This study compared the transmural distribution of high-energy phosphate (HEP) depletion during oxidative stress induced by pacing- and dobutamine-induced tachycardia in myocardium perfused by a flow-limiting coronary stenosis. Myocardial blood flow (MBF) was measured with radioactive microspheres. Creatine phosphate (CrP), ATP, and Pi were measured with transmurally localized 31P NMR spectroscopy. In normal dogs a hydraulic occluder was used to produce a left anterior descending coronary artery stenosis, which maintained constant flow measured with a Doppler probe. Tachycardia was induced by rapid pacing (200 beats/min,n = 11) or by dobutamine infusion (20 μg ⋅ kg−1 ⋅ min−1 iv,n = 13) to produce a similar heart rate. In the presence of stenosis, pacing and dobutamine caused similar reductions of subendocardial (Endo)-to-subepicardial (Epi) MBF ratios (0.66 ± 0.06 vs. 0.63 ± 0.08, respectively). Stenosis plus pacing caused a decrease of the CrP-to-ATP ratio (CrP/ATP) in Endo from 2.00 ± 0.07 to 1.65 ± 0.08 (P < 0.05) with no significant change in Epi. Stenosis plus dobutamine caused HEP changes across the left ventricular wall, which were most marked in the outer myocardial layer (Epi CrP/ATP decreased from 2.33 ± 0.11 to 1.67 ± 0.12; Endo CrP/ATP decreased from 1.99 ± 0.09 to 1.64 ± 0.12). Thus HEP changes during oxidative stress that are produced by pacing parallel the pattern of hypoperfusion and are most severe in the subendocardium. In contrast, in response to inotropic stimulation, the transmural metabolic changes did not correspond to the pattern of the hypoperfusion.
- myocardial blood flow
- phosphorus-31 nuclear magnetic resonance spectroscopy
in the heart, several aspects of myocardial bioenergetics, perfusion, and systolic function are known to be transmurally nonuniform and are importantly affected by changes in systemic hemodynamics. These nonuniformities are amplified both during and subsequent to an ischemic insult, especially when a perfusion deficit is induced by a coronary stenosis. In a study (8) of dog myocardium distal to a flow-limiting coronary stenosis, the blood flow deficiency induced changes in myocardial high-energy phosphate (HEP) and Pi levels, which were progressively more severe in the inner layers of the left ventricular (LV) wall. These findings demonstrate that the inner layers of the LV wall are most vulnerable to a coronary stenosis insult. In contrast, in a study (15) of normal hearts at very high work states induced by a high dose of catecholamine stimulation, it was found that HEP changes across the LV wall were uniform with a tendency for most pronounced changes in the outer layers of the LV wall where blood flow was higher. These data suggest that during very high work states the energy expenditure of the subepicardium exceeds that of the subendocardium. This evidence of greater subepicardial (Epi) than subendocardial (Endo) energy expenditure in the catecholamine-stimulated normal heart is at variance with previous observations (13) indicating that under normal perfusion conditions myocardial energy expenditure is greatest in the subendocardium.
The present studies were performed in an open-chest canine model in which wall-thickening fraction, spatially localized31P NMR measurements of HEP and Pi, transmural blood flow, and ischemic region myocardial oxygen consumption (MV˙o 2) were measured during pacing- and dobutamine-induced episodes of tachycardia. In these studies mean myocardial blood flow was maintained constant at control levels during experimental interventions by adjustments of the severity of the imposed coronary artery stenosis. The purpose of the current investigation was to compare the transmural heterogeneity of bioenergetic responses to pacing- and dobutamine-induced tachycardia in myocardium in which flow reserve was virtually eliminated by means of a coronary artery stenosis.
Studies were performed on 24 normal mongrel dogs. All experimental procedures performed were approved by the University of Minnesota Animal Resources Committee. The investigation conformed to theGuide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 85–23, Revised 1985, Office of Science and Health Reports, Bethesda, MD 20892].
