Carbamyl phosphate-dependent ATP synthesis catalyzed by formyltetrahydrofolate synthetase.

Formyltetrahydrofolate synthetase (formate:tetrahydrofolate ligase (ADP-forming), EC 6.3.4.3) from Clostridium cylindrosporum catalyzes phosphate transfer from carbamyl phosphate to ADP. This activity is lost when monovalent cations are removed and is recovered when K+ is added back. Carbamyl phosphate is an inhibitor of the formyltetrahydrolfolate synthetase forward reaction, and formate as well as phosphate inhibit the ATP synthesis reaction. Acetyl phosphate and phosphonoacetate are inhibitors of both reactions. The results of kinetic studies support the concept that carbamyl phosphate is an analog of the putative intermediate of the formyltetrahydrofolate synthetase reaction, formyl phosphate.

Magnetic resonance characterization of the peri-infarction zone of reperfused myocardial infarction with necrosis-specific and extracellular nonspecific contrast media.

BACKGROUND: Because ischemically injured myocardium is frequently composed of viable and nonviable portions, a method to discriminate the two is useful for clinical management. METHODS AND RESULTS: Ischemically injured myocardium was characterized with extracellular nonspecific (Gd-DTPA) and necrosis-specific (mesoporphyrin) MR contrast media in rats. Relaxation rates (R1) were measured on day 1 and day 2 by inversion-recovery echoplanar imaging. Spin-echo imaging was used to define contrast-enhanced regions and regional wall thickening. Gadolinium concentration, area at risk, and infarct size were measured at postmortem examination. DeltaR1 ratio (DeltaR1(myocardium)/DeltaR1(blood)) after administration of Gd-DTPA was greater in ischemically injured myocardium (1.20+/-0.15) than in normal myocardium (0.47+/-0.05, P<0.05), which was attributed to differences in gadolinium concentration and water content. The Gd-DTPA-enhanced region on day 2 was larger (32.8+/-0.9%) than true infarction as demonstrated by triphenyltetrazolium chloride (TTC) (24.6+/-1.4%, P<0.001, r=0.21). Bland-Altman analysis revealed that the Gd-DTPA-enhanced region overestimated true infarct size by 7.8+/-5.9%. On the other hand, the mesoporphyrin-enhanced region (26.9+/-1.8%, P=NS, r=0.87) and true infarct size were identical. The difference in the areas demarcated by the 2 agents is the peri-infarction. Systolic and diastolic MR images revealed no wall thickening in the mesoporphyrin-enhanced region (0.3+/-3.3%) but reduced thickening in the Gd-DTPA-enhanced rim (8.5+/-5.5%, P<0.05). CONCLUSIONS: The Gd-DTPA-enhanced region encompasses both viable and nonviable portions of the ischemically injured myocardium. The Gd-DTPA-enhanced area overestimated infarct size, but the mesoporphyrin-enhanced area matched true infarct size. The salvageable peri-infarction zone can be characterized with double-contrast-enhanced and functional MR imaging; the mismatched area of enhancement between the 2 agents shows residual wall thickening.

Delineation of acute myocardial infarction with dysprosium DTPA-BMA: influence of dose of magnetic susceptibility contrast medium.

