Catabolism of 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) by isolated rat hearts.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
F F Knapp
Publications and source records attributed to F F Knapp.
Studies of a new fatty acid analog (DMIVN) in hypertensive rats and the effect of verapamil using ARG microimaging.
Studies of myocardial utilization of fatty acids and analogs has focused on coronary heart disease. This study addresses the topic of radioiodinated fatty acid utilization in hypertensive-cardiomyopathy. The new fatty acid analog 19-iodo-3,3-dimethyl-18 nonadecenoic acid (DMIVN) was studied by autoradiographic microimaging (ARG) in salt-sensitive (S) hypertensive (salt-fed) and in salt-sensitive (S) normotensive (low-salt diet), Dahl-strain rats. A salt fed, S-strain group was treated with verapamil and the results were compared to those in a hypertensive, non-treated group. The distribution of DMIVN in the hearts of normotensive rats was uniform. In the myocardium of hypertensive rats nonuniform DMIVN concentration was seen in the subendocardial and mid-layers of the left ventricle (LV). Verapamil given to salt-fed rats prevented hypertension and uniform DMIVN uptake similar to normotensive controls was seen. The data suggest that DMIVN may be suitable for the detection of hypertension induced myocardial changes and for assessing therapy. The distribution and clearance characteristics of DMIVN indicate that DMIVN may be a useful agent for SPECT imaging in man.
Animals↗
Effect of 3-methyl-branching on the myocardial retention of radioiodinated 19-iodo-18-nonadecenoic acid analogues.
The effect of methyl-branching at the 3(beta-)-position on myocardial uptake and retention of fatty acids where radioiodide has been stabilized as a terminal trans-(E)-vinyl iodide has been evaluated in fasted rats. The syntheses of two new dimethyl-branched fatty acids, 17-iodo-3,3-dimethylheptadecanoic acid (14) and (E)-19-iodo-3,3-dimethyl-18-nonadecenoic acid (19), are described. Tissue distribution studies in fasted rats with [125I]-19 showed significant heart uptake (2 min, 4.56% dose/g), and prolonged retention (60 min 4.10% dose-g). These results suggest that [123I]-19 is a good candidate for further studies of regional myocardial fatty acid uptake patterns by SPECT.
Animals↗
Three decades of scientific liaison between Oak Ridge and Bonn.
Explore the source record for details and available documents.
Germany, West↗
Clinical usefulness of ultrashort-lived iridium-191m from a carbon-based generator system for the evaluation of the left ventricular function.
Ultrashort-lived 191mIr (4.96 sec; 63-74 and 129 keV photons) is potentially advantageous for first-pass radionuclide angiocardiography, offering the opportunity to perform repeat studies with very low absorbed radiation dose to the patient. Left ventricular (LV) first-pass studies were performed in 72 patients with 191mIr from a new bedside 1.3 Ci (48.1 GBq) 191Os/191mIr generator system using an activated carbon support that offers high 191mIr yields (15-18%) and consistent low 191Os breakthrough (2-4 x 10(-4)%/bolus). Using a single crystal digital gamma camera, uncorrected end-diastolic counts in the left ventricular representative cycle ranged from 10 up to 30 k counts. The reproducibility of repeated LV ejection fraction (LVEF) determination at 2-min intervals in 50 patients was r = 0.97, mean diff. = 2.08 +/- 1.55 EF units. Comparison between 191mIr (80-120 mCi; 2,960-4,400 MBq) and 99mTc (20-25 mCi; 750-925 MBq) LV count rates indicates a 3 wk useful shelf life of this new generator system for cardiac studies. Iridium-191m determined LVEF correlated closely with 99mTc determined LVEF in 32 patients (r = 0.96, mean diff. = 1.87 +/- 1.23 EF units). Parametric images for LV wall motion analysis were comparable with both isotopes. We conclude that rapid, repeat, and reproducible high count rate first-pass left ventricular studies can be obtained with 191mIr from this new 191Os/191mIr generator system using a single crystal digital gamma camera.
