Dissociation between muscle metabolism and oxygen kinetics during recovery from exercise in patients with chronic heart failure.
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OBJECTIVE: To estimate muscle metabolism and oxygen delivery to skeletal muscle in patients with chronic heart failure. METHODS: 13 patients with chronic heart failure and 15 controls performed calf plantar flexion for six minutes at a constant workload of 50% of one repetition maximum. During recovery from exercise, skeletal muscle content of oxygenated haemoglobin (oxy-Hb) and the level of phosphocreatine (PCr) were measured by near-infrared spectroscopy and (31)P-magnetic resonance spectroscopy, respectively. RESULTS: The mean (SD) time constants of PCr and oxy-Hb during recovery from exercise were significantly greater in patients with chronic heart failure than in normal subjects (tau PCr: 76.3 (30.2) s v 36.5 (5.8) s; tau oxy-Hb: 48.3 (7.3) s v 30.1 (7.7) s; p < 0.01). Both time constants were similar in normal subjects, while the tau PCr was significantly greater than the tau oxy-Hb in patients with chronic heart failure. CONCLUSIONS: The slower recovery of PCr compared with oxy-Hb in patients with chronic heart failure indicates that haemoglobin resaturation is not a major rate limiting factor of PCr resynthesis. It is suggested that muscle metabolic recovery may depend more on oxygen utilisation than on haemoglobin resaturation or oxygen delivery in patients with chronic heart failure. (+info)
Human calf microvascular compliance measured by near-infrared spectroscopy.
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The purpose of this study is to develop a new method for the measurement in humans of the compliance of the microvascular superficial venous system of the lower limb by near-infrared spectroscopy (NIRS). This method is complementary to strain-gauge plethysmography, which does not allow compliance between deep and superficial venous or between venous and arterial compartments to be distinguished. In practice, hydrostatic pressure (P) changes were induced in a calf region of interest by head-up tilt of the subject from alpha = -10 to 75 degrees. For P < or = 24 mmHg, the measured compliance [0.086 +/- 0.005 (SD) ml. l(-1). mmHg(-1)] based on NIRS data of total, deoxygenated, and oxygenated hemoglobin, reflects essentially that of the superficial venous system. For P > or = 24 mmHg, no distinction can be made between arterial and venous volumes changes. However, by following the changes in oxy- and deoxyhemoglobin in the P range -16 to 100 mmHg, it appears to be possible to assess the characteristics of the vasomotor response of the arteriolar system. (+info)
Glycosylation of hemoglobin in vitro: affinity labeling of hemoglobin by glucose-6-phosphate.
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To determine the mechanism for the formation of hemoglobin A1c (Hb A1c) in vivo, we incubated human hemoglobin with glucose and metabolites of glucose. [14C]Glucose-6-phosphate (G6P) reacted readily with deoxyhemoglobin, and formed a covalent linkage. The reaction rate was considerably reduced in the presence of carbon monoxide or 2,3-diphosphoglycerate (2,3-DPG). Purified G6P hemoglobin had a lowered oxygen affinity and decreased reactivity with 2,3-DPG compared to Hb A. G6P behaved as a 2,3-DPG analog and reacted specifically at the NH2-terminal amino group of the beta chain. In contrast, the interaction of hemoglobin with glucose was much slower, and was unaffected by carbon monoxide or 2,3-DPG. Neither glucose-1-phosphate, fructose-6-phosphate, nor fructose-1,6-diphosphate formed a reaction product with hemoglobin. G6P behaves as an affinity label with the phosphate group forming electrostatic bonds at the 2,3-DPG binding site and the aldehvde group reacting with the NH2-terminal amino group of the beta chain. Thus, G6P hemoglobin may be an intermediate in the conversion of Hb A to Hb A1c. (+info)
Nitric oxide, prostanoid and non-NO, non-prostanoid involvement in acetylcholine relaxation of isolated human small arteries.
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The main purpose of the study was to clarify to which extent nitric oxide (NO) contributes to acetylcholine (ACh) induced relaxation of human subcutaneous small arteries. Arterial segments were mounted in myographs for recording of isometric tension, NO concentration and smooth muscle membrane potential. In noradrenaline-contracted arteries, ACh induced endothelium-dependent relaxations. The NO synthase inhibitor, N(G)-nitro-L-arginine (L-NOARG) had a small significant effect on the concentration-response curves for ACh, and in the presence of L-NOARG, indomethacin only caused a small additional rightward shift in the ACh relaxation. The NO scavenger, oxyhaemoglobin attenuated relaxations for ACh and for the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Inhibition of guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), and inhibition of protein kinase G with beta-phenyl-1, N2-etheno-8-bromoguanosine- 3', 5'- cyclic monophosphorothioate, Rp-isomer, slightly attenuated ACh relaxation, but abolished SNAP induced relaxation. ACh induced relaxation without increases in the free NO concentration. In contrast, for equivalent relaxation, SNAP increased the NO concentration 32+/-8 nM. ACh hyperpolarized the arterial smooth muscle cells with 11.4+/-1.3 mV and 10.5+/-1.3 mV in the absence and presence of L-NOARG, respectively. SNAP only elicited a hyperpolarization of 1.6+/-0.9 mV. In the presence of indomethacin and L-NOARG, ACh relaxation was almost unaffected by lipoxygenase inhibition with nordihydroguaiaretic acid, or cytochrome P450 inhibition with 17-octadecynoic acid or econazole. ACh relaxation was strongly reduced by the combination of charybdotoxin and apamin, but small increments in the extracellular potassium concentration induced no relaxations. The study demonstrates that the NO/L-arginine pathway is present in human subcutaneous small arteries and to a limited extent is involved in ACh induced relaxation. The study also suggests a small contribution of arachidonic acid metabolites. However, ACh relaxation is mainly dependent on a non-NO, non-prostanoid endothelium dependent hyperpolarization. British Journal of Pharmacology (2000) 129, 184 - 192 (+info)
The oxygen trail: tissue oxygenation.