Twenty-four mongrel dogs weighing 19–25 kg were anesthetized with pentobarbital sodium (30 mg/kg iv), and adequate anesthesia was maintained with a continuing infusion of this agent (4 mg ⋅ kg−1 ⋅ h−1). The animals were intubated and ventilated with a respirator using room air supplemented with oxygen. A heparin-filled polyvinyl chloride catheter (3.0-mm OD) was inserted into the left femoral artery and advanced into the descending aorta. A left thoracotomy was performed through the fourth intercostal space. The pericardium was opened, and the heart was suspended in a pericardial cradle. Heparin-filled catheters were inserted into the left ventricle through the apical dimple and into the left atrium through the atrial appendage and secured with purse-string sutures. Coronary venous blood sampling was accomplished with a catheter introduced through the right atrial appendage and advanced into the coronary sinus until the tip could be palpated at the origin of the anterior interventricular vein. The proximal left anterior descending coronary artery (LAD) was dissected free, and a hydraulic occluder constructed of polyvinyl chloride tubing (2.7-mm OD) was placed around the artery proximal to the first major arterial branch. A Doppler flow probe was placed on the LAD proximal to the occluder, and a bipolar pacing electrode was sutured onto the right atrial appendage.
The region of the left ventricle that became cyanotic on inflation of the arterial occluder was determined by visual inspection, and a 28-mm-diameter NMR surface coil was sutured onto the epicardium overlying the ischemic area. To measure LV wall-thickening fraction, a single epicardial microcrystal was sutured onto the epicardium adjacent to the surface coil and within the ischemic region. The pericardial cradle was then released and the heart allowed to assume its normal position. The surface coil leads were connected to a balanced, tuned circuit, and the animals were placed within the magnet.
NMR data were acquired at 4.7 tesla using a SISCO (Spectroscopy Imaging System, Fremont, CA) instrument. Spatially localized31P NMR spectroscopy was performed with the rotating-frame experiment using adiabatic plane-rotation pulses for phase modulation (RAPP)-imaging-selected in vivo spectroscopy (ISIS) technique (RAPP/ISIS; Refs. 6, 11,14). The use of the adiabatic pulses ensured uniform spin rotations within the sensitive volume of the surface coil. Signal origin was restricted to a 18 × 18-mm column perpendicular to the surface coil plane and hence the LV wall. Localization along the column and therefore across the LV wall was achieved using the radio frequency magnetic field magnitude generated by the surface coil (B 1) gradient-based phase encoding. The number of transients accumulated for each phase-encoded step was weighted according to a nine-term Fourier series window, as previously described (6, 14). The phase-encoded data were used to generate a voxel or a “window” that could be shifted arbitrarily by postdata acquisition processing along the phase-encoded direction. Consequently, voxels were generated at different distances or “depths” from the outer LV wall (6, 11, 14). We normally present five voxels centered about 45°, 60°, 90°, 120°, and 135° phase angles as previously described (6, 11, 16). The position of the voxels relative to the coil was set according to theB 1strength at the coil center, which was experimentally determined in each case by measuring the 90° pulse length with a reference in the center of the coil (6, 11, 14). The 18 × 18-mm column was defined using sech/tanh-modulated, 1.5- to 2-ms-long adiabatic inversion pulses, and 2.5–3.0 G/cm static magnetic field (B 0) gradients. The adiabatic excitation pulse that follows the adiabatic inversion pulse in RAPP-ISIS was based on optimized functions and was typically 1 ms in length (6, 11, 14).
Complete transmural data sets were obtained in 10-min time blocks using a 6- to 7-s interpulse delay, which was sufficiently long to permit full relaxation of the ATP and Piresonances, and ∼95% relaxation of creatine phosphate (CrP) resonance as previously observed (6, 11, 14). The extent of CrP resonance saturation was determined for each heart at the beginning of the study by comparing nontransmural spectra obtained with either the 6- or ∼15-s interpulse delay. This saturation factor was subsequently employed to correct the CrP and CrP-to-ATP ratios (CrP/ATP) measured from the spectra. NMR data acquisition was gated to the cardiac and respiratory cycles by using the cardiac cycle as the master clock as previously described (6, 11, 14). This gating program also turned off the Doppler flow signal during the NMR data acquisition period (200 ms) to eliminate interference from the Doppler signal. The resonances in the NMR spectra were quantified using integral routine provided by SISCO.
Radio frequency transmission and signal detection were performed with the 28-mm-diameter surface coil described above. The coil was cemented to a sheet of silicone rubber 0.7 mm thick and 3.5 cm in diameter, with a capillary containing 15 μl of 3 M phosphonoacetic acid placed at the coil center to serve as a reference resonance. The proton signal from water detected with the surface coil was used to homogenize the magnetic field and to adjust the position of the animal in the magnet so that the coil was at or near the magnet and gradient isocenters (6, 11, 14). This was accomplished using a spin-echo experiment and a readout gradient. The information gathered in this step was also used to center the ISIS column for the RAPP-ISIS experiment. Chemical shifts were measured relative to CrP, which was assigned a chemical shift of −2.55 parts per million (ppm) relative to 85% phosphoric acid at 0 ppm.
