Estrogen receptor (ER) status by immunohistochemistry (IHC) of cancer tissue is currently used to direct endocrine therapy in breast cancer. Positron emission tomography (PET) with 16α-18F-fluoro-17β-estradiol (18 F-FES) noninvasively characterizes ER ligand-binding function of breast cancer lesions. Concordance of imaging and tissue assays should be established for 18 F-FES PET to be an alternative or complement to tissue biopsy for metastatic lesions. We conducted a metaanalysis of published results comparing 18 F-FES PET and tissue assays of ER status in patients with breast cancer. PubMed and EMBASE were searched for English-language manuscripts with at least 10 patients and low overall risk of bias. Thresholds for imaging and tissue classification could differ between studies but had to be clearly stated. We used hierarchical summary receiver-operating characteristic curve models for the meta-analysis. The primary analysis included 113 nonbreast lesions from 4 studies; an expanded analysis included 327 total lesions from 11 studies. Treating IHC results as the reference standard, sensitivity was 0.78 (95% confidence region 0.65-0.88) and specificity 0.98 (0.65-1.00) for the primary analysis of nonbreast lesions. In the expanded analysis including non-IHC tissue assays and all lesion sites, sensitivity was 0.81 (0.73-0.87) and specificity 0.86 (0.68-0.94). These results suggest that 18 F-FES PET is useful for characterization of ER status of metastatic breast cancer lesions. We also review current best practices for conducting 18 F-FES PET scans. This imaging assay has potential to improve clinically relevant outcomes for patients with (historically) ER-positive metastatic breast cancer, including those with brain metastases and/or lobular histology.

Several 8-arylimidazo[1,2-a]pyridines, 8-arylimidazo[1,5-a]pyridines, and 8-arylimidazo[1,5-a]pyridinones were prepared and tested in vitro for potential cardiac inotropic and electrophysiological activity. Selected analogues were further tested in vivo in canine hemodynamic and cardiac electrophysiology models. Compounds having an imidazole substituent consistently showed activity. A pharmacophoric relationship between heterocycle-phenyl-imidazole and positive inotropic activity was noted. The significance of this relationship is discussed.

SUMMARY Canine cardiac Purkinje fibers exposed Co sodiumfree solutions containing 16 m,\i CaCL, 20 mM tetraethvlammonium chloride, 108 m\i tetramethylammonium chloride, and 2.7 m\i KCI may be quiescent at a resting potential of either -5 0 mV or -9 0 mV. The membrane potential of these fibers can be switched from -50 mV to -90 mV by a hyperpolarizing current pulse and from -90 mV to -50 mV by a depolarizing current pulse. The transition from -50 mV to -90 raV depends on a voltage-dependent increase in potassium conductance, that conductance being low at -50 mV and high at -90 mV. A reduction in potassium conductance causes the fiber to depolarize from -9 0 mV to -5 0 mV because of the presence of an inward current which apparently is carried mainly by Ca. Fibers that show a high resting potential cannot be excited except by depolarizing stimuli strong enough to move the membrane from -9 0 mV to a threshold potential of about -4 0 raV. Fibers that show a low resting potential are more easily excited and may show rhythmic activity sustained by afterpotentials that appear only if the low membrane potential is accompanied by a low potassium conductance. Slow changes in membrane potential also are seen; these changes may result from movements of chloride.CARDIAC PURKINJE FIBERS bathed in Na-free solutions can show two stable resting potentials, one near -90 mV and one near -50 mV.1 2 We now report that within a critical range of [KJ 0 the membrane potential can be shifted from either level to the other by the application of hyperpolarizing or depolarizing current pulses. This transition appears to be governed primarily by a voltage-dependent change in potassium conductance, that conductance being high at the -9 0 mV level and low at the -5 0 mV level. This phenomenon assumes special interest because cardiac fibers can produce two distinct types of propagated action potentials. One type, dependent on a rapid increase in sodium conductance, is abolished by voltage-dependent inactivation when the resting potential is low. The other type, called the slow response, depends on an increase in permeability which occurs at membrane potentials between -5 0 and +10 mV. Various cardiac arrhythmias arise in fibers in which a loss of resting potential causes the rapid upstroke to be replaced by the slow response.' The possibility that cardiac fibers are characterized not only by an ability to produce two types of action potential, but also by an ability to display the two levels of resting potential from which those action potentials can arise, is therefore intriguing. MethodsMongrel dogs of either sex weighing 15-20 kg were anesthetized with an intravenous injection of pentobarbital sodium (30 mg/kg). The heart was rapidly excised and immersed in Tyrode's solution (Table 1). Bundles of Purkinje fibers (false tendons) 4-12 mm long were removed from the right and left ventricles, placed in a tissue bath, and perfused with Tyrode's solution at 36-37 c C. Fibers which, had a membrane potential of less than -8

No abstract

To examine the role of each component in the heterocycle-phenyl-imidazole inotropic pharmacophore, several imidazolone derivatives, an arylimidazole, a substituted 3,4-dihydro-4-oxopyrimidine, and a quinolin-2(1H)-one derivative were prepared as structural fragments or representatives from this relationship. Tests for cardiac inotropic activity in ferret papillary muscle strips (FPM) and for inhibition of crude cAMP phosphodiesterase obtained from canine cardiac tissue suggest that, while all three components contribute significantly toward potent activity (active at less than 1 microM concentrations in FPM), any combination of two components, in approximately a preferred geometry, represents the minimal requirements for weak activity (active at less than 25 microM concentrations). No single component appears to be requisite in an absolute sense.