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Aerobic cellular respiration depends on the efficient supply of oxygen and substrate to the mitochondria. There is an oxygen cascade from the environment to the subcellular environment. Efficient oxygen delivery depends on the coordinated interaction between the respiratory and circulatory systems. The circulation at both macro- and microvascular levels is under the control of humoral and neural factors. There is local autoregulation of flow at the tissue level by metabolic factors which reflect the energy state of the tissues. The response to hypoxia involves the activation of cytokines and genetically controlled factors which maximise capillary perfusion and haemoglobin concentration, and regulate cell metabolism. The formation of reactive oxygen species under such conditions has a detrimental effect on the mitochondria with respiratory chain dysfunction, increased permeability transition, and cell death. This review aims to explore the mechanisms by which the body attempts to maintain tissue oxygen levels at conditions optimal for cell survival. (+info)
Oxygen dependency of cerebral oxidative phosphorylation in newborn piglets.
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Changes in hemoglobin oxygenation and oxidation state of the CuA centre of cytochrome oxidase were measured with full spectral near infrared spectroscopy simultaneously with phosphorus metabolites using nuclear magnetic resonance 31P spectroscopy at high time resolution (10 seconds) during transient anoxia (FiO2 = 0.0 for 105 seconds) in the newborn piglet brain. During the onset of anoxia, there was no change in either phosphocreatine (PCr) concentration or the oxidation state of the CuA centre of cytochrome oxidase until there was a substantial fall in cerebral hemoglobin oxygenation, at which point the CuA centre reduced simultaneously with the decline in PCr. At a later time during the anoxia, intracellular pH decreased rapidly, consistent with a fall in cerebral metabolic rate for O2 and reduced flux through the tricarboxylic acid cycle. The simultaneous reduction of CuA and decline in PCr can be explained in terms of the effects of the falling mitochondrial electrochemical potential. From these observations, it is concluded that, at normoxia, oxidative phosphorylation and the oxidation state of the components of the electron transport chain are independent of cerebral oxygenation and that the reduction in the CuA signal occurs when oxygen tension limits the capacity of oxidative phosphorylation to maintain the phosphorylation potential. (+info)
Aerobic, anaerobic and combination estimates of cerebral hypoperfusion during and after cardiac surgery.
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We studied 15 patients undergoing cardiac surgery involving hypothermic cardiopulmonary bypass (CPB). Cerebral arteriovenous difference in oxygen content (AVDO2) was significantly less during CPB and for up to 18 h after operation compared with pre-CPB values (P < 0.05). There were no significant changes in mean jugular bulb oxyhaemoglobin saturation (SjvO2), cerebral arteriovenous difference in lactate content or lactate-oxygen index (LOI). SjVO2 and arterial carbon dioxide tension (PaCO2) (P = 0.005) were positively correlated as were AVDO2 and haemoglobin concentration (P = 0.012). AVDO2 and PaCO2 (P = 0.007) were negatively correlated as were LOI and arterial oxyhaemoglobin saturation (P = 0.037). There were no significant correlations between mean arterial pressure and any of the variables. SjVO2 and AVDO2 may require correction for changes in PaCO2 and haemoglobin concentration before relating these variables to cerebral outcome. (+info)
Site-directed mutagenesis in hemoglobin: test of functional homology of the F9 amino acid residues of hemoglobin alpha and beta chains.
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The cysteine residue at F9(93) of the human hemoglobin (Hb A) beta chain, conserved in mammalian and avian hemoglobins, is located near the functionally important alpha1-beta2 interface and C-terminal region of the beta chain and is reactive to sulfhydryl reagents. The functional roles of this residue are still unclear, although regulation of local blood flow through allosteric S-nitrosylation of this residue is proposed. To clarify the role of this residue and its functional homology to F9(88) of the alpha chain, we measured oxygen equilibrium curves, UV-region derivative spectra, Soret-band absorption spectra, the number of titratable -SH groups with p-mercuribenzoate and the rate of reaction of these groups with 4, 4'-dipyridine disulfide for three recombinant mutant Hbs with single amino acid substitutions: Ala-->Cys at 88alpha (rHb A88alphaC), Cys-->Ala at 93beta (rHb C93betaA) and Cys-->Thr at 93beta (rHb C93betaT). These Hbs showed increased oxygen affinities and impaired allosteric effects. The spectral data indicated that the R to T transition upon deoxygenation was partially restricted in these Hbs. The number of titratable -SH groups of liganded form was 3.2-3.5 for rHb A88alphaC compared with 2.2 for Hb A, whereas those for rHb C93betaA and rHb C93betaT were negligibly small. The reduction of rate of reaction with 4,4'-dipyridine disulfide upon deoxygenation in rHb A88alphaC was smaller than that in Hb A. Our experimental data have shown that the residues at 88alpha and 93beta have definite roles but they have no functional homology. Structure-function relationships in our mutant Hbs are discussed. (+info)