (1). Recently, it has been shown that with small pacing-induced HR changes (30 bpm above sinus rate) as the metabolic stimulus, myocardial ischemia can be avoided (24). This was confirmed in the present study because, with the exception of one patient who developed myocardial lactate production during pacing at control, there were no signs or symptoms of ischemia. This increase in HR was, however, large enough to elicit substantial changes in MVO2, leading to metabolic coronary vasodilation (24). Using this approach, mechanisms involved in physiological metabolic coronary flow regulation may be studied while avoiding possible confounding factors induced by myocardial ischemia.

There is conflicting evidence regarding the effect of NTG on coronary vessels and basal coronary blood flow (25,26). In general, it is believed that NTG mainly affects larger epicardial arteries, whereas it has only limited effect on flow-regulating coronary resistance vessels (27). In addition, it has been suggested that NTG has an effect on collateral vessels (20) and epicardial stenoses (28).

In the present study, CSBF at sinus rhythm remained unchanged during infusion of NTG 1 and 2 µg · kg-1 · min-1. Nevertheless, in our patients with CAD, potential vasodilation of epicardial arteries or epicardial stenoses may have occurred in response to NTG infusion (29). Epicardial vessels are conductance vessels, whereas smaller coronary vessels are flow-regulating resistance vessels, which can adapt to changes in pressure or MVO2. In case of a subcritical stenosis, coronary autoregulation would probably have compensated for the additional resistance caused by the stenosis, thereby leaving coronary blood flow unaffected, both at control and during NTG infusion (30). This makes detection of such a subcritical stenosis by means of the measurement of coronary blood flow in the coronary sinus hardly possible. If a critical stenosis had been present in our patients, then a substantial decrease in ScsO2 should have occurred in response to pacing. However, this did not occur in any of the participating patients at any time. We also did not observe an increase in ScsO2 at sinus rhythm in response to NTG infusion. Therefore, we assume that possible vasodilation of critical epicardial stenoses by NTG did not play a major role in the present study, although potential changes in regional ScsO2 may have been undetected in the coronary sinus.

Although CSBF at sinus rhythm remained unchanged, a decrease in calculated CVR was found during the infusion of NTG 2 µg · kg-1 · min-1, which suggests coronary vasodilation. However, this decrease in CVR can also be explained on the basis of coronary autoregulation because the infusion of NTG 2 µg · kg-1 · min-1 was associated with a significant decrease in MAP (i.e., coronary perfusion pressure) (17). This seems especially so because ScsO2 at sinus rhythm remained unchanged. The constant ScsO2 also argues against the presence of intracoronary shunting (coronary steal) in response to NTG because, in the case of shunting, an increase in ScsO2 would have been expected. In addition, none of the patients complained of angina or showed ECG changes or myocardial lactate production during NTG infusion. On the contrary, the only patient who had myocardial lactate production during pacing at control showed lactate extraction during pacing in the presence of NTG. This is in line with the concept that NTG, unlike other vasodilators, does not induce coronary steal (19,31).

Parallel to the conflicting evidence regarding the effect of NTG on basal coronary blood flow, it has been reported that NTG may either decrease MVO2 (23) or leave MVO2 unchanged (25). Frequently, changes in MVO2 are explained on the basis of changes in RPP, although it is known that the RPP is only a poor reflection of MVO2 (32). In the present study, RPP at sinus rhythm did not change during NTG infusion. MVO2 at sinus rhythm was only reduced during the administration of NTG 1 µg · kg-1 · min-1, but not during the administration of NTG 2 µg · kg-1 · min-1, despite a reduction in left ventricular preload, reflected by a significant decrease in PCWP. The absence of a change in MVO2 in the presence of a reduction in preload during the infusion of NTG 2 µg · kg-1 · min-1 may be explained by the small but significant increase in HR from 65 bpm at control to 69 bpm during the infusion of NTG 2 µg · kg-1 · min-1.