OBJECTIVES: The contrast enhancement of acutely infarcted myocardium produced by the nonionic magnetic susceptibility-enhancing agent dysprosium diethylenetriamine pentaacetic acid-bis-methylamide (DyDTPA-BMA [S-043 Injection]) was assessed in the current study to establish the lowest dose that would yield optimal contrast between normal and acutely infarcted myocardium. BACKGROUND: Magnetic susceptibility contrast agents enhance differences between normal and ischemic tissue by reducing the signal of the normally perfused tissue to which they distribute. METHODS: Acute myocardial infarctions were produced by ligation of the left coronary artery. At 3 to 4 h after occlusion, a dose of 0.1, 0.3 or 0.5 mmol/kg of DyDTPA-BMA was injected intravenously into eight rats each in group 1, 2 or 3, respectively; a fourth group of seven rats served as a control group. Nuclear magnetic resonance (NMR) transverse relaxation time (T2)-weighted images (electrocardiographically gated to every 5th beat, echo delay time [TE] = 60 ms) were acquired before and for 1 h after administration of contrast agent. RESULTS: Images obtained before the injection of contrast agent showed moderate differences in signal intensity between normal and infarcted myocardium (p < 0.05). The contrast enhancement and the duration of delineation between infarcted and normal myocardium produced by this agent were dose dependent. At doses of 0.1, 0.3 and 0.5 mmol/kg, DyDTPA-BMA produced signal loss in normal myocardium: 63 +/- 5%, 41 +/- 4% and 28 +/- 4% of the baseline values, respectively, without any significant reduction in signal intensity of the infarcted region. The reduction in signal of normal myocardium and delineation of the infarct persisted for 5 min at a dose of 0.1 mmol/kg, for 20 min at a dose of 0.3 mmol/kg and for 40 min at a dose of 0.5 mmol/kg. No change in signal intensity or signal intensity ratio between normal and infarcted myocardium was observed in the control group during the same observation period. CONCLUSIONS: These results suggest that low doses of this agent, comparable to those of longitudinal relaxation time (T1)-enhancing agents, can delineate acutely infarcted myocardium. A dose of 0.3 mmol/kg of DyDTPA-BMA (S-043 Injection) provides reasonably persistent demarcation of acute myocardial infarction. Because this dose dramatically suppresses the NMR signal of normal myocardium, it shows the infarcted region as a region of high intensity (bright spot) on NMR images.

Influence of severity of myocardial injury on distribution of macromolecules: extravascular versus intravascular gadolinium-based magnetic resonance contrast agents.

OBJECTIVES: This study sought to 1) compare the distribution of extravascular (573 Da) and intravascular (92 kDa) magnetic resonance (MR) contrast agents in reperfused infarcted myocardium, and 2) investigate the effect of injury severity on these distribution patterns. BACKGROUND: Myocardial distribution of low and high molecular weight contrast agents depends on vascular permeability, diffusive/convective transport within the interstitium and accessibility of the intracellular compartment (cellular integrity). METHODS: To vary the severity of myocardial injury, 72 rats were subjected to 20, 30, 45 or 75 min (n = 18, respectively) of coronary artery occlusion. After 2 h of reflow, the animals received either 0.05 mmol/kg of gadolinium-diethylenetriaminepentaacetic acid-bismethylamide (Gd-DTPA-BMA) (n = 24), (Gd-DTPA)30-albumin (n = 24) or saline (control group, n = 24). Three minutes after injection, the hearts were excised and imaged (spin-echo imaging parameters: repetition time 300 ms, echo time 8 ms, 2-tesla system), followed by triphenyltetrazolium chloride staining for infarct detection and sizing. RESULTS: Histomorphometric and MR infarct size (expressed as percent of slice surface) correlated well: r = 0.96 for Gd-DTPA-BMA; r = 0.95 for (Gd-DTPA)30-albumin. On Gd-DTPA-BMA-enhanced images, reperfused myocardial infarctions were homogeneously enhanced. The ratio of signal intensity of infarcted/ normal myocardium increased with increasing duration of ischemia (overall p < 0.0001, analysis of variance [ANOVA]), indicating an increase in the distribution volume of Gd-DTPA-BMA in postischemic myocardium. On (Gd-DTPA)30-albumin-enhanced images, reperfused infarctions consisted of a bright border zone and a less enhanced central core. The extent of the core increased with increasing duration of ischemia (overall p value < 0.0001, ANOVA). CONCLUSIONS: At 2 h of reperfusion, the distribution of MR contrast agents in postischemic myocardium is 1) specific for extravascular and intravascular agents, and 2) modulated by the duration of ischemia.

Effects of nicardipine, a calcium antagonist, on myocardial salvage and high energy phosphate stores in reperfused myocardial injury.

