Brief myocardial ischemia not only evokes a local cardioprotective or "preconditioning" effect but also can render remote myocardium resistant to sustained ischemia. We propose the following hypotheses: remote protection is initiated by a humoral trigger; brief ischemia-reperfusion will result in release of the humoral trigger (possibly adenosine and/or norepinephrine) into the coronary effluent; and transfer of this effluent to a virgin acceptor heart will elicit cardioprotection. To test these concepts, effluent was collected during normal perfusion from donor-control hearts and during preconditioning ischemia-reperfusion from donor-preconditioned (PC) hearts. After reoxygenation occurred and aliquots for measurement of adenosine and norepinephrine content were harvested, effluent was transfused to acceptor-control and acceptor-PC hearts. All hearts then underwent 40 min of global ischemia and 60 min of reperfusion, and infarct size was delineated by tetrazolium staining. Mean infarct size was smaller in both donor- and acceptor-PC groups (9% of left ventricle) than in donor- and acceptor-control groups (36% and 34%; P < 0.01). Protection in acceptor-PC hearts could not, however, be attributed to adenosine or norepinephrine. Thus preconditioning-induced cardioprotection can be transferred between rabbit hearts by transfusion of coronary effluent. Although adenosine and norepinephrine are apparently not responsible, these results suggest that remote protection is initiated by a humoral mechanism.

Neutron activation is an accurate analytic method in which trace quantities of isotopes of interest in a sample are activated and the emitted radiation is measured with high-resolution detection equipment. This study demonstrates the application of neutron activation for the measurement of myocardial perfusion using stable isotopically labeled microspheres. Stable labeled and standard radiolabeled microspheres (15 microm) were coinjected in an in vivo rabbit model of myocardial ischemia and reperfusion. Radiolabeled microspheres were detected with a standard gamma-well counter, and stable labeled microspheres were detected with a high-resolution Ge detection after neutron activation of the myocardial and reference blood samples. Regional myocardial blood flow was calculated from the deposition of radiolabeled and stable labeled microspheres. Both sets of microspheres gave similar measurements of regional myocardial blood flow over a wide range of flow with a high linear correlation (r = 0.95-0.99). Neutron activation is capable of detecting a single microsphere in an intact myocardial sample while providing simultaneous quantitative measurements of multiple isotope labels. This high sensitivity and capability for measuring perfusion in intact tissue are advantages over other techniques, such as optical detection of microspheres. Neutron activation also can provide an effective method for reducing the production of low-level radioactive waste generated from biomedical research. Further applications of neutron activation offer the potential for measuring other stable labeled compounds, such as fatty acids and growth factors, in conjunction with microsphere measured flow, providing the capability for simultaneous measurement of regional metabolism and perfusion.

One area that has been overlooked in the evolution of magnetic nanoparticle technology is the possibility of introducing informational atoms into the iron oxide core of the coated colloid. Introduction of suitable atoms into the iron oxide core offers an opportunity to produce a quantifiable probe, thereby adding one or more dimensions to the magnetic colloid's informational status. Lanthanide-doped iron oxide nanoparticles have been synthesized to introduce informational atoms through the formation of colloidal mixed ferrites. These colloids are designated ultrasmall mixed ferrite iron oxides (USMIOs). USMIOs containing 5 mol % europium exhibit superparamagnetic behavior with an induced magnetization of 56 emu/g Fe at 1.5 T, a powder X-ray diffraction pattern congruent with magnetite, and R1 and R2 relaxivity values of 15.4 (mM s) (-1) and 33.9 (mM s) (-1), respectively, in aqueous solution at 37 degrees C and 0.47 T. USMIO can be detected by five physical methods, combining the magnetic resonance imaging (MRI) qualities of iron with the sensitive and quantitative detection of lanthanide metals by neutron activation analysis (NA), time-resolved fluorescence (TRF), X-ray fluorescence, along with detection by electron microscopy (EM). In addition to quantitative detection using neutron activation analysis, the presence of lanthanides in the iron oxide matrix confers attractive optical properties for long-term multilabeling studies with europium and terbium. These USMIOs offer high photostability, a narrow emission band, and a broad absorption band combining the high sensitivity of time-resolved fluorescence with the high spatial resolution of MRI. USMIO nanoparticles are prepared through modifications of traditional magnetite-based iron oxide colloid synthetic methods. A 5 mol % substitution of ferric iron with trivalent europium yielded a colloid with nearly identical magnetic, physical, and chemical characteristics to its magnetite colloid parent.

