Muscle metaboreflex-induced increases in cardiac sympathetic activity vasoconstrict the coronary vasculature.

Ischemia of active skeletal muscle evokes a powerful blood pressure-raising reflex termed the muscle metaboreflex (MMR). MMR activation increases cardiac sympathetic nerve activity, which increases heart rate, ventricular contractility, and cardiac output (CO). However, despite the marked increase in ventricular work, no coronary vasodilation occurs. Using conscious, chronically instrumented dogs, we observed MMR-induced changes in arterial pressure, CO, left circumflex coronary blood flow (CBF), and coronary vascular conductance (CVC) before and after alpha1-receptor blockade (prazosin, 100 microg/kg iv). MMR was activated during mild treadmill exercise by partially reducing hindlimb blood flow. In control experiments, MMR activation caused a substantial pressor response-mediated via increases in CO. Although CBF increased (+28.1 +/- 3.7 ml/min; P < 0.05), CVC did not change (0.45 +/- 0.05 vs. 0.47 +/- 0.06 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P > 0.05). Thus all of the increase in CBF was due to the increase in arterial pressure. In contrast, after prazosin, MMR activation caused a greater increase in CBF (+55.9 +/- 17.1 ml/min; P < 0.05 vs. control) and CVC rose significantly (0.59 +/- 0.08 vs. 0.81 +/- 0.17 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P < 0.05). A greater increase in CO also occurred (+2.01 +/- 0.1 vs. +3.27 +/- 1.1 l/min, control vs. prazosin, respectively; P < 0.05). We conclude that the MMR-induced increases in sympathetic activity to the heart functionally restrain coronary vasodilation, which may limit increases in ventricular function.     

Deer mouse aerobic performance across altitudes: effects of developmental history and temperature acclimation

Aerobic physiology at high altitudes has been studied in many animals. Prior work on laboratory-bred deer mice (a species with a wide altitudinal range) showed depression of aerobic capacity at high altitude, even after acclimation. However, wild deer mice show no reduction in thermogenic performance at high altitude, and performance limits seem to be due to physiological and anatomical adjustments to environmental temperature and not to oxygen availability. We asked whether across-altitude performance differences exist in deer mice after accounting for temperature acclimation (approximately 5 degrees and 20 degrees -25 degrees C) and prenatal and neonatal development altitude (340 vs. 3,800 m). We measured maximal thermogenic oxygen consumption (VO2sum) in cold exposure and ran mice on a treadmill to elicit maximal exercise oxygen consumption (VO2max). We found a 10% reduction in VO2max at 3,800 m compared with that at 340 m; thus, the mice were able to compensate for most of the 37% reduction in oxygen availability at the higher altitude. Development altitude did not affect VO2max. There was no effect of test altitude or development altitude on VO2sum in warm-acclimated animals, but both test and development altitude strongly affected VO2sum in cold-acclimated mice, and compensation for hypoxia at 3,800 m was considerably less than that for exercise.     

The expanded cattle <Emphasis Type="Italic">KIR</Emphasis> genes are orthologous to the conserved single-copy <Emphasis Type="Italic">KIR3DX1</Emphasis> gene of primates

Cattle are the only non-primate species for which expansion of the killer cell immunoglobulin-like receptor (KIR) genes has been reported. We analyzed cattle KIR sequences to determine their relationship to the two divergent lineages of primate KIR: one comprising the KIR3DX1 gene of unknown function, the second comprising all other primate KIR genes, which encode variable major histocompatibility complex class I receptors. Phylogenetics and analysis of repetitive elements shows that cattle KIR subdivide into the same two lineages as primate KIR. Unlike the primates, the lineage of variable and likely functional cattle KIR corresponds to the KIR3DX1 lineage of primate KIR, whereas the variable lineage of primate KIR is represented in cattle by one KIR gene and a related gene fragment.     

Insights into the nature of the hydrogen bonding of *Tyr272 in apo-galactose oxidase

The synthesis and structure of an o-methylthio-phenol-imidazole, 2-(2'-(4'-tert-butyl-6'-methylsulfanyl)-hydroxyphenyl))-4,5-diphenyl-imidazole ((MeS)LH), is reported; X-ray crystallographic studies have shown that (MeS)LH involves an O-H...N(+) hydrogen bond between the phenol and an imidazole nitrogen. (MeS)LH undergoes a reversible, one-electron, oxidation to form the radical cation [(MeS)LH](*)(+) the EPR spectrum of which is remarkably similar to that of (*)Tyr(272) in Cu-free, oxidized, apo-GO. Density Functional Theory calculations, have shown that the proton-transferred (R-O(*)...H-N(+)) form of [(MeS)LH](*)(+) has a spin density distribution--with a substantial delocalization of the unpaired electron spin density onto the ortho sulfur atom--and EPR properties that are in good agreement with those of (*)Tyr(272) in Cu-free, oxidized, apo-GO whereas the non-proton-transferred (R-O(*)(+)-H...N) form does not. The results reported herein are a further demonstration of the influence of hydrogen bonding on the nature and properties of phenoxyl radicals and strongly suggest that the phenoxyl oxygen of (*)Tyr(272) in Cu-free, oxidized, apo-GO is involved in a O(*)...H-O/N hydrogen bond.     

Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons

Development of appropriate dendritic arbors is crucial for neuronal information transfer. We show, using seizure-related gene 6 (sez-6) null mutant mice, that Sez-6 is required for normal dendritic arborization of cortical neurons. Deep-layer pyramidal neurons in the somatosensory cortex of sez-6 null mice exhibit an excess of short dendrites, and cultured cortical neurons lacking Sez-6 display excessive neurite branching. Overexpression of individual Sez-6 isoforms in knockout neurons reveals opposing actions of membrane-bound and secreted Sez-6 proteins, with membrane-bound Sez-6 exerting an antibranching effect under both basal and depolarizing conditions. Layer V pyramidal neurons in knockout brain slices show reduced excitatory postsynaptic responses and a reduced dendritic spine density, reflected by diminished punctate staining for postsynaptic density 95 (PSD-95). In behavioral tests, the sez-6 null mice display specific exploratory, motor, and cognitive deficits. In conclusion, cell-surface protein complexes involving Sez-6 help to sculpt the dendritic arbor, in turn enhancing synaptic connectivity.     

Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: synthesis, in vitro profile, molecular modeling studies, and in vivo experiments

Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.