Adult↗
Absorption of theophylline administered via colostomy.
Explore the source record for details and available documents.
Adult↗
Effects of fasting on the myocardial subcellular distribution and lipid distribution of terminal p-iodophenyl-substituted fatty acids in rats.
The myocardial lipid pool distribution and subcellular distribution of radiolabeled methyl-branched fatty acids in rats was evaluated under conditions of fasting (24 h) and feeding. With the unbranched iodophenyl fatty acid, fasting resulted in increased myocardial extraction and clearance time with a decrease in the incorporation into triglycerides and greater radioactivity in the mitochondrial fraction. With the monomethyl-branched analogue, the effects of fasting on lipid and subcellular distribution were minor except for a decrease in triglyceride incorporation. Like the unbranched analogue, the dimethyl-branched iodophenyl fatty acid showed increased myocardial extraction with fasting, however, this structurally-modified fatty acid showed increased rather than decreased incorporation into triglycerides.
Animals↗
Localization and activity of inflammatory bowel disease using 111In leukocyte imaging.
A prospective study was initiated to compare the clinically proven results concerning localization/extent and activity of inflammatory bowel diseases with those of 111In-oxine leukocyte imaging. All patients studied were completely examined with barium enema x-ray, clinical and laboratory investigations, and endoscopy with histopathology. A total of 31 leukocyte scans were performed in 15 patients (12 with Crohn's disease, 3 with ulcerative colitis). The scans were graded by comparing the cell uptake of a lesion (when present) and a bone marrow area providing a count ratio (CR). The inflammatory lesions were correctly localized on 26 leukocyte scans, and in 21 scans the scintigraphically estimated extent of disease was identical to endoscopy. In 5 cases the disease extent was underestimated, 4 scans in patients with relapse of Crohn's disease were falsely negative, and in one patient with remission truly negative. The scintigraphically assessed disease activity was also in a good agreement with clinical disease activity based on histopathology in all cases. We conclude that leukocyte imaging provides valuable information about localization and activity of inflammatory bowel disease.
Adult↗
Detection of cardiomyopathy in an animal model using quantitative autoradiography.
A fatty acid analog (15-p-iodophenyl)-3,3 dimethyl-pentadecanoic acid (DMIPP) was studied in cardiomyopathic (CM) and normal age-matched Syrian hamsters. Dual tracer quantitative wholebody autoradiography (QARG) with DMIPP and 2-[14C(U)]-2-deoxy-2-fluoro-D-glucose (FDG) or with FDG and 201Tl enabled comparison of the uptake of a fatty acid and a glucose analog with the blood flow. These comparisons were carried out at the onset and mid-stage of the disease before congestive failure developed. Groups of CM and normal animals were treated with verapamil from the age of 26 days, before the onset of the disease for 41 days. In CM hearts, areas of decreased DMIPP uptake were seen. These areas were much larger than the decrease in uptake of FDG or 201Tl. In early CM only minimal changes in FDG or 201Tl uptake were observed as compared to controls. Treatment of CM-prone animals with verapamil prevented any changes in DMIPP, FDG, or 201Tl uptake. DMIPP seems to be a more sensitive indicator of early cardiomyopathic changes as compared to 201Tl or FDG. The trial of DMIPP and SPECT in the diagnosis of human disease, as well as for monitoring the effects of drugs which may prevent it seems to be warranted.
Animals↗
Effect of 3-methyl-branching on the metabolism in rat hearts of radioiodinated iodovinyl long chain fatty acids.