This research was designed to test the hypothesis that ischemic preconditioning can be transferred between animals via whole blood transfusion. Preconditioning at a distance refers to the reduction in myocardial infarct size seen when coronary artery occlusion is preceded by brief ischemic episodes of noncardiac tissue. Isolation of the trigger signal responsible for this effect may be useful in the diagnosis and treatment of acute coronary occlusive syndromes. Rabbits were paired by crossmatching blood samples prior to experimentation. Crossmatched pairs were placed into either preconditioned (P) or control sets. Rabbits in the preconditioned sets were further divided into donor (PD) and acceptor (PA) animals. PD animals underwent five episodes of circumflex and renal artery occlusion followed by reperfusion. Before and after each preconditioning episode, a whole blood exchange was performed between PD and PA animals. Alternatively, control rabbits underwent the same surgical procedures and time-sequenced transfusion without preconditioning. All animals then underwent prolonged circumflex occlusion (60 minutes) followed by reperfusion (30 minutes). The area of myocardium at risk (R) was determined by isotope-labeled microsphere injection. Infarct size (I) was determined by NBT staining. The percent infarct within the risk area (I/R) was then compared. The I/R was significantly lower in the PA (14.0% +/- 12.2) and PD (14.3% +/- 11.2) groups as compared with controls (61% +/- 20. 6). There was no significant difference between the tPA and TPD groups. In conclusion, the ischemic preconditioning effect can be transferred to nonpreconditioned animals via whole blood transfusion, suggesting a humoral mechanism for preconditioning at a distance.

The clinical implication of these observations suggests that initial and delayed imaging after tetrofosmin administration would reflect both the initial regional blood flow pattern and myocardial viability.

OBJECTIVE-To evaluate use of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) to estimate glomerular filtration rate (GFR) by plasma clearance and use of an ELISA as the method of Gd-DTPA quantification. ANIMALS-16 dogs of various sexes and breeds (12 dogs were clinically normal, and 4 dogs were polyuric and polydipsic with no other clinical or biochemical abnormalities). PROCEDURES-GFR was estimated by measuring the plasma clearance of Gd-DTPA and iohexol by use of an ELISA and high-performance liquid chromatography (HPLC), respectively. The GFR was determined by use of a 1-compartment model for both methods. The GFRs obtained by Gd-DTPA plasma clearance were compared with those obtained by iohexol plasma clearance by use of correlation analysis, paired t tests, and limits of agreement analysis. A paired t test was used to evaluate differences between the 2 plasma clearance methods. RESULTS-A strong linear correlation (r(2) = 0.90) was found between GFRs derived from the plasma clearance of Gd-DTPA and those derived from the plasma clearance of iohexol. By use of limits of agreement analysis, almost all (13/14) dogs had Gd-DTPA GFRs that were within 12% of iohexol GFRs. The remaining dog had a Gd-DTPA GFR that was 45% higher than the iohexol GFR. There was no significant difference between Gd-DTPA GFRs and those obtained with iohexol. CONCLUSIONS AND CLINICAL RELEVANCE-This study revealed that plasma clearance of Gd-DTPA measured by use of an ELISA is an effective method to estimate GFR in dogs because it compared favorably with results for the iohexol-HPLC method.

Simultaneous dual-radionuclide 99mTc/201Tl myocardial scintigraphy is feasible with 99mTc crossover correction specific to each acquisition. The proposed dual-radionuclide 99mTc/201Tl method and the principles on which it is based can be applied to a broad range of dual-radionuclide pairs.

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