bms-181321 and Myocardial-Ischemia

Conventional perfusion scintigraphy assesses disparities in regional myocardial blood flow but does not directly detect hypoxic tissue. Nitroimidazoles labeled with positron-emitting radionuclides have recently shown promise as direct markers of myocardial hypoxia. This study evaluates a new 99mTc-labeled nitroimidazole of potential benefit in standard myocardial scintigraphy.. Technetium-99m-labeled nitroimidazole was administered to rabbits during the early reperfusion phase after 10 min (Group 1) or 60 (Group 2) min of coronary occlusion or after 10 min of a fixed coronary occlusion (Group 3). Tracer retention at 1 hr was assessed in relation to microsphere-determined blood flow during coronary occlusion and at tracer injection. The pattern of nitroimidazole retention on autoradiographs was then compared with the pattern of myocardial hypoperfusion defined by fluorescein photography to precisely define tracer localization.. The retention of nitroimidazole in Group 1 rabbits (brief occlusion) was independent of both occlusion and reperfusion blood flow and was uniformly distributed on the autoradiographs. In contrast, nitroimidazole retention in Groups 2 and 3 increased with the severity of hypoperfusion during the occlusion phase and precisely delineated the ischemic zone on all autoradiographs.. This 99mTc-labeled hypoxia-avid tracer delineates severe ischemia even after blood flow to the compromised myocardium has been restored. This class of compounds can potentially enhance the physiological assessment of patients with ischemic heart disease.

Topics: Animals; Autoradiography; Coronary Circulation; Fluoresceins; Heart; Myocardial Ischemia; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Photography; Rabbits; Radionuclide Imaging; Time Factors; Tissue Survival

Delineation of viable ischemic myocardium is an important problem in nuclear cardiology. To determine the feasibility of using a technetium-labeled nitroimidazole as an indicator of ischemic myocardium at risk of infarction, we characterized the distribution of a 2-nitroimidazole-derivatized PnAO ligand and its 99mTc complex, 99mTcO(PnAO)-1-CH2-(2NI) (BMS-181321) in the ischemic territory of the left anterior descending (LAD) coronary artery of the rabbit. In preliminary experiments, the performance of 14C-deoxyglucose (14C-2DG) and 14C-misonidazole was assessed relative to apparent regional relative myocardial blood flow (rMBF) indicated by 99mTc-teboroxime using double-label autoradiography in the rabbit LAD occlusion model. After demonstrating that 14C-2DG and 14C-misonidazole are selectively retained in the lateral border of the ischemic territory, BMS-181321 was co-injected intravenously, with either 14C-2DG or 14C-misonidazole, 20 min after LAD occlusion. In a separate experiment, 99mTcO(PnAO)-6-CH3, a complex with the same lipophilicity (log k' 0.26 vs. 0.31) as BMS-181321 but which lacks the 2NI moiety, was co-injected with 14C-2DG. After 30 min, the rabbits were sacrificed and 14C/99mTc autoradiograms were obtained from the same tissue sections. The autoradiograms revealed that BMS-181321 was retained with the same microregional distribution as both 14C-2DG and 14C-misonidazole in the border zone of the ischemic LAD territory. The selective retention of BMS-181321 depends on the presence of the nitroimidazole group, since 99mTcO(PnAO)-6-CH3 has a uniformly low myocardial distribution in contrast to the enhanced uptake of co-injected 14C-2DG. These data demonstrate that BMS-181321 is selectively retained in hypoxic myocardium and demarcates the ischemic border zone in a manner similar to 14C-2DG and 14C-misonidazole.

Topics: Animals; Antimetabolites; Autoradiography; Deoxyglucose; Heart; Hemodynamics; Image Processing, Computer-Assisted; Male; Misonidazole; Myocardial Ischemia; Nitroimidazoles; Organotechnetium Compounds; Rabbits; Radiation-Sensitizing Agents; Radionuclide Imaging; Radiopharmaceuticals