Of special interest is the attenuated pacing-induced increase in MVO2 after NTG infusion (Fig. 2). A comparable observation was reported by Ihlen et al. (20), who studied the effects of NTG on pacing-induced myocardial ischemia. Studying patients with CAD in the catheterization laboratory by using left ventricular catheters, they found that NTG 1 µg · kg-1 · min-1 reduced MVO2 during pacing-induced ischemia by 38% (20). They concluded that this reduction in MVO2 during pacing was attributable to related changes in triple product, i.e., the product of HR, SBP, and left ventricular ejection time. Because we measured only radial artery pressure, not left ventricular pressure, we calculated RPP instead of triple product. In keeping with the study of Ihlen et al. (20), we found that RPP was reduced by large-dose NTG during pacing, whereas the RPP during sinus rhythm was unaffected (Fig. 2). During pacing, the NTG-induced decrease in RPP resulted from the decrease in SBP because the pacing rate remained unchanged. At sinus rhythm, SBP was also decreased by NTG, but HR was increased, thereby counteracting the effect of the decreased SBP on RPP, ultimately resulting in an unchanged RPP. Hence, there was a 22% lesser increase in RPP during the administration of NTG 2 µg · kg-1 · min-1 compared with control. However, this probably only partly explains the >50% reduction in pacing-induced increase in MVO2 (33).

An additional explanation for the attenuated increase in MVO2 during NTG infusion may have resided in NTG-induced changes in preload. Preload during pacing was reduced during the administration of NTG 2 µg · kg-1 · min-1, but during sinus rhythm, the same reduction in preload did not lead to detectable changes in MVO2. From the remaining determinants of MVO2—e.g., SVR, left ventricular wall stress, and contractility—we could only measure SVR, which did not change in response to NTG. Thus, it may be that changes in wall stress or contractility or that direct effects of NTG on myocardial function (34) have contributed to the attenuated pacing induced increase in MVO2 during NTG infusion.

The effect of IV NTG on metabolic coronary flow regulation in response to submaximal changes in HR has not been previously reported. In dogs, it has been shown that exogenous NO, administered as NTG 20 mg/kg IV, improved myocardial oxygen supply-consumption ratios of partially ischemic areas of canine myocardium (35), which led Kedem et al. (36) to the conclusion that exogenous NO improved the microregional relationship between coronary blood flow and metabolism. During the administration of NTG 2 µg · kg-1 · min-1, we found a relatively larger increase in DVO2, related to the pacing-induced increases in MVO2, which suggests that IV NTG influenced coronary metabolic regulation (Fig. 3). Because evidence is accumulating that endogenous NO is a mediator in metabolic coronary vasodilation (5–7), it is conceivable that NTG, as a donor of NO, may influence this regulation process.

In patients with CAD, metabolic flow regulation is reduced (5,6,37,38), most probably as a result of reduced endogenous NO activity (12) in the presence of endothelial dysfunction (9,10,39). Parker and Parker (31) suggested that NO substance donors, such as NTG, may act as a substitute therapy for a failing physiological mechanism, partly restoring the effect of the reduced endogenous NO activity. Our finding that an infusion of NTG 2 µg · kg-1 · min-1 is associated with more pronounced vasodilation in response to a metabolic stimulus supports this hypothesis. More studies focused on the role of the nitrovasodilators in coronary metabolic flow regulation in patients with CAD are warranted.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
References
 
NTG per se, in the absence of pacing, did not have a detectable effect on flow regulating coronary resistance vessels. Furthermore, a large-dose NTG infusion (2 µg · kg-1 · min-1) significantly blunted pacing-induced increases in MVO2 without altering MVO2 at sinus rhythm. In addition, during NTG infusion, DVO2 increased more than was required on the basis of the pacing-induced increase in MVO2. It is hypothesized that this drug and, thus, exogenous NO may restore coronary metabolic flow regulation in patients with CAD in whom endogenous NO activity is supposedly reduced.


   Footnotes
 
Presented in part at the annual meeting of the American Society of Anesthesiologists, October 1997.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 

  1. Feigl EO. Coronary physiology. Physiol Rev 1983;63:1–205.[Abstract/Free Full Text]
  2. Broten TP, Feigl EO. Role of myocardial oxygen and carbon dioxide in coronary autoregulation. Am J Physiol 1992;262:H1231–7.[Abstract/Free Full Text]
  3. Vergroesen I, Kal JE, Spaan JAE, Van Wezel HB. Myocardial oxygen supply: demand ratio as reference for coronary vasodilatory drug effects in humans. Heart 1997;78:117–26.[Abstract/Free Full Text]
  4. Vergroesen I, Noble MIM, Wieringa PA, Spaan JAE. Quantification of O2 consumption and arterial pressure as independent determinants of coronary flow. Am J Physiol 1987;252:H545–53.[Abstract/Free Full Text]
  5. Quyyumi AA, Dakak N, Andrews NP, et al. Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation 1995;92:320–6.[Abstract/Free Full Text]
  6. Gilligan DM, Panza JA, Kilcoyne CM, et al. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 1994;90:2853–8.[Abstract/Free Full Text]
  7. Jones CJ, Kuo L, Davis MJ, et al. Role of nitric oxide in the coronary microvascular responses to adenosine and increased metabolic demand. Circulation 1995;91:1807–13.[Abstract/Free Full Text]
  8. Abrams J. Hemodynamic effects of nitroglycerin and long-acting nitrates. Heart J 1985;110:216–24.
  9. Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990;81:491–7.[Abstract/Free Full Text]
  10. Zeiher AM, Krause T, Schächinger V, et al. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation 1995;91:2345–52.[Abstract/Free Full Text]
  11. Egashira K, Inou T, Hirooka Y, et al. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med 1993;328:1659–64.[Abstract/Free Full Text]
  12. Oemar BS, Tschudi MR, Godoy N, et al. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation 1998;97:2494–8.[Abstract/Free Full Text]
  13. Mathey DG, Chatterjee K, Tyberg JV, et al. Coronary sinus reflux: a source of error in the measurement of thermodilution coronary sinus flow. Circulation 1978;57:778–86.[Abstract/Free Full Text]
  14. Ganz W, Tamura K, Marcus HS, et al. Measurement of coronary sinus blood flow by contious thermodilution in man. Circulation 1971;44:181–95.[Abstract/Free Full Text]
  15. Hoffman JIE, Spaan JAE. Pressure-flow relations in coronary circulation. Physiol Rev 1990;70:331–89.[Abstract/Free Full Text]
  16. Lamprecht W, Stein P, Heinz F. Lactate. In: Methoden der Enzymatischen Analyse. Weinheim:Verlag Chemie, 1974:1729–37.
  17. Vergroesen I, Kal JE, Van Wezel HB. Coronary vasodilating drug effects or normal coronary blood flow regulation? J Cardiothorac Vasc Anesth 1998;12:450–6.[Web of Science][Medline]
  18. Noble MIM. Myocardial supply and demand. Heart 1997;78:105–6.[Free Full Text]
  19. Harrison DG, Bates JN. The nitrovasodilators: new ideas about old drugs. Circulation 1993;87:1461–7.[Abstract/Free Full Text]
  20. Ihlen H, Myhre E, Smith HJ. Potential deleterious haemodynamic effects of glyceryl trinitrate on myocardial ischaemia in man. Br Heart J 1984;52:510–5.[Abstract/Free Full Text]
  21. Choong CY, Freedman SB, Roubin GS, et al. Comparison of the effects of nifedipine and nitroglycerin on hemodynamic determinants of myocardial oxygen consumption and supply during exertional angina. Cardiovasc Pharmacol 1989;13:361–9.[Web of Science][Medline]
  22. Kedem J, Talafih K, Weiss HR. Improvement in regional myocardial O2 supply and O2 consumption by nitroglycerin during ischemia. Eur J Pharmacol 1985;112:47–55.[Web of Science][Medline]
  23. Fuchs RM, Brinker JA, Guzman PA, et al. Regional coronary blood flow during relief of pacing-induced angina by nitroglycerin: implications for mechanism of action. Am J Cardiol 1983;51:19–23.[Web of Science][Medline]
  24. Van Wezel HB, Kal JE, Vergroesen I, et al. Rate of coronary flow adaptation in response to changes in heart rate before and during anesthesia for coronary artery surgery. Anesthesiology 1996;84:1107–18.[Web of Science][Medline]
  25. Kern MJ, Eilen SD, Park RC, O'Rourke RA. Alterations in regional myocardial blood flow after nitroprusside and nitroglycerin in patients with and without significant coronary artery disease. Am J Cardiol 1986;58:443–8.[Web of Science][Medline]
  26. Davis ME, Jones CJH, Feneck RO, Walesby RK. The effects of intravenous nitroglycerin and isosorbide dinitrate on hemodynamics and myocardial metabolism. J Cardiothorac Anesth 1989;3:712–9.[Medline]
  27. Zhang J, Somers M, Cobb FR. Heterogeneous effects of nitroglycerin on the conductance and resistance coronary arterial vasculature. Am J Physiol 1993;264:H1960–8.[Abstract/Free Full Text]
  28. Gage JE, Hess OM, Murakami T, et al. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986;73:865–76.[Abstract/Free Full Text]
  29. Brown BG, Bolson E, Petersen RB, et al. The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. Circulation 1981;64:1089–97.[Abstract/Free Full Text]
  30. Kanatsuka H, Lamping KG, Eastham CL, Marcus ML. Heterogeneous changes in epimyocardial microvascular size during graded coronary stenosis: evidence of the microvascular site for autoregulation. Circ Res 1990;66:389–96.[Abstract/Free Full Text]
  31. Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med 1998;338:520–31.[Free Full Text]
  32. Moffitt EA, Sethna DH, Gray RJ, et al. Rate-pressure product correlates poorly with myocardial oxygen consumption during anaesthesia in coronary patients. Can Anaesth Soc J 1984;31:5–12.[Web of Science][Medline]
  33. Braunwald E, Sobel BE. Coronary blood flow and myocardial ischemia. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. London:WB Saunders, 1992:1162–3.
  34. Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans: assessment by bicoronary sodium nitroprusside infusion. Circulation 1994;89:2070–8.[Abstract/Free Full Text]
  35. Joselevitz-Goldman J, Acad BA, Weiss HR. Effects of nitroglycerin on regional O2 supply and O2 consumption in reperfused dog myocardium. Pharmacol 1989;166:283–93.
  36. Kedem J, Grover GJ, Weiss HR. Nitroglycerin improves the distribution of regional oxygenation in partially ischemic canine myocardium. J Cardiovasc Pharmacol 1985;7:760–6.[Web of Science][Medline]
  37. Sambuceti G, Marzilli M, Marraccini P, et al. Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease. Circulation 1997;95:2652–9.[Abstract/Free Full Text]
  38. Nabel EG, Selwyn AP, Ganz P. Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate. Circulation 1990;81:850–9.[Abstract/Free Full Text]
  39. Quyyumi AA, Cannon RO, Panza JA, et al. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 1992;86:1864–71.[Abstract/Free Full Text]
Accepted for publication October 23, 1998.




This article has been cited by other articles:


Home page
 CirculationHome page
J.-P. Bin, A. Doctor, J. Lindner, E. M. Hendersen, D. E. Le, H. Leong-Poi, N. G. Fisher, J. Christiansen, and S. Kaul
Effects of Nitroglycerin on Erythrocyte Rheology and Oxygen Unloading: Novel Role of S-Nitrosohemoglobin in Relieving Myocardial Ischemia
Circulation, May 30, 2006; 113(21): 2502 - 2508.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kal, J. E.
Right arrow Articles by van Wezel, H. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kal, J. E.
Right arrow Articles by van Wezel, H. B.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press