Search

To further explore the limitations to maximal [O.sub.2] consumption (V[O.sub.2 max]) in exercise-trained skeletal muscle, six cyclists performed graded knee-extensor exercise to maximum work rate (W[R.sub.max]) in hypoxia (12% [O.sub.2]), hyperoxia (100% [O.sub.2]), and hyperoxia + femoral arterial infusion of adenosine (ADO) at 80% W[R.sub.max]. Arterial and venous blood sampling and thermodilution blood flow measurements allowed the determination of muscle [O.sub.2] delivery and [O.sub.2] consumption. At W[R.sub.max], [O.sub.2] delivery rose progressively from hypoxia (1.0 [+ or -] 0.04 l/min) to hyperoxia (1.20 [+ or -] 0.09 l/min) and hyperoxia + ADO (1.33 [+ or -] 0.05 l/min). Leg V[O.sub.2] max varied with [O.sub.2] availability (0.81 [+ or -] 0.05 and 0.97 [+ or -] 0.07 l/min in hypoxia and hyperoxia, respectively) but did not improve with ADO-mediated vasodilation (0.80 [+ or -] 0.09 l/min in hyperoxia + ADO). Although a vasodilatory reserve in the maximally working quadriceps muscle group may have been evidenced by increased leg vascular conductance after ADO infusion beyond that observed in hyperoxia (increased blood flow but no change in blood pressure), we recognize the possibility that the ADO infusion may have provoked vasodilation in nonexercising tissue of this limb. Together, these findings imply that maximally exercising skeletal muscle may maintain some vasodilatory capacity, but the lack of improvement in leg V[O.sub.2max] with significantly increased [O.sub.2] delivery (hyperoxia + ADO), with a degree of uncertainty as to the site of this dilation, suggests an ADO-induced mismatch between [O.sub.2] consumption and blood flow in the exercising limb. exercise; blood flow; vasodilatory reserve doi: 10.1152/ajpheart.01396.2006.

Regulation of tree radical outflow from an isolated muscle bed in exercising humans. Am J Physiol Heart Circ Physiol 287: H1689-H1699, 2004. First published May 20, 2004; 10.1152/ajpheart. 00148.2004.--Incremental knee extensor (KE) exercise performed at 25, 70, and 100% of single-leg maximal work rate (W[R.sub.MAX]) was combined with ex vivo electron paramagnetic resonance (EPR) spectroscopic detection of [alpha]-phenyl-tert-butylnitrone (PBN) adducts, lipid hydroperoxides (LH), and associated parameters in five males. Blood samples were taken from the femoral arterial and venous circulation that, when combined with measured changes in femoral venous blood flow, permitted a direct examination of oxidant exchange across a functionally isolated contracting muscle bed. KE exercise progressively increased the net outflow of LH and PBN adducts (100% > 70% > 25% W[R.sub.MAX], P < 0.05) consistent with the generation of secondary, lipid-derived oxygen ([O.sub.2])-centered alkoxyl and carboncentered alkyl radicals. Radical outflow appeared to be more intimately associated with predicted decreases in intracellular [Po.sub.2] ([iPo.sub.2]) as opposed to measured increases in leg [O.sub.2] uptake, with greater outflow recorded between 25 and 70% W[R.sub.MAX] (P < 0.05 vs. 70-100% W[R.sub.MAX]) This bias was confirmed when radical venoarterial concentration differences were expressed relative to changes in the convective components of [O.sub.2] extraction and flow (25-70% W[R.sub.MAX] P < 0.05 vs. 70-100% W[R.sub.MAX], P > 0.05). Exercise also resulted in a net outflow of other potentially related redox-reactive parameters, including hydrogen ions, norepinephrine, myoglobin, lactate dehydrogenase, and uric acid, whereas exchange of lipid/lipoproteins, ascorbic acid, and selected lipid-soluble anti-oxidants was unremarkable. These findings provide direct evidence for an exercise intensity-dependent increase in free radical outflow across an active muscle bed that was associated with an increase in sarcolemmal membrane permeability. In addition to increased mitochondrial electron flux subsequent to an increase in [O.sub.2] extraction and flow, exercise-induced free radical generation may also be regulated by changes in [iPo.sub.2], hydrogen ion generation, norepinephrine autoxidation, peroxidation of damaged tissue, and xanthine oxidase activation. electron paramagnetic resonance: spin-trapping; lipid peroxidation; antioxidants; mitochondrial redox

To further explore the limitations to maximal O2 consumption (Vo2 max) in exercise-trained skeletal muscle, six cyclists performed graded knee-extensor exercise to maximum work rate (WRmax) in hypoxia (12% O2), hyperoxia (100% O2), and hyperoxia + femoral arterial infusion of adenosine (ADO) at 80% WRmax. Arterial and venous blood sampling and thermodilution blood flow measurements allowed the determination of muscle O2 delivery and O2 consumption. At WRmax, O2 delivery rose progressively from hypoxia (1.0 ± 0.04 l/min) to hyperoxia (1.20 ± 0.09 l/min) and hyperoxia + ADO (1.33 ± 0.05 l/min). Leg Vo2 max varied with O2 availability (0.81 ± 0.05 and 0.97 ± 0.07 I/min in hypoxia and hyperoxia, respectively) but did not improve with ADO-mediated vasodilation (0.80 ± 0.09 l/min in hyperoxia + ADO). Although a vasodilatory reserve in the maximally working quadriceps muscle group may have been evidenced by increased leg vascular conductance after ADO infusion beyond that observed in hyperoxia (increased blood flow but no change in blood pressure), we recognize the possibility that the ADO infusion may have provoked vasodilation in nonexercising tissue of this limb. Together, these findings imply that maximally exercising skeletal muscle may maintain some vasodilatory capacity, but the lack of improvement in leg Vo2 max with significantly increased O2 delivery (hyperoxia + ADO), with a degree of uncertainty as to the site of this dilation, suggests an ADO-induced mismatch between O2 consumption and blood flow in the exercising limb. [ABSTRACT FROM AUTHOR]

Abstract: Two series of fused tricyclic indoles were identified as potent and selective S1P1 agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P3 receptor in vitro, and correspondingly did not produce S1P3 mediated bradycardia in telemeterized rat. [Copyright &y& Elsevier]

Abstract: S1P1 receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P1 receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P1 receptor agonists. [Copyright &y& Elsevier]

The discovery of a novel, selective and fully efficacious CB 2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB 2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain., Competing Interests: The authors declare no competing financial interest.