The purpose of the present study was to determine whether graded levels of low-flow ischemia would lead to graded differences in uptake and clearance of BMS181321. Using a perfused rat heart model, 7.4 MBq (200 microCi) of BMS181321 was infused over 20 min, followed by a 60-min clearance phase. Activity was monitored using an NaI detector. Four groups were studied using Krebs-Henseleit buffer perfusion using low flow or hypoxia: group 1=12 ml/min, group 2=3 ml/min, and group 3=1 ml/min during uptake and clearance phases, and group 4=12 ml/min with hypoxia during clearance. Control and low-flow groups were also perfused using red blood cells and albumin. There was a stepwise increase in peak myocardial uptake (% injected dose) as flow progressively decreased (group 1=2.4%+/-0.2% SEM, group 2=13.1%+/-0.7%, group 3=28.6%+/-2.4%, P <0.05). Group 3/group 1 mean peak activity ratio was 12:1. Mean 1-h fractional retention significantly increased in a stepwise manner as flow decreased (group 1=0.32+/-0.02, group 2=0.43+/-0.03, group 3=0.59+/-0.05, P <0.05). Group 3/group 1 mean 1-h clearance activity ratio was 30:1. Groups 5 and 6 perfused with red blood cells and albumin demonstrated similar increases in peak uptake and 1-h retention in the low-flow hearts. This study demonstrates a stepwise increase in uptake and a stepwise increase in retention rate of BMS181321 with progressive reduction in flow.

Topics: Animals; Hypoxia; Myocardial Ischemia; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Rats; Technetium; Time Factors

We tested the hypotheses that prolonged, demand-induced myocardial ischemia plateaus and that on relief of stress, myocardial function remains depressed, with proportionate reductions in blood flow and oxygen consumption indicative of hibernation.. Closed-chest swine (n = 20) were prepared with an 80% coronary stenosis. Hemodynamics, myocardial blood flow, oxygen, and lactate metabolism were measured in group 1 (n = 9) (1) at baseline, (2) at 10 and 30 minutes of atrial pacing plus intravenous norepinephrine infusion, and (3) in 5 of 9 (group 1a) at approximately 50 minutes after stress. Group 1a had ischemia assessed with 99mTc-labeled BMS 181321. In group 2 (n = 11), myocardial function was determined with radionuclide ventriculography (n = 8), and myocardial necrosis was looked for with trichlorotetrazolium chloride staining (n = 7), histology (n = 10), and myocardial creatine kinase concentration (n = 4). Baseline stenotic-zone endocardial blood flow was reduced versus the normal zone (0.94 +/- 0.33 versus 1.38 +/- 0.27 mL.min-1.g-1, mean +/- SD; P < .05), whereas epicardial flows were comparable (1.15 +/- 0.36 versus 1.16 +/- 0.26 mL.min-1.g-1). Stenotic-zone endocardial flow was unchanged versus baseline at 10 and 30 minutes of stress, whereas epicardial flow increased (1.62 +/- 0.53 mL.min-1.g-1 at 10 minutes and 1.44 +/- 0.51 mL.min-1.g-1 at 30 minutes, both P < .05). Myocardial oxygen consumption increased versus baseline (10.8 +/- 2.9 mL.min-1.100 g-1) at 10 and 30 minutes of stress (14.9 +/- 5.2 and 13.9 +/- 4.5 mL.min-1.100 g-1, both P < .05). After stress, stenotic-zone blood flow and oxygen consumption were reduced approximately 30% (P < .01) versus baseline. In group 2, stenotic-zone contraction with stress declined versus baseline and remained depressed throughout recovery. Histological and biochemical evidence of myocardial necrosis was absent in group 2.. Myocardial ischemia induced by a sustained increase in oxygen demand may not progress to necrosis but may instead plateau. After relief of stress, myocardial function remains depressed, with a proportionate reduction in blood flow and oxygen consumption consistent with myocardial hibernation.

Topics: Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Creatine Kinase; Heart; Heart Rate; Hemodynamics; Lactates; Myocardial Ischemia; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Oxygen Consumption; Radionuclide Imaging; Stress, Physiological; Swine; Time Factors

To evaluate the utility of 99mTc-labeled nitroimidazole (BMS) in the detection of ischemic or reperfused myocardium, we performed dual-tracer autoradiography with BMS and [125I]iodoantipyrine (IAP).. In open-chest rats, the left coronary artery was ligated to produce 15- or 60-min ischemia followed by reperfusion or 60-min ischemia without reperfusion. BMS was injected just before ligation, 1 min before reperfusion or 15 min after reperfusion.. In the area at risk, regional myocardial blood flow (rMBF) evaluated by IAP recovered to the level in the nonischemic septum in all hearts, except in 60-min occlusion without reperfusion. In myocardium reperfused after 15-min ischemia (stunned), normalized BMS uptake (%BMS) in the area at risk was significantly increased only when BMS was injected before ischemia. When BMS was injected before 60-min ischemia or just before reperfusion, %BMS was significantly higher at the marginal zone of infarction than in the infarcted area. In contrast, %BMS was significantly lower in the infarcted area when BMS was injected during reperfusion. After 60 min of occlusion without reperfusion (permanent occlusion), rMBF in the area at risk was significantly decreased as was %BMS. In the peripheral zone of the area at risk, rMBF was significantly reduced, but %BMS was significantly increased.. BMS images stunned myocardium only when it is injected before ischemia, while it images the area at risk subjected to prolonged ischemia when it is injected up to the time of reperfusion. The infarcted area can be negatively visualized when BMS is injected after reperfusion.