The current study determined the effectiveness of nicardipine, a 1,4-dihydropyridine calcium antagonist, in preserving reperfused myocardium in a cat model of temporary coronary occlusion and ascertained if replenishment of myocardial phosphate stores during reperfusion as defined by phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy was indicative of salvage. Twenty open chest, anesthetized cats were studied with use of a snare ligature around the proximal left anterior descending coronary artery, with a coil sutured to the epicardial surface overlying the distribution of the artery. Peak areas of phosphocreatine, inorganic phosphate and adenosine triphosphate (ATP) NMR signals were measured during 1 h of occlusion followed by 1.5 h of reperfusion. Infarct size and jeopardy area were determined in vitro by simultaneous infusion of phthalocyanine blue dye and triphenyltetrazolium chloride into the aorta and the left anterior descending coronary artery, respectively, after 5 h of myocardial reperfusion. Nicardipine-treated and control groups had similar jeopardy area values (41.2 +/- 1.6% versus 47.4 +/- 3.1% of the left ventricle), but infarct area was significantly reduced in the nicardipine-treated group (3.2 +/- 1.1% versus 24.9 +/- 7.5% of jeopardy area, p less than 0.01). High energy phosphate compounds remained markedly altered during reperfusion in both groups. No significant improvement in phosphocreatine or inorganic phosphate recovery was observed in animals pretreated with nicardipine despite an 87% reduction in infarct size. Myocardial ATP was greater during reperfusion in the nicardipine-treated compared with the control group (average over initial 90 min of reperfusion 58 +/- 6% versus 46 +/- 3% of baseline values, p less than 0.05), suggesting improved recovery of ATP. However, the measured levels of high energy phosphate compounds during reperfusion and their ratios did not correlate with infarct size and thus were not predictive of myocardial salvage.

Microvascular injury in reperfused infarcted myocardium: noninvasive assessment with contrast-enhanced echoplanar magnetic resonance imaging.

OBJECTIVES: The purpose of this study was to measure the accumulation of labeled albumin and to visualize its distribution pattern in reperfused infarcted myocardium as a function of time between onset of reperfusion and administration of the tracer. BACKGROUND: Myocardial microvascular injury leads to leakage of albumin from the intravascular space. Quantitative measurements of GdDTPA-albumin with inversion recovery echoplanar imaging (IR-EPI) may allow noninvasive monitoring of microvascular injury. METHODS: After 1 h of coronary artery occlusion, 56 rats were injected with GdDTPA-albumin or 123I-GdDTPA-albumin either immediately before reperfusion or 1/2, 1 or 24 h after reperfusion. GdDTPA-albumin in blood, normal myocardium and reperfused infarction was dynamically measured with IR-EPI during 1 h postinjection (PI). Autoradiograms were obtained at 15 min PI. Accumulation of labeled albumin in myocardium was expressed as the ratio of myocardial to blood content. RESULTS: In normal myocardium, the ratio of changes of relaxation rate-ratio (deltaR1-ratio) was 0.12+/-0.01 and did not change over 1 h. In reperfused infarction, however, the deltaR1-ratio increased after administration. Animals given GdDTPA-albumin before reperfusion exhibited fastest accumulation (deltaR1-ratio 15 min PI: 0.56+/-0.03) and essentially homogeneous distribution. The accumulation was slower when administered at 1/2, 1 and 24 h after reperfusion (deltaR1-ratios 15 min PI: 0.39+/-0.03; 0.31+/-0.04; 0.16+/-0.01; p < 0.001 compared to administration before reperfusion). Moreover, the tracer accumulated predominantly in the periphery of the injury zone. CONCLUSIONS: Amount and distribution pattern of labeled albumin in reperfused infarction are modulated by duration of reperfusion. The accumulation of GdDTPA-albumin can be quantified by IR-EPI. Thus, IR-EPI may be useful to noninvasively monitor myocardial microvascular injury in reperfused infarction.

Correlations between in vivo 31P NMR spectroscopy measurements, tumor size, hypoxic fraction and cell survival after radiotherapy.

Phosphorus metabolite levels were measured non-invasively using 31P magnetic resonance spectroscopy (MRS) in SCCVII/SF tumors, subcutaneously transplanted into the legs of unanesthetized C3Hf/Sed mice. Shortly after MRS measurements, tumors were irradiated with a single dose of 20 Gy, and cell survival and radiobiologic hypoxic fraction were determined with an in vitro cloning assay. Significant correlations were found between tumor size and surviving fraction, hypoxic fraction, pH, and phosphorus metabolite ratios. With increase of tumor size, surviving fraction and hypoxic fraction both increased, the ratios of inorganic phosphate and phosphomonoesters to nucleoside triphosphates (Pi/NTP and PME/NTP, respectively) and inorganic phosphate to phosphocreatine (Pi/PCr) increased and pH decreased. However, considerable heterogeneity of MRS spectral parameters, even in tumors of similar size, precluded accurate prediction of hypoxic fraction and cell survival after radiotherapy.