The metabolism of two new 3-methyl-branched iodovinyl fatty acids in rat hearts was evaluated by determining the subcellular and lipid pool distribution of these radiolabeled analogues after intravenous injection. Methyl branching had been introduced into the straight chain analogue, 19-iodo-18-nonadecenoic acid (IVN), to produce the monomethyl analogue, 19-iodo-3-(R,S)-methyl-18-nonadecenoic acid (BMIVN) and the dimethyl derivative, 19-iodo-3,3-dimethyl-18-nonadecenoic acid (DMIVN) in the hope of inhibiting beta oxidation. Since the presence of 3-methyl branching results in delayed myocardial clearance in rats, differences were sought in the lipid and subcellular distribution of these branched analogues that might correlate with the prolonged retention and reflect differences in metabolism. Hearts of rats injected intravenously with the radiolabeled fatty acids were removed and homogenized and the homogenates partitioned between the chloroform-methanol (organic) fraction and the aqueous fraction. Comparison of the distribution of radioactivity between the organic and aqueous fractions showed that most of the DMIVN and BMIVN activity was in the organic fraction with IVN activity initially divided equally between the two fractions. Identification of the lipid components of these organic fractions showed that there was slow incorporation of DMIVN into the triglyceride and polar lipid fractions with a slow loss from the free fatty acid fraction. With the straight chain IVN analogue which shows rapid washout from rat hearts, there was loss of activity from all 3 lipid components during the 60 min. The monomethyl branched BMIVN analogue demonstrated predominant storage in the polar lipid fraction with some incorporation into triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Evaluation of the metabolism in rat hearts of two new radioiodinated 3-methyl-branched fatty acid myocardial imaging agents.
The biological fate of two new radioiodinated 3-methyl-branched fatty acids has been evaluated in rat hearts following intravenous administration. Methyl-branching was introduced in [15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) and 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) to inhibit beta-oxidation. The goals of these studies were to correlate the effects of methyl-branching on the incorporation of these agents into the various fatty acid pools and subcellular distribution profiles, and to relate these data to the myocardial retention properties. The properties of BMIPP and DMIPP were compared with the 15-(p-iodophenyl)pentadecanoic acid straight-chain analogue (IPP). Differences in the heart retention of the analogues after intravenous administration in rats correlated with differences observed in subcellular distribution patterns. The dimethyl DMIPP analogue showed the longest retention and the highest association with the mitochondrial and microsomal fractions (34%, 38%) 30 min after injection. These data are in contrast to the rapid clearance of the straight-chain IPP analogue which showed much lower relative association with the mitochondria and microsomes (18%, 15%). The distribution patterns of each analogue in the various lipid pools appeared consistent with the expected capacity of the analogues to be metabolized by beta-oxidation. In contrast to the rapid oxidation of the straight-chain IPP analogue, the 3-monomethyl BMIPP analogue appeared to undergo slower oxidation and clearance, whereas the dimethyl-branched DMIPP analogue was apparently not catabolized by the myocardium. All three analogues showed some incorporation into triglycerides. The metabolism patterns of the branched analogues reported here may provide useful information in the description of the mechanisms by which BMIPP and DMIPP are retained in rat myocardium.
Animals↗
New radioiodinated methyl-branched fatty acids for cardiac studies.
The effects of 3-methyl substitution on the heart retention and metabolism of 3-R,S-methyl-(BMIPP) and 3,3-dimethyl-(DMIPP) analogues of 15-(p-iodophenyl)-pentadecanoic acid (IPP) were studied in rats. Methyl substitution considerably increased the myocardial half-time values in fasted rats: IPP, 5-10 min; BMIPP, 30-45 min; DMIPP, 6-7 h. Because of the observed differences in the relative myocardial uptake and retention of these agents, an evaluation of the subcellular distribution profiles and the distribution of radioactivity within various lipid pools extracted from cell components was performed. Studies with DMIPP in food-deprived rats have shown high levels of the free fatty acid and only slow conversion to triglycerides. These data are in contrast to the rapid clearance of the straight chain IPP analogue and rapid incorporation into triglycerides, and suggest that the prolonged myocardial retention observed with DMIPP in vivo may result from inhibition of beta oxidation. Subcellular distribution studies have shown predominant association of DMIPP and BMIPP with the mitochondrial and microsomal fractions, while IPP was primarily found in the cytoplasm. Because of the unique "trapping" properties and the high heart:blood ratios, [123I]DMIPP should be useful for evaluation of aberrations in regional myocardial uptake.