Topics: Animals; Antipyrine; Coronary Circulation; Female; Iodine Radioisotopes; Myocardial Ischemia; Myocardial Stunning; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Technetium; Time Factors

This investigation evaluates the efficacy of a 99mTc-labeled nitroimidazole (BMS-181321) in identifying oxygen-deprived tissue in two canine models of myocardial ischemia.. For both models (A and B), epicardial microvascular oxygen pressure (mPO2) was monitored by measuring the oxygen-dependent quenching of phosphorescence lifetime of Palladium mesotetra (4-carboxyphenyl) porphine. In Model A (beagles, n = 5), BMS-181321 was administered intravenously and a distal branch of the left anterior descending coronary artery (LAD) was ligated completely 40 sec later. Ten minutes later, the ligature was released establishing tissue reoxygenation. In Model B, flow through the LAD was reduced until the mPO2 was about 2 Torr. After bolus administration of BMS-181321 (50-60 mCi), coronary ischemia was continued for a residence period of up to 4 hr.. With Model A, SPECT reconstructions revealed a small ischemic area in three of five dogs, however, a transmural accumulation of the compound was evident in the autoradiograms from all dogs. In the two animals in which the defect was not observed by SPECT, the ischemic episode had nominal effects on the ratio of +/- dp/dt (< 4% change as compared to baseline values). In Model B, SPECT reconstructions showed positive images of the oxygen-deprived area within the mid- to apical regions of the left ventricle (n = 5). Autoradiographic analysis showed a transmural association with cells resulting in an ischemic-to-nonischemic ratio of 3.5 +/- 0.4 (n = 4) for animals with similar residence times.. The results from both models suggest that BMS-181321 provides a noninvasive marker of regional ischemia in the heart and that this compound may have clinical utility for detection of coronary artery disease.

Topics: Animals; Autoradiography; Dogs; Heart; Image Processing, Computer-Assisted; Myocardial Ischemia; Nitroimidazoles; Organotechnetium Compounds; Time Factors; Tomography, Emission-Computed, Single-Photon

A new nitroimidazole complex, 99mTc-propylene amine oxime-1,2-nitroimidazole (BMS-181321), has been developed to allow the positive imaging of hypoxic myocardium by standard gamma camera techniques.. To determine the myocardial kinetics of BMS-181321 during myocardial ischemia and reperfusion, seven open-chest swine were prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thickness) and substrate use in the left anterior descending (LAD) region ([14C]palmitate and [3H]glucose infusions) were determined. Measurements were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minutes of reperfusion. Three aerobic control hearts were also studied in which LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres injected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynamic planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15 +/- 11 mumol.h-1.g dry wt-1, mean +/- SEM), systolic wall thickening (20 +/- 6%), and myocardial oxygen consumption (3 +/- 1 mL.min-1.100 g-1) and an increase in exogenous glucose utilization (75 +/- 13 mumol.h-1.g dry wt-1). Systolic wall thickening recovered by only 8 +/- 3% with reperfusion. Initial distribution of BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically perfused LAD bed in the control group (t1/2 = 136 +/- 1 versus 80 +/- 1 minutes, P < .05), allowing visualization of the LAD region during reperfusion. Tissue activity of BMS-181321 was inversely related to LAD blood flow during ischemia (r = -.68 +/- .05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7 +/- 0.2. Control swine lacked regional deposition of the tracer in the normally perfused LAD distribution.. Thus, acute regional ischemia in these studies was visualized as an increase in retention of BMS-181321, suggesting its applicability in the imaging of clinical conditions of myocardial hypoperfusion.

Topics: Animals; Coronary Circulation; Heart; Microspheres; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Oxygen Consumption; Radionuclide Imaging; Swine; Time Factors