Control peak integrals (defined as 100%) were used to calibrate subsequent spectra. Thus normalized values (relative to those present during the control period) for ATP and CrP were determined in five transmural layers during each experimental intervention, as was the CrP/ATP. Pi was undetectable in any layer under basal conditions but appeared during subsequent experimental conditions. To prevent the possible confounding effect resulting from 2,3-diphospho-d-glycerate in erythrocytes from the LV chamber cavity, all Pi values were determined and reported as ΔPi, which was calculated from the difference between the baseline of the integral in the Pi region and each experimental condition. Myocardial pH was estimated from the difference in the positions of the Pi and CrP resonances when Pi was detectable (1, 9, 16). Data are reported for the Epi, midmyocardial (Mid), and Endo voxels.
Hemodynamic and LV function measurements.
Aortic and LV pressures were measured using Spectromed TNF-R pressure transducers positioned at midchest level, and diastolic duration was determined from the LV pressure recordings. Transmural LV wall thickening was measured using the single epicardial microcrystal transducer and the 10-MHz pulsed-Doppler technique (4). All data were recorded on an eight-channel direct-writing recorder (model R14–28, Coulbourne).
Myocardial blood flow measurements.
Mean (on-line) LAD blood flow was measured with the Doppler flow probe. Transmural myocardial blood flow was measured using radionuclide-labeled microspheres (8), 15 μm in diameter, suspended in low-molecular-weight dextran. Microspheres labeled with four different radioisotopes (51Cr,85Sr,95Nb, and46Sc) were agitated in an ultrasonic mixer for 10 min before injection. Microsphere suspension containing 2 × 106microspheres was injected through the left atrial catheter and flushed with 10 ml of normal saline. A reference sample of arterial blood was drawn from the aortic catheter at a rate of 15 ml/min beginning 5 s before microsphere injection and continuing for 120 s. Radioactivity in the myocardial and blood reference specimens was determined using a gamma spectrometer with a multichannel analyzer (model 5912, Packard Instrument, Downers Grove, IL) at window settings chosen for the combination of radioisotopes used during the study. Activity in each energy window, background activity, and sample weight were entered into a digital computer programmed to correct for overlap between isotopes, for background activity, and to compute the corrected counts per minute per gram of myocardium. Knowing the rate of withdrawal of the reference blood specimen (Q˙r) and the radioactivity of the reference specimen (Cr), we used myocardial radioactivity (Cm) to compute myocardial blood flow (Q˙m) from the equation Q˙m =Q˙r(Cm/Cr). Microsphere blood flow measurements were expressed as milliliters per minute per gram of myocardium.
MV˙ o 2 measurements. For studies in which MV˙o 2 was determined, blood specimens were withdrawn anaerobically into iced syringes from the aortic and coronary venous catheters (3 ml each). , , and pH were measured with a blood gas analyzer (model 1304, Instrumentation Laboratory, Lexington, MA) calibrated with known gas mixtures. Hemoglobin content was determined by the cyanmethemoglobin method. Coronary venous and aortic oxyhemoglobin saturation values were calculated from the blood , pH, and temperature using the oxygen dissociation curve for dog blood (10). Blood oxygen content was calculated as hemoglobin × 1.34 × percent O2 saturation + (0.0031 × ). MV˙o 2 was computed as the product of myocardial blood flow measured with microspheres and the difference in oxygen content between aortic and coronary venous blood.
Study protocol group 1.
Ventilator rate, volume, and inspired oxygen content were adjusted (on the basis of arterial blood gas and pH measurements) as required to maintain physiological values (n = 11 hearts). Aortic and LV pressures and LV wall-thickening fraction were monitored continuously throughout the study. During each intervention, myocardial contractile function, blood flow, and hemodynamic measurements were collected simultaneously with the acquisition of transmural 31P NMR spectra. After control observations, the coronary artery occluder was inflated with a micrometer-driven syringe to reduce mean coronary blood flow (CBF; determined with the Doppler flow probe) to a level associated with a just-detectable decrease in LV wall-thickening fraction. The occluder was subsequently monitored and finely adjusted to maintain CBF at this reduced level until the end of the study. Thus the stenosis was used to maintain a constant level of mean CBF that was close to the basal value and that would be expected to exhaust autoregulation in the subendocardium (2). After we allowed ∼10 min to ensure a hemodynamic steady state, atrial pacing was begun at a rate of 200 beats/min, and all measurements were repeated in the presence of the coronary stenosis.