Animals↗
Structurally modified fatty acids: clinical potential as tracers of metabolism.
Recently 15-p-iodophenyl-beta-methyl-pentadecanoic acid (BMPPA) was proposed for use in myocardial scintigraphy, as a possible probe of metabolic processes other than beta-oxidation. In 19 patients (CAD/15, St.p. Mi/7; control 4) myocardial scintigraphy was carried out after i.v. I-123-BMPPA (2-4 mCi). Data were collected (LAO 45 degrees/14; anterior/5) for 100 min in the fasted patients. Organ to background (BG) ratios were calculated for the heart (H) and liver (L), and the elimination (E) behaviour was analyzed from BG (vena cava region) corrected time activity curves. In 10 patients plasma and urine were examined. By CHCl3/MeOH extraction of plasma samples (90 min after injection), both in water and in organic medium soluble catabolites were found. TLC fractionation showed that those were co-migrating, compared to standards, with bencoic acid, BMPPA and triglycerides. In the urine (0-2 h after injection, 4.1% dose) hippuric acid was found. The mean t-max of BMPPA occurred at 15 min in the heart and at 9 min in the liver (P less than 0.01), with H/BG and L/BG ratios of 1.8 and 2.1, respectively. The elimination of BMPPA was slower from the heart than from the liver (P less than 0.01). It was biexponential from the liver in all cases (means: t/2 I, 11.4 min; t/2 II, 92 min; t/2 I uncor., 38 min) with the size of phase I smaller than that of phase II (means: I/II, 0.57). From the heart BMPPA turnover was biexponential in 11 patients (means: t/2 I, 13.8 min; t/2 II, 187 min; t/2 I uncor., 65 min; I/II, 0.34), but monoexponential in 8 (means: t/2, 218 min).(ABSTRACT TRUNCATED AT 250 WORDS)
Coronary Disease↗
Experimental basis of metabolic imaging of the myocardium with radioiodinated aromatic free fatty acids.
For the investigation of myocardial perfusion and left ventricular pump function, advanced radioisotopic techniques have been established. New developments in radiopharmacology and single-photon emission computed tomography have recently enabled the investigation of parameters of regional energy metabolism in well defined areas of the heart muscle. For this purpose, various iodine (123I)-labeled free fatty acids (FFA) have been synthesized. The diagnostic application of labeled FFA in heart disease may be important, since FFA are the preferred substrates for cardiac energy production at rest in the fasting state. In addition, regional myocardial FFA uptake and regional myocardial blood flow are tightly coupled in normal myocardium with beta-oxidation which is extremely sensitive to oxygen deprivation. This article outlines the basic physiologic pathways of FFA in normal and ischemic myocardium and reviews the results of animal experiments validating the application of these principles for metabolic imaging of the heart by means of the aromatic radioiodinated FFA, 15-(p-iodophenyl)pentadecanoic acid. In addition, the development, physiologic properties, and potential applications of a new generation of 3-methyl-substituted radioiodinated fatty acids that show high myocardial uptake but prolonged retention are discussed.
Animals↗
[Results of fatty acid SPECT of the myocardium in coronary disease].
New developments in radiopharmacology of 123I-labeled metabolic tracers and single-photon emission computerized tomography (SPECT) allow now-a-days the assessment of parameters of cardiac energy metabolism in well-defined areas of the heart muscle. This article will present a brief outline of the basic pathophysiological principles used in the application of 123I-labeled phenyl fatty acids for the evaluation of CAD. First clinical results suggest an important application of cardiac fatty acid metabolic imaging to the detection, localisation and conceivable quantitation of myocardial ischemia, myocardial infarction and assessment of tissue viability. In addition to the diagnostic applications in CAD, cardiac fatty acid metabolic imaging may provide new perspectives to pathophysiological investigations of the coupling of local flow and substrate utilisation in vivo and the effect of therapeutic interventions.
Coronary Disease↗
A new osmium-191/iridium-191m radionuclide generator system using activated carbon.