31P magnetic resonance spectroscopy of animal uveal melanoma.

Scleral surface coils were used to obtain in vivo magnetic resonance spectra (MRS) of Greene melanoma implanted in the rabbit uvea. Well-localized tumor spectra (4.7 Tesla) with good signal-to-noise ratios (S/N) were obtained from the tumor with a "single-pulse" sequence in less than 1 hour. Tumor localization was confirmed with one-dimensional spectroscopic imaging studies. Serial 31P spectra were obtained during tumor growth and after both optimal and suboptimal hyperthermia. Early 31P MRS change is correlated with tumor treatment response and preceded histologic evidence of cell destruction. Twenty-four to 48 hours after successful treatment, the inorganic phosphate/nucleoside triphosphate (NTP), and phosphomonoester/NTP ratios were significantly increased from 1.2 +/- 0.1 to 1.7 +/- 0.1 and 1.3 +/- 0.1 to 1.8 +/- 0.2, respectively. In contrast, untreated or ineffectively treated tumors showed little change. Interpretation of 31P MRS data in this animal uveal melanoma model after the first week was complicated by decreased S/N, increased contamination from contiguous tissues, ingrowth of fibroblasts, macrophages, and intratumor hemorrhage.

Effect of ethanol on cholecystokinin-induced enzyme secretion from isolated rat pancreatic acini.

Cholecystokinin octapeptide (CCK8)-stimulated amylase release in isolated rat pancreatic acini was inhibited over 30% by 600 mM ethanol. The configuration of the dose-response curve for CCK8, however, in the presence of ethanol was similar to that of the control. Amylase release elicited by maximal concentrations of CCK8 (300 pM) was inhibited by increasing concentrations of ethanol (0.3 to 1.3 M), and this inhibition was concentration dependent. In addition, the binding of [125I]CCK33 to specific membrane receptors on acini was inhibited by ethanol in a dose-dependent manner. A positive correlation between the inhibitory effects of ethanol on CCK binding and CCK-induced amylase release was observed. Furthermore, these inhibitory effects of ethanol were reversible. Basal amylase release, however, was increased 20-50% by ethanol between the concentrations of 0.3 and 1.3 M; higher concentrations caused a leakage of amylase from the acini both in the absence and presence of 300 pM CCK8. This is confirmed by 51Cr release from prelabeled acini which revealed no significant damage to acinar cell membrane between 0.3 and 1.6 M ethanol, but significant damage to acini at higher concentrations. These data suggest that the 600 mM ethanol-induced inhibition of CCK action in acini is due to reversible perturbation of the acinar cell membrane.

Irreversible inhibition by acetaldehyde of cholecystokinin-induced amylase secretion from isolated rat pancreatic acini.

Acetaldehyde inhibited both amylase secretion induced by maximal concentrations (300 pM) of cholecystokinin octapeptide and the binding of radioiodinated cholecystokinin to receptors on isolated rat pancreatic acini. This inhibition was concentration dependent (10 mM to 1 M for amylase secretion and 100 mM to 1 M for binding). However, a correlation between the two inhibitory effects could not be obtained. Furthermore, the inhibitory effects were not reversible. Acetaldehyde did not alter the basal amylase secretion between 6 and 45 mM concentrations. However, 60, 100 and 300 mM acetaldehyde significantly decreased basal amylase secretion; no significant change in amylase secretion was observed at 600 mM and 1 M. Higher concentrations of acetaldehyde produced a 2- to 10-fold increase in basal amylase secretion. 51Cr release from prelabeled acini revealed no significant cell membrane damage between 10 and 600 mM acetaldehyde. These data suggest that acetaldehyde inhibition of cholecystokinin-induced amylase secretion is intracellularly mediated.

Cardiovascular responses after ionic and nonionic magnetic resonance contrast media in rats with acute myocardial infarction.