Study protocol group 2.
To examine the transmural heterogeneity of bioenergetic and thickening fraction changes in response to dobutamine-induced tachycardia, a second set of experiments was performed (n = 13 hearts). Surgical preparation and measurements were performed as described for group 1. Baseline measurements were obtained, and then infusion of dobutamine (20 μg ⋅ kg−1 ⋅ min−1iv) was initiated. After waiting for ∼10 min for a new hemodynamic steady state, we inflated the occluder to a degree sufficient to reduce mean LAD blood flow to baseline level. After waiting for 5 min, we repeated all measurements.
HEP and Pi spectral resonances were integrated using SISCO integral software. Hemodynamic data were measured from the strip-chart recordings. Systolic contractile function was obtained from the thickening fraction, which was measured as follows (4). For the whole wall thickening, gating depth (D) was set at 1.0 cm; end-diastolic thickness was measured at the initiation of the upstroke of the LV pressure tracing, whereas end-systolic thickness was measured 20 ms before peak decrease in pressure development over time. The values for 6–10 beats (corresponding to one respiratory cycle) were averaged. Whole wall thickening was defined as the difference between end-systolic and end-diastolic thicknesses divided by the gating depth.
Data were analyzed with Student’st-test. A value ofP < 0.05 was considered significant. Results are expressed as means ± SE.
Hemodynamic and LV systolic thickening fraction.
Hemodynamic and systolic wall-thickening data are shown in Table1. In both groups, heart rate increased comparably during pacing and dobutamine (P < 0.01). Ingroup 1, mean aortic pressure and LV systolic pressure (LVSP) decreased significantly during stenosis plus pacing. In group 2, LVSP increased significantly during dobutamine stimulation plus coronary stenosis. LV end-diastolic pressure (LVEDP) rose modestly, but significantly, during pacing in group 1; LVEDP was not affected by dobutamine in group 2. Ingroups 1 and2, the rate-pressure product (RPP = heart rate × LVSP) increased significantly during the interventions and increased more in group 2. LV contractile function became dyskinetic in both groups during coronary stenosis.
Myocardial blood flow.
The regional myocardial blood flow measurements are shown in Table2. In group 1, stenosis plus pacing tended to increase Epi and decrease Endo blood flow, which resulted in a decrease of the Endo-to-Epi blood flow ratio (Endo/Epi) (P < 0.01). Ingroup 2 application of the coronary stenosis and dobutamine infusion resulted in an increase of blood flow in the Epi layer and decrease of Endo flow, resulting in a marked decrease of the Endo/Epi (P < 0.01). In both groups, during tachycardia induced by rapid pacing or dobutamine, myocardial blood flow was lower in all myocardial layers in the ischemic region compared with the nonischemic region (Table 2) as was the Endo/Epi (P < 0.01).
MV˙o 2 in the ischemic region tended to increase during tachycardia stresses but did not achieve statistical significance (Table 3).
Myocardial HEP and Pi levels.
A transmural set of myocardial spectra from a group 1 experiment is shown in Fig.1, and a set from a group 2 experiment is shown in Fig.2. Blood flows, RPP, and MV˙o 2 data are given in the figure legends. In these transmural spectra every other voxel is virtually nonoverlapping; however, adjacent voxels partially overlap. The spectrum at the bottom of the transmural stack (voxel 1) is always located near the coil and hence the outer myocardial wall; therefore, it arises from the subepicardium and accordingly it is labeled as “Epi.” The location of this voxel is easily identified because it includes a resonance (not shown) at ∼15 ppm arising from a phosphonate compound contained in a small chamber placed in the center of the surface coil plane on the outer LV wall (11, 14, 16). Spectra from the midwall (voxel 3) and the subendocardium (voxel 5) are labeled as “Mid” and “Endo,” respectively, and have been rigorously tested previously (11, 14, 16). Prominent CrP and ATP resonances are observed in all voxels as expected (Fig.1 A). Under baseline conditions, Pi was too low to be detected in any myocardial layer at the signal-to-noise ratio of the spatially localized spectra, which was consistent with previous findings in the in vivo canine heart under baseline conditions (11, 14, 16). As illustrated in Fig. 1 B, during stenosis plus pacing the decrease of CrP and increase of Pi peaks are more severe in the inner layers of the LV wall. This change was concordant with the ischemic regional blood flow pattern (see Fig. 1). A set of spectra obtained from a heart in group 2 is illustrated in Fig. 2. During stenosis plus dobutamine a significant increase of Pi and decrease of CrP were observed across the LV wall with a tendency toward more pronounced changes in the outer layers of the LV wall where the regional blood flow was higher (Tables 2 and4).