Canine cardiac Purkinje fibers exposed to Na-free solutions containing 128 mM TEA and 16 mM Ca show resting potentials in the range -50 to -90 mV; if the concentration of Na in the perfusate is raised from 0 to 4 to 24 mM, hyperpolarization follows. If the initial resting potential is low, the hyperpolarization tends to be greater; the average increase in the presence of 8 mM Na is 14 mV. Such hyperpolarization is not induced by adding Na to K-free solutions, is not seen in cooled fibers, or in fibers exposed to 10 -3 M ouabain, nor is it induced by adding Li and thus may result from electrogenic sodium extrusion. Fibers exposed to Na-free solutions are often spontaneously active; if they are quiescent they often show repetitive activity during depolarizing pulses. Such spontaneous or repetitive activity is suppressed by the addition of Na. This suppression may or may not be related to the hyperpolarization.Propagated action potentials dependent on Ca as a carrier of inward current can occur in canine cardiac Purkinje fibers exposed to sodium-free solutions (Aronson and Cranefield, 1973). Such action potentials presumably result from the flow of inward current through the so-called "slow channel." Voltage-clamp studies suggest that the slow channel is permeable both to Ca and to Na (Rougier et al., 1969;Vitek and Trautwein, 1971; for review see Reuter, 1973, andTrautwein, 1973). Since a very small amount of Na may remain in bundles of Purkinje fibers exposed to Na-free solutions (Aronson and Cranefield, 1973;Reuter, 1973), the action potentials seen in fibers exposed to Nafree solutions might depend at least in part on Na as a carrier of inward current. To examine this possibility we added small amounts of NaCl to initially Na-free perfusates. Such an addition of Na may transiently increase the overshoot of the action potential but the almost invariable result is the abolition of spontaneous activity followed by a marked increase in resting potential. The hyperpolarization suggests that the addition of Na to the previously Na-free perfusate induces electrogenic extrusion of sodium. We report below results consistent with this hypothesis, supporting the belief that electrogenic

SUMMARY The inotropic actions of isoproterenol in cat papillary muscles or trabeculae bathed in a salt solution containing 4 mM KCl were compared to those in similar muscles bathed in a salt solution containing 22 mM KCl. Although isoproterenol evoked the same increase in force of contraction in both groups of muscles, the time course of contraction differed markedly. In muscles bathed in 4 mM KCl, isoproterenol caused a concentration-dependent decrease in time-to-pealt force, but in muscles bathed in 22 mM KCl, isoproterenol caused a concentration-dependent increase in time-to-peak force. These data suggest that ventricular muscle activated by slow response action potentials may utilize a different mechanism of excitation-contraction coupling than do muacles activated by Na-dependent action potentials. Circ Res 49: [718][719][720][721][722][723][724][725] 1981 ISOPROTERENOL and other y3-adrenergic agonists have positive inotropic effects in mammalian myocardium. In the presence of normal extracellular potassium (4 mM), the spectrum of this positive inotropic effect has been well established: isoproterenol increases both force of contraction and the maximum rate of force development while causing an abbreviation of both the time-to-peak force and total contraction time (Scholz, 1980). /3-adrenergic agonists also enhance the slow inward current in potassium-depolarized cardiac fibers (for review, see Cranefield, 1975) and many investigators have made use of this property to induce "slow response" type action potentials in mammalian ventricular muscle. Watanabe and Besch (1974) showed that isoproterenol has a concentration-dependent positive inotropic effect in such "slow response-activated" muscle, and most investigators appear to have assumed that the inotropic actions of isoproterenol are identical in muscles activated by "fast response" and by "slow response" action potentials. However, there have been no systematic studies comparing this activity, and there are isolated observations (see for example, Fig. 4 in Becker et al., 1977) which suggest that, in slow response activated muscle, isoproterenol increases time-to-peak force. I have therefore, reexamined the inotropic actions of isoproterenol in cat ventricular muscle to assess the degree of which the inotropic activities of the drug are altered by extracellular potassium. The results show that the spectrum of inotropic activity Received December S, 1980. acrrpted for publication April 7, 1981. of isoproterenol is markedly dependent on extracellular potassium; in the presence of elevated [K]o, the positive inotropic effect of isoproterenol is strongly dependent on an increase in time-to-peak force. One interpretation of these results is that the mechanism for excitation-contraction coupling changes in the presence of elevated [K] o . A brief report of these results has been published (Wiggins, 1980a).Methods Cats (1.5-3.0 kg, unselected for breed or sex) were obtained from the Hillsborough County (Florida) Animal Control Office and housed in the Vivar...

The electrophysiologic, inotropic, and muscarinic effects of antiarrhythmic peptide (AAP) were examined in canine cardiac Purkinje fibers, ferret papillary muscle, and canine cardiac membranes, respectively. Aside from a prolongation of time to peak force in papillary muscle, no biologically significant effects of AAP could be determined in any preparation, suggesting that its antiarrhythmic effects are not mediated by direct membrane actions.