RATIONALE AND OBJECTIVES: Contrast media may have quantitatively or even qualitatively different effects in the presence of underlying pathologic states compared with normal states. This study was designed to examine and compare the hemodynamic effects of bolus administration of ionic (gadopentetate dimeglumine) and nonionic (gadodiamide) magnetic resonance (MR) contrast media in rats subjected to acute myocardial infarction. METHODS: Acute myocardial infarction was induced in two groups of rats (n = 20) by ligating the left coronary artery. Each animal received four bolus injections, iso-osmolar glucose followed by three incremental doses of either an ionic or a nonionic MR contrast agent (0.1, 0.3, and 0.5 mmol/kg). The effects of iso-osmolar glucose and each dose of MR contrast agent on the cardiovascular system were monitored for 15 minutes. RESULTS: Iso-osmolar glucose injection did not cause hemodynamic parameters to significantly differ from baseline values. Nonionic gadodiamide produced no significant hemodynamic effects at all injected doses compared with iso-osmolar glucose. However, ionic gadopentetate dimeglumine caused significant deleterious hemodynamic effects in a dose-dependent fashion. Gadopentetate dimeglumine caused depression in left ventricular (LV) systolic pressure and systemic arterial pressure at the lowest dose (0.1 mmol/kg). At the maximum dose (0.5 mmol/kg), gadopentetate dimeglumine decreased systolic arterial pressure by 48%, rate-pressure product by 55%, LV end systolic pressure by 48%, rate of rise of LV pressure (dP/dt) by 55%, and heart rate by 10%. LV end diastolic pressure increased by 46%. Arrhythmias were observed in 20% (2/10) of the animals after injection of gadopentetate dimeglumine, but not after gadodiamide. CONCLUSIONS: Compared with ionic gadopentetate dimeglumine, nonionic gadodiamide is a hemodynamically safe MR contrast agent in this experimental model when it is injected as a rapid bolus at high doses and in the presence of acute myocardial infarction.

Measurement of blood flow and perfusion in the cardiovascular system.

Complete evaluation of cardiovascular disease by a single imaging technique requires measurement of bulk flow in blood vessels and estimation of relative or ideally absolute perfusion at the tissue level. Magnetic resonance (MR) measurement of blood flow in arteries and veins has been done using the velocity-encoded phase cine gradient echo technique. This technique has been applied with cine MR to measure normal and pathologically high velocities. Measurement of relative perfusion in the myocardium has used the intravenous injection of T1 relaxation enhancing and magnetic susceptibility MR contrast media with rapid image acquisition using echoplanar imaging. MR images (MRIs) acquired during steady-state distribution or during the first passage of these contrast media have depicted ischemic myocardial regions.

Depiction of reperfused myocardial infarction using contrast-enhanced spin echo and gradient echo magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors used gadolinium (Gd) chelate as a T1, T2, and T2* enhancing agent in reperfused myocardial infarction to compare the appearance of reperfused myocardial infarction on spin echo and gradient echo magnetic resonance (MR) sequences. METHODS: Rats (n = 28) were subjected to reperfused myocardial infarction and received no contrast medium, 0.2, 0.5, or 1.0 mmol/kg Gd DTPA-BMA. Spin echo and gradient echo MR images of the excised hearts (n = 7 rats per group) were acquired using 2.0 T system: repetition time (TR)/echo time (TE) = 300/20 ms for T1-weighted spin echo, TR/TE = 4000/80 ms for T2-weighted spin echo, and TR/TE = 600/10, 15, 20, and 30 ms for gradient echo imaging. Regional T2 and T2* relaxation times were measured. Triphenyl tetrazolium chloride was used to verify regional infarction. RESULTS: Unenhanced spin echo images failed to distinguish infarcted from normal myocardium. On Gd DTPA-BMA enhanced T1-weighted spin echo images, infarction was depicted as a high-intensity region "hot spot." On the other hand, the infarcted region was visualized as a low-signal region "cold spot" on Gd DTPA-BMA enhanced T2-weighted images. Changes in signal intensity and T2 relaxation time on T2 weighted images were dose dependent. On gradient recalled echo images, the infarcted region was discriminated from normal myocardium by a dark boundary zone, which was visible only at 1.0 mmol/kg. The presence of infarction was documented in every heart. CONCLUSIONS: The contrast between normal and infarcted myocardium was affected greatly by the dose and imaging parameters. The results indicate that spin echo and gradient echo images have greatly differing sensitivities to extracellular gadolinium chelates. Changes in myocardial T2 relaxation time, but not T2*, correlated well with the dose.