Myocardial HEP levels, CrP/ATP, ΔPi/CrP, and pH for all dogs are shown in Table 4. Under baseline conditions, the CrP/ATP was slightly lower in the subendocardium than in the subepicardium. Ingroup 1 during stenosis plus pacing, decrease of CrP and the CrP/ATP and an increase of ΔPi/CrP were most prominent in the subendocardium. In group 2 in response to stenosis plus dobutamine, a marked decrease of CrP and the CrP/ATP and an increase of ΔPi/CrP occurred in every layer across the LV wall with a tendency toward the most pronounced changes being present in the outer layers. During tachycardia stresses the calculated myocardial pH tended to decrease to below 7.0 except for subepicardial pH at stenosis plus pacing (Table 4).
The present data indicate that, in a constant coronary flow model of myocardial underperfusion, tachycardia stresses resulting from either pacing or dobutamine are associated with a common pattern of transmural blood flow maldistribution; i.e., Epi blood flow exceeds that present in the subendocardium. However, the HEP and Pi responses to the two interventions are dissimilar. During pacing the alterations in HEP and Pi are largely confined to the inner myocardial layers and are therefore concordant with the transmural blood flow gradient. In contrast, during dobutamine infusion the HEP and Pi abnormalities are transmurally severe and tend to be more pronounced in the subepicardium, a pattern that is discordant with the transmural blood flow gradient.
Transmural blood flow distribution during tachycardia in flow-limited myocardium.
Cardiac contraction generates extravascular compressive forces that are the greatest in the deeper myocardial layers and normally impede perfusion markedly in the subendocardium during systole. Even during diastole, a transmural pressure gradient exists, which equals intrathoracic pressure at the epicardial surface and matches or exceeds cavity pressure in the subendocardium. Under normal conditions, autoregulation of the resistance vessels compensates for the inhibitory extravascular forces in the subendocardium. Unlike the situation in the subendocardium, in the subepicardium some flow normally continues throughout systole because extravascular pressure is lower than the perfusion pressure. Thus, whereas the duration of diastole and diastolic coronary pressure are major determinants of Endo perfusion, Epi flow can also be influenced by the difference between tissue and coronary pressure during systole. In the present study, the stenosis was slowly tightened until a barely perceptible decrease of systolic wall thickening was observed. This degree of stenosis results in exhaustion of the autoregulatory reserve in the resistance vessels of the subendocardium, whereas the Epi vessels still have the capacity for further vasodilation. Consequently, when the duration of diastole available for perfusion of the subendocardium was shortened by the tachycardia produced by pacing or dobutamine, the Endo vessels could not undergo further vasodilation and blood flow fell. In contrast, the Epi vessels were able to undergo additional vasodilation in response to the increased metabolic demands produced by pacing or dobutamine, so that Epi flow increased (Table 2).
Transmural distribution of metabolite levels and contractile work.
In the group 1 studies the stenosis alone was associated with slight reductions of Endo blood flow and systolic wall thickening (data not shown), suggesting the presence of slight metabolic stress. During pacing Epi blood flow was increased somewhat relative to baseline values and was identical to that in a nonischemic reference region. Therefore, compared with the normal zone, oxygen delivery to the subepicardium was normal, and the increased rate of energy utilization associated with the elevated heart rate remained in balance with energy-generating capacity; hence, ΔPi/CrP, CrP, and ATP were unaffected. However, in the subendocardium, blood flow fell during pacing relative to baseline values and was significantly lower than that in the nonischemic region. The decrease in Endo blood flow during pacing likely occurred because the stenosis had resulted in exhaustion of autoregulatory reserve in the subendocardium. As a result, the decrease in duration of diastole during pacing-induced tachycardia could not be countered by further vasodilation, resulting in a decrease in Endo blood flow. In the subendocardium, energy supply was perfusion limited compared with the normal zone, and demand exceeded energy-generating capacity with the result that the levels of CrP/ATP and the ΔPi/CrP were affected. These changes are consistent with the presence of ischemia (8, 15). Thus during rapid pacing the metabolic ischemia pattern across the LV wall was concordant with the blood flow distribution. Although a similar transmural redistribution of blood flow occurred during dobutamine-induced tachycardia, loss of phosphocreatine characteristic of ischemia was seen in the subepicardium (Table 4). This likely occurred because the inotropic effect of dobutamine caused a greater increase in energy demand than rapid pacing. What is interesting, however, is that the ischemic changes in the subendocardium during dobutamine were not greater than those observed during pacing. This suggests that after the subendocardium reached the level of energy supply-demand imbalance, it did not respond to the inotropic stimulation (and associated increase in energy demands) produced by dobutamine.
