Metabolic evidence for sequestration of low-density lipoprotein in abdominal aorta of normal rabbits.
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In rabbits, atherosclerosis develops preferentially at branch sites compared with the adjacent uniform aorta. This study investigated the hypothesis that low-density lipoprotein (LDL) is "sequestered" (present in a form that exchanges slowly with plasma LDL) in the aortas of normal rabbits and that more LDL is sequestered at branch sites. Thus 33 normal rabbits were injected with LDL labeled with (125)I-labeled tyramine cellobiose ((125)I-TC) to trace both undegraded LDL and aortic LDL degradation products. For 25 rabbits, LDL was also labeled with (131)I to trace undegraded LDL alone. The time-dependent aortic (125)I-TC and (131)I accumulation was determined from 0.6 to 120 h after injection. Compartmental modeling provided metabolic evidence for sequestration of LDL at the branch (P < 0.01) and uniform (P < 0.005) abdominal aorta. Concentrations of sequestered LDL were 109 +/- 28% higher (P < 0.0005) for branch sites. LDL mean residence time was 23.5 +/- 3.1 h for branch sites, 7.6 +/- 3.5 h longer (P < 0.05) than for the uniform abdominal aorta. Enhanced retention of higher concentrations of sequestered LDL at branch sites could account for the increased susceptibility of these aortic sites to atherosclerosis. (+info)
Dynamics and consequences of potassium shifts in skeletal muscle and heart during exercise.
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Since it became clear that K(+) shifts with exercise are extensive and can cause more than a doubling of the extracellular [K(+)] ([K(+)](s)) as reviewed here, it has been suggested that these shifts may cause fatigue through the effect on muscle excitability and action potentials (AP). The cause of the K(+) shifts is a transient or long-lasting mismatch between outward repolarizing K(+) currents and K(+) influx carried by the Na(+)-K(+) pump. Several factors modify the effect of raised [K(+)](s) during exercise on membrane potential (E(m)) and force production. 1) Membrane conductance to K(+) is variable and controlled by various K(+) channels. Low relative K(+) conductance will reduce the contribution of [K(+)](s) to the E(m). In addition, high Cl(-) conductance may stabilize the E(m) during brief periods of large K(+) shifts. 2) The Na(+)-K(+) pump contributes with a hyperpolarizing current. 3) Cell swelling accompanies muscle contractions especially in fast-twitch muscle, although little in the heart. This will contribute considerably to the lowering of intracellular [K(+)] ([K(+)](c)) and will attenuate the exercise-induced rise of intracellular [Na(+)] ([Na(+)](c)). 4) The rise of [Na(+)](c) is sufficient to activate the Na(+)-K(+) pump to completely compensate increased K(+) release in the heart, yet not in skeletal muscle. In skeletal muscle there is strong evidence for control of pump activity not only through hormones, but through a hitherto unidentified mechanism. 5) Ionic shifts within the