Effect of lidocaine on acute regional myocardial ischemia and reperfusion in the cat. An in-vivo 31P magnetic resonance spectroscopy study.

RATIONALE AND OBJECTIVES: The authors examined the relationship between myocardial infarction, high-energy phosphate compounds, and regional contractility after myocardial ischemia and reperfusion in cats. METHODS: Hemodynamic measurements, high-energy phosphate levels, and segmental shortening were measured every 30 minutes in two groups of cats subjected to 2 hours of occlusion of the left anterior descending coronary artery and 4 hours reperfusion. Group 1 (n = 10) animals were infused with a low level of lidocaine, 0.05 mg/kg/hr, while group 2 (n = 10) received a higher dose, 7.5 mg/kg/hr. The infarcted region was measured postmortem. RESULTS: Group 1 animals had larger infarcts (39 +/- 6 vs. 12 +/- 5% of jeopardy, P < .05) and less phosphocreatine recovery during reflow (52 +/- 7% vs. 73 +/- 2% of control, P < .01) than did group 2. Group 2 showed recovery of percentage systolic shortening during reflow (1.4 +/- 2% at 30 minutes vs. 7.1 +/- 2.3% at 4 hours, P < .05), whereas group 1 exhibited no improvement. A significant correlation was found between infarct size under the surface coil and phosphocreatine content during reflow, but not between contractile function and infarction size or metabolite levels during reflow. CONCLUSIONS: Lidocaine infusion enhanced recovery of myocardial contractility during reperfusion and decreased infarct size. Greater recovery of phosphocreatine during reperfusion was predictive of greater myocardial salvage during reperfusion.

The use of contrast-enhanced magnetic resonance imaging to define ischemic injury after reperfusion. Comparison in normal and hypertrophied hearts.

RATIONALE AND OBJECTIVES: Magnetic resonance imaging (MRI) was used to demonstrate the infarction size in reperfused ischemic myocardium of normal and hypertrophied hearts, and to test the hypothesis that hypertrophied hearts manifest greater susceptibility to ischemia. METHODS: Normal rats (n = 11) and rats subjected to left ventricular hypertrophy (LVH) by aortic banding (n = 13) were studied. After 7 weeks, the left coronary artery was occluded for 25 minutes and reperfused for 1 hour before MRI. Electrocardiogram-gated spin-echo images were acquired before and after administration of 0.3 mmol/kg gadoteridol. To quantify the hyperintense area demarcated by gadoteridol, 3 transaxial images were acquired at different levels. Jeopardy and infarcted areas were measured in the same three slices postmortem using blue dye and triphenyltetrazolium chloride (TTC) stain, respectively. RESULTS: Before administration, there was no significant difference in signal intensity between nonischemic (0.42 +/- 0.03 arbitrary units) and ischemic (0.41 +/- 0.03) myocardium in either group. After gadoteridol injection, signal intensity of the reperfused injured region was higher than that of nonischemic myocardium (1.48 +/- 0.16 vs. 0.72 +/- 0.06, P < .05). Magnetic resonance delineation of the hyperintense area persisted for at least 30 minutes. The size of the hyperintense area was larger in LVH than in control hearts (25 +/- 5% vs. 7 +/- 3% of LV surface area, P < .05) and did relate closely to the area of myocardial infarction (r = .97), but not with the jeopardy area (r = .42). On TTC staining, the infarction size also was significantly greater in LVH than in normal group (18 +/- 5% vs. 5 +/- 2% of LV surface area, P < .05). The jeopardy areas of normal and LVH hearts showed no significant difference (46 +/- 2% vs. 47 +/- 3%). CONCLUSION: Magnetic resonance imaging confirms the concept that reperfused myocardial injury is larger in LVH than normal hearts after brief coronary occlusion. Contrast-enhanced MRI can define the size of reperfused myocardial injury. Thus, MRI is a suitable technique to assess conditions accentuating ischemic injury.

Comparison of cardiovascular response to ionic and nonionic magnetic resonance susceptibility contrast agents.