In large and small animal models studies of myocardial hypoxia or ischemia, it has been demonstrated previously that increase of Pi (5) or decrease of intracellular pH (9) performs an important role in downregulation of myocardial contractile force. In the present study, the observations that a transmural gradient increase of Pi led to the most pronounced changes in Endo layers during pacing-induced tachycardia and that this gradient disappeared as oxygen demand further increased, as indicated by RPP (Table 1) during dobutamine stimulation, suggest that metabolic ischemic markers (increase of Pi and decrease of pH) could play a role in redistributing the myocardial work more toward the outer layers where the blood flow was higher. During pacing, this transfer of systolic load was accommodated without evidence of ischemia in the Epi muscle, likely because Epi blood flow was able to increase sufficiently to support Epi contractile function. This “downregulation” of regional myocardial work in response to the oxygen availability is somewhat similar to the concept of myocardial “hibernation” (7). The data of the present study indicate that this downregulation can occur transmurally and almost instantly when regional ischemia occurs. It could be speculated that this response is protective of myocyte integrity at the expense of acute contractile dysfunction (Table 1) as long as residual blood flow exceeds a certain level.
MV˙o 2 measurements in a regional ischemic model have some limitations. Unless contamination of anterior coronary venous blood by efflux from a nonischemic region is rigorously excluded, the calculated ischemic zone MV˙o 2 may be inaccurate. Although it is likely that our coronary venous samples represent mainly ischemic zone efflux, a small but unknown degree of contamination cannot be excluded. However, even if some degree of contamination were present, the conclusions drawn from the data would not be significantly modified. For example, if the extraction fraction of contaminating blood was less than that in ischemic zone blood, then actual ischemic zone MV˙o 2 would be underestimated, not overestimated. Hence, the reported MV˙o 2 measurements indicate that there was significant residual oxidative phosphorylation in the ischemic zone.
The differential effects of pacing and dobutamine on systolic wall stress were not examined in the present study because measurements of chamber diameter could not be obtained during magnetic resonance spectroscopy. However, LVSP decreased modestly during pacing but increased during dobutamine infusion. Rooke and Feigl (12) observed that when they used the systolic pressure-heart rate product, proportional changes in heart rate and systolic pressuring had equal effects on oxygen consumption. They also obtained data using both isoproterenol and dobutamine as interventions that had positive inotropic and chronotropic effects; they observed that the triple product and the tension-time index showed inotropic oxygen wastage, whereas the pressure-work index and the heart rate-systolic pressure product did not. Rooke and Feigl (12) concluded that1) indexes that include the duration of systole are especially prone to show oxygen wastage during catecholamine infusion, because increasing contractility shortens the duration of systole, whereas it increases energy cost; and2) if the pressure-work index or RPP is used, it is unlikely that the measurements are confounded by the inotropic oxygen wasting factor. Thus in the present study the greater RPP during dobutamine infusion compared with atrial pacing would likely be a reasonable estimate of the greater metabolic demand during dobutamine.
In conclusion, in a constant ischemic flow model the HEP changes during oxidative stress produced by pacing paralleled the pattern of hypoperfusion and were most severe in the subendocardium. In contrast, in response to inotropic stimulation the transmural metabolic changes did not correspond to the pattern of the hypoperfusion. Residual blood flow level is a crucial factor for adequate downregulation to occur.
This work was supported by National Heart, Lung, and Blood Institute Grants HL-21872, HL-33600, HL-50470, HL-57994, and HL-58067. J. Zhang is recipient of an Established Investigator Award from the American Heart Association.
Address for reprint requests and other correspondence: J. Zhang, Box 508, Univ. of Minnesota Health Science Center, 420 Delaware St. SE, Minneapolis, MN 55455 (E-mail:).
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- Copyright © 1999 the American Physiological Society