A new osmium-191/iridium-191m (191Os/191mIr) radionuclide generator system has been developed based on the absorption of K2OsCl6 (Os-IV) on 140-230 mesh heat-treated activated carbon. The generator is eluted with pH 2 saline solution containing 0.25 g/l Kl to give 191mIr in good yield. The generator eluent is neutralized to physiologic pH and isotonicity with Tris buffer immediately prior to i.v. injection. No scavenger column is required. As an example, elution of the prototype generator with a 2-ml bolus results in elution of 191mIr in approximately 18% yield with an 191Os breakthrough of only 2 X 10(-4)%/bolus. The prototype generator has consistent performance over a 2-wk period with no change in 191mIr yield or 191Os breakthrough. Loading of up to 1.5 Ci of 191Os results in no observed radiolysis. Continuous elution of this system is also possible with a mean 191mIr yield of 3.7%/ml and a mean 191Os breakthrough of 2 X 10(-5)%/ml at a flow rate of 12 ml/min. This new system represents a readily available source of 191mIr for radioangiography. Adsorbed radiation dose calculations indicate a total-body dose of only 3.9 mrad for a 100 mCi injected bolus.
Adsorption↗
Radioiodinated 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid: a useful new agent to evaluate myocardial fatty acid uptake.
Radioiodinated 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) has been prepared as a new terminal iodophenyl-substituted fatty acid containing dimethyl-branching at the beta position. For the synthesis of this new agent, chain homologation was accomplished by fabrication of a 2,5-disubstituted thiophene by successive Friedel-Crafts acylation and Wolff-Kishner reduction reactions, followed by thiophene ring opening. The dimethyl-branching was introduced using the monomethyl ester of dimethylglutaryl chloride. Radioiodination of the 15-phenyl-3,3-dimethylpentadecanoic acid substrate in the para position then gave DMIPP. Iodine-125-labeled DMIPP showed rapid, high myocardial uptake (min, mean % injected dose/g) in fasted rats (5, 4.67; 30, 5.06; 60, 4.79; 120, 4.37), and also exhibited good heart:blood ratios (min, heart:blood: 5, 3:1; 30, 12:1; 60, 12:1; 120, 13:1). To further evaluate the effects of dimethyl-branching, the biodistribution properties of DMIPP were compared with the 3-monomethyl-branched (15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid; BMIPP) and the unbranched (15-(p-iodophenyl)pentadecanoic acid; IPP) analogs. A triple-labeled [123I]DMIPP/[131I]BMIPP/[125I]IPP mixture was administered to groups of fasted rats. These results confirmed the greater myocardial retention and higher heart:blood ratios observed with DMIPP in comparison with both the 3-monomethyl-(BMIPP) and unbranched (IPP) analogs. These data suggest that [123I]DMIPP is an excellent candidate for clinical evaluation of regional energy substrates (fatty acid) uptake.
Animals↗
Dual tracer autoradiographic study of beta-methyl-(1-14C) heptadecanoic acid and 15-p-(131I)-iodophenyl-beta-methylpentadecanoic acid in normotensive and hypertensive rats.
The myocardial distribution of 15-p-[131I]iodophenyl-3-(R,S)-methylpentadecanoic acid (BMPDA) and 1[14C]-3-(R,S)-methylheptadecanoic acid (BMHDA) was compared in normotensive and hypertensive rats using quantitative dual tracer autoradiographic techniques. The myocardial distribution of carbon-14 [14C] BMHDA and iodine-131 [131I] BMPDA was nearly homogeneous in the normotensive rats, while both tracers showed similar, though very heterogeneous, distribution in hypertensive hearts with decreased uptake in the endocardial region. Our data demonstrate that myocardial distribution of [131I]BMPDA was essentially the same as [14C]BMHDA, and thus single photon emission computed tomographic imaging with 123I-labeled BMPDA could be useful for the detection of regional changes of myocardial fatty acid uptake in patients with prolonged and severe hypertension.
Animals↗