RATIONALE AND OBJECTIVES: Bolus injection of magnetic resonance (MR) contrast media has been used in recent years to exploit the diagnostic advantage of newer fast MR imaging sequences. The bolus effects of three equimolar dosages of ionic and nonionic magnetic susceptibility contrast agents on several cardiovascular functional parameters are investigated in normal rats and in rats subjected to acute myocardial infarction. These results are related to the osmolalities of the injected solutions. METHODS: Four groups of rats were examined (n = 10 rats per group). Twenty normal rats were studied. Acute myocardial infarction was produced by ligating the anterior branch of the left coronary artery for 2 hours in another 20 rats. Sequential equimolar doses of 0.1, 0.3, and 0.5 mmol/kg of ionic dysprosium diethylenetriamine pentaacetic acid dimeglumine ([NMG]2DyDTPA) or nonionic dysporosium diethylenetriamine pentaacetic acid-bis-methylamide (DyDTPA-BMA) (sprodiamide injection) were administered intravenously into the left jugular vein as a bolus. Hemodynamic parameters (heart rate, left ventricular pressures, rate of rise of left ventricular pressure [+/- dP/dt], and electrocardiogram as well as central and peripheral pressures) were continuously monitored for 15 minutes after each dose. Left ventricular developed pressure and rate pressure product, as indicators of myocardial oxygen consumption, were calculated. Osmolalities of the injected solutions were determined from freezing-point depression and correlated with the observed hemodynamic alterations. RESULTS: Bolus administration of 0.1, 0.3, and 0.5 mmol/kg DyDTPA-BMA produced no significant effect on the various hemodynamic parameters. (NMG)2DyDTPA caused dose-dependent attenuations in heart rate, left ventricular pressures, +/- dP/dt, rate pressure product and arterial blood pressures in both normal and infarcted rats. The magnitude of the response was dose dependent. Significant correlations were observed between osmolality and peak change of hemodynamic variables (r values between 0.99-1.00) after the administration of (NMG)2DyDTPA, but not after the injection of DyDTPA-BMA. CONCLUSIONS: Bolus administration of (NMG)2DyDTPA resulted in transient negative inotropic and chronotropic effects and hypotension in both healthy and infarcted animals. DyDTPA-BMA, administered as a bolus even at high doses, caused no appreciable hemodynamic alterations.

Real-time dynamics of an extravascular magnetic resonance contrast medium in acutely infarcted myocardium using inversion recovery and gradient-recalled echo-planar imaging.

RATIONALE AND OBJECTIVES: The purposes of this study are to evaluate the first-pass profile of gadolinium-BOPTA/Dimeg (Gd-BOPTA/Dimeg) during its transit through hearts subjected to acute myocardial infarction, and to delineate these infarcted regions by the use of ultrafast magnetic resonance imaging (MRI). METHODS: Regional ischemia was induced in anesthetized rats by occluding the left coronary artery. Imaging parameters for single shot EPI included TE, 10 mseconds; AT, 33 mseconds; and 64 x 64-pixel matrix. Consecutive images were obtained every 1 to 2 seconds over a 30-second period. After approximately two images, Gd-BOPTA/Dimeg was injected intravenously (0.05 and 0.25 mmol/kg). RESULTS: Gd-BOPTA/Dimeg (0.05 mmol/kg), with inversion recovery EPI, produced a substantial increase in signal intensity of right and then left ventricular blood. Normally perfused myocardium also was enhanced, but not the acutely infarcted region. Clear delineation of the infarcted region as negatively enhanced "cold spots" persisted for at least 20 seconds. Gd-BOPTA/Dimeg (0.25 mmol/kg) with standard gradient-recalled EPI produced a different profile of signal intensity changes. Signal intensities of ventricular blood and normal myocardium were greatly reduced, leaving the infarcted zone as a positively enhanced "hot spot." Delineation of the infarcted region persisted for 6 to 8 seconds. The infarcted zone detected with MRI corresponded to that observed at autopsy. CONCLUSIONS: Regions of acute myocardial infarction can be detected as negatively enhanced "cold spots" or positively enhanced "hot spots" by studying the first-pass dynamics of Gd-BOPTA/Dimeg through hearts with regional ischemia by use of single shot EPI.

Preservation of high-energy phosphate reserves in a cat model of post-ischemic myocardial dysfunction.