Experimental data have indicated that [99mTc]-nitroimidazole (BMS-181321) is preferentially taken up in hypoxic tissue; its kinetics, however, has not been fully investigated. The purpose of this study was to address the relation between perfusate oxygen level and myocardial retention of [99mTc]nitroimidazole.. Bolus injection and constant infusion experiments were performed in Langendorff buffer-perfused rat hearts in normoxic and hypoxic conditions. Data were acquired with a pair of NaI detectors. The initial clearance rate of [99mTc]nitroimidazole was approximately 20 seconds and independent of perfusate oxygen level. The slow clearance rate was greater than 3 hours in all perfusion conditions. The tissue retention of [99mTc]nitroimidazole varied from 0.61 +/- 0.14% in normoxic conditions to 5.94 +/- 1.16% in the most severe hypoxic conditions. In addition, tissue retention was inversely proportional to perfusate oxygen level in a sigmoidal manner. The constant infusion experiments established that the binding rate at 25% oxygen level (1.94 +/- 0.38 mL of perfusate/min-g dry wt) was twofold of that at 40% and sevenfold at 100%. The binding rate of [99mTc]nitroimidazole was independent of the perfusion sequence, suggesting irreversible binding.. These data indicate that [99mTc]nitroimidazole may be a useful tracer for the identification of myocardial hypoxia. A sigmoidal relation was demonstrated for the uptake of the tracer, which suggests that a threshold level of hypoxia is necessary for the uptake of the tracer.

Topics: Animals; Cell Hypoxia; Heart; Male; Myocardial Ischemia; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Oxygen Consumption; Perfusion; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Sodium Pertechnetate Tc 99m; Technetium Tc 99m Pentetate; Time Factors

A new technetium-99m-labeled nitroimidazole (BMS181321) has been proposed for positive imaging of myocardial ischemia.. An in vivo open-chest canine model of partial coronary occlusion and pacing-induced demand ischemia was used to correlate myocardial retention of BMS181321, following an intravenous injection at peak stress, with regional microsphere blood flow. Postmortem measurements of myocardial BMS181321 activity and flow were correlated with in vivo planar and ex vivo SPECT images. Myocardial and hepatic clearance of BMS181321 was derived from ROI analysis of serial planar images.. Anaerobic metabolism was documented in the ischemic region by selective venous and arterial sampling for lactate and oxygen consumption. Normalized myocardial BMS181321 activity (165% +/- 42% nonischemic) in the central ischemic region (flow < 0.3 ml/min/gm) was significantly greater than activity in normal regions (p < 0.05). Quantitative circumferential analysis of SPECT images revealed a comparable increase in myocardial BMS181321 activity in the ischemic region. Sixty minutes after injection of BMS181321, liver activity was 423% of ischemic myocardial activity.. BMS181321 was preferentially retained in ischemic but viable canine myocardium and was inversely related to regional myocardial blood flow. Although enhanced retention of BMS181321 was detectable by ex vivo SPECT imaging, an unfavorable heart-to-liver ratio was observed with in vivo planar imaging which may limit its use in clinical myocardial imaging.

Topics: Animals; Coronary Circulation; Dogs; Heart; Lactates; Lactic Acid; Myocardial Ischemia; Nitroimidazoles; Organotechnetium Compounds; Oxygen Consumption; Tomography, Emission-Computed, Single-Photon

Topics: Animals; Coronary Circulation; Dogs; Heart; Myocardial Ischemia; Nitroimidazoles; Organotechnetium Compounds; Tomography, Emission-Computed, Single-Photon

Topics: Animals; Cardiomyopathies; Disease Models, Animal; Dogs; Hypoxia; Luminescent Measurements; Myocardial Ischemia; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Oxygen; Radionuclide Imaging

This study focused on the kinetics of the newly developed 99mTc-nitroimidazole, propyleneamine oxime-1,2-nitroimidazole (BMS181321) in the different setting of myocardial perfusion states and oxygenation levels, and compared the kinetics of BMS181321 with those of other technetium analogues.. The kinetics of BMS181321 were evaluated in isolated perfused rat hearts. Technetium-99m-hexamethylpropyleneamine oxime (HMPAO) and a non-nitroimidazole-containing analogue of BMS181321 (6-methyl propyleneamine oxime; PAO-6-Me) were used to compare their kinetics with those of BMS181321.. BMS181321 cleared quickly from normoxic hearts and the retention in the myocardium 10 min after injection was 0.84% +/- 0.04% ID/g wet wt (mean +/- s.e.m.). In contrast, BMS181321 was retained after reperfusion when it was injected before ischemia; the uptake in the myocardium 10 min after reperfusion was significantly greater than in controls (23.9% +/- 3.9% ID/g wt, p < 0.05).. These results indicate that 99mTc-BMS181321 is well trapped in ischemic myocardium and moderately trapped in hypoxic myocardium, but washed out quickly in stunned myocardium. The residence time influences the amount retained.

Topics: Animals; Female; Heart; Myocardial Ischemia; Myocardial Stunning; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Oximes; Oxygen Consumption; Perfusion; Radionuclide Imaging; Rats; Technetium Tc 99m Exametazime