Section Editor: Kenneth J. Tuman.
Regulation of coronary blood flow is dependent on metabolic, myogenic, neurohumoral, and endothelial responses . 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 . 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 . In patients with coronary artery disease (CAD) who have endothelial dysfunction [9-11], reduced endogenous NO activity , 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.
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. beta-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 side-branching 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 . 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) . 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 (Figure 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 [micro sign]g [center dot] kg-1 [center dot] min (-1), respectively.
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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] min-1, the infusion rate of NTG was increased to 2 [micro sign]g [center dot] kg-1 [center dot] 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 .
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 . 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 arteriocoronary 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 ScsO (2) 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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] 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.
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.
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, beta-adrenergic blocking drugs, and calcium entry-blockers. One patient was not using a beta-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.
In our patients who were taking beta-blockers until the morning of surgery, HR increased from 65 bpm at control to 69 bpm during the infusion of NTG 2 [micro sign]g [center dot] kg-1 [center dot] min-1. Therefore, pacing-induced changes in HR were smaller during the infusion of NTG 2 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] min-1, respectively. In accordance with the venodilating properties of NTG , 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 [micro sign]g [center dot] kg-1 [center dot] min-1 nor 2 [micro sign]g [center dot] kg-1 [center dot] min-1 changed systemic vascular resistance (SVR).
MVO2 at sinus rhythm was 13.7 +/- 3.4 mL O2/min at control. NTG 1 [micro sign]g [center dot] kg-1 [center dot] min-1 decreased MVO (2) to 12.9 +/- 3.3 (P = 0.016). However, during the infusion of NTG 2 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] min-1, and NTG 2 [micro sign]g [center dot] kg-1 [center dot] min-1, respectively) nor ScsO2. Coronary sinus PO (2) also remained unchanged throughout the study (20 +/- 2 mm Hg at control, 22 +/- 3 mm Hg during NTG 1 [micro sign]g [center dot] kg-1 [center dot] min-1, and 21 +/- 3 mm Hg during NTG 2 [micro sign]g [center dot] kg-1 [center dot] 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. ScsO (2) 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 [micro sign]g [center dot] kg-1 [center dot] 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 (Figure 2). MVO2 increased by 40% +/- 15% during control, 33% +/- 20% during the administration of NTG 1 [micro sign]g [center dot] kg-1 [center dot] min-1 (P = 0.39 compared with the increase at control), and only 19% +/- 10% during the administration of NTG 2 [micro sign]g [center dot] kg (-1) [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] min (-1) (Table 2).
During pacing, the infusion of NTG 1 and 2 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] 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).
This study in awake patients with CAD showed that an infusion of NTG 2 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] min-1 to deal with the potential variation in individual sensitivity to NTG . The small dose of 1 [micro sign]g [center dot] kg-1 [center dot] 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.  in a comparable study. The high infusion rate of 2 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] 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 . 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 . 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 . 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 . In addition, it has been suggested that NTG has an effect on collateral vessels  and epicardial stenoses .
In the present study, CSBF at sinus rhythm remained unchanged during infusion of NTG 1 and 2 [micro sign]g [center dot] kg-1 [center dot] min-1. Nevertheless, in our patients with CAD, potential vasodilation of epicardial arteries or epicardial stenoses may have occurred in response to NTG infusion . 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 . 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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] min-1 was associated with a significant decrease in MAP (i.e., coronary perfusion pressure) . 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  or leave MVO2 unchanged . 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 . 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 [micro sign]g [center dot] kg-1 [center dot] min (-1), but not during the administration of NTG 2 [micro sign]g [center dot] kg (-1) [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] 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 [micro sign]g [center dot] kg-1 [center dot] min-1.
Of special interest is the attenuated pacing-induced increase in MVO (2) after NTG infusion (Figure 2). A comparable observation was reported by Ihlen et al. , 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 [micro sign]g [center dot] kg-1 [center dot] min-1 reduced MVO2 during pacing-induced ischemia by 38% . 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. , we found that RPP was reduced by large-dose NTG during pacing, whereas the RPP during sinus rhythm was unaffected (Figure 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 [micro sign]g [center dot] kg-1 [center dot] min-1 compared with control. However, this probably only partly explains the >50% reduction in pacing-induced increase in MVO2 .
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 [micro sign]g [center dot] kg-1 [center dot] 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  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 , which led Kedem et al.  to the conclusion that exogenous NO improved the microregional relationship between coronary blood flow and metabolism. During the administration of NTG 2 [micro sign]g [center dot] kg-1 [center dot] 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 (Figure 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  in the presence of endothelial dysfunction [9,10,39]. Parker and Parker  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 [micro sign]g [center dot] kg-1 [center dot] 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.
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 [micro sign]g [center dot] kg-1 [center dot] 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.
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