Brief episodes of myocardial ischemia are known to cause reversible depression of regional myocardial contraction after reperfusion. One of the mechanisms of this persistent regional dysfunction has been proposed to be depletion of high-energy phosphate compounds. Eight cats were prepared with a reversible snare occluder around the left anterior descending artery (LAD); a surface coil sutured to the epicardial surface over the LAD territory for measurement of 31-phosphorus (31P) magnetic resonance spectroscopy (MRS) spectra; and a pair of ultrasonic crystals implanted in the mid-myocardium for measurement of regional segment length shortening. The baseline value of percent segment length shortening (%SS) was 12.8 +/- 1.4%. Increased afterload did not significantly alter high-energy phosphate levels or %SS. All animals exhibited passive systolic bulging during occlusion (-8.4 +/- 3.6% systolic shortening) as well as reduced phosphocreatine (PRc, 30 +/- 3% of control) and increased inorganic phosphorus (Pi) (239 +/- 18%), but there was no change in adenosine triphosphate (ATP). During reflow, %SS did not completely recover (4.0 +/- 2.9%, P less than .05 versus baseline). PCr and Pi returned to control levels during the first 30 minutes of reperfusion. Increased afterload had no significant effect on high-energy phosphates or %SS in stunned hearts. These findings indicate a lack of correlation between recovery of high-energy phosphate stores and regional myocardial contractility in stunned myocardium. High-energy phosphate reserves are preserved in stunned myocardium and are unlikely to be a direct cause of myocardial dysfunction.

Comparison of T1-enhancing and magnetic susceptibility magnetic resonance contrast agents for demarcation of the jeopardy area in experimental myocardial infarction.

RATIONALE AND OBJECTIVES: This study compared the areas demarcated by a T1-enhancing agent, Gd-DTPA-BMA, and a magnetic susceptibility agent, Dy-DTPA-BMA, with 201thallium autoradiography (indicator of perfusion) and postmortem histochemical staining with triphenyltetrazolium chloride (TTC)(indicator of infarction). METHODS: Thirteen rats were subjected to coronary artery occlusion for 3 to 4 hours before acquisition of four sets of electrocardiogram-gated spin-echo magnetic resonance (MR) images: T1-weighted images before and after 0.2 mmol/kg Gd-DTPA-BMA; and T2-weighted images before and after 0.3 mmol/kg Dy-DTPA-BMA. After MR imaging, intravenous 201thallium delineated the area of decreased myocardial perfusion. At autopsy, TTC staining delineated the area of myocardial infarction. RESULTS: A myocardial region in the distribution of the occluded artery was delinated as a hyperintense area ("hot-spot") by Dy-DTPA-BMA and as a hypointense area ("cold-spot") by Gd-DTPA-BMA. The hyperintense area demarcated by Dy-DTPA-BMA (51 +/- 3% of the area of the midequitorial slice of the left ventricle) showed a closer relationship to the area of decreased myocardial perfusion (jeopardized area) (46 +/- 3%), determined by 201thallium autoradiography, than the area of myocardial infarction (36 +/- 4%), determined by histochemical staining. However, the hypointense area demarcated by Gd-DTPA-BMA (29 +/- 2%) did not relate as closely to the area of decreased myocardial perfusion (slope = 0.54) or the area of myocardial infarction (r = 0.46). CONCLUSIONS: The abnormal myocardial area delineated by the magnetic susceptibility agent showed a closer relationship to the area of deficient myocardial perfusion (jeopardy area) after coronary occlusion than that defined by T1-enhancing contrast media.

Magnetic resonance imaging of diffusion and perfusion.

Two promising advances in MRI have recently evolved. Water proton directional "diffusion" as well as "perfusion" processes can be imaged in a rapid (on the order of milliseconds) and accurate manner. MR diffusion imaging is shown to effectively allow determination of the presence of anisotropic water diffusion in animal and human cerebral and spinal white matter and in peripheral nerves. In another important application, the measured apparent water proton diffusion is observed to be significantly slowed in cerebral gray matter within the first minutes following experimental stroke suggesting that MRI could be useful in rapid initial assessments of ischemic damage. MR contrast media can cause regional changes due to either magnetic susceptibility-induced T2* shortening or to paramagnetic-induced T1 shortening. The passage of a contrast bolus through the microcirculation can be monitored using high-speed MRI and can provide significant contrast enhancement in ischemic and normally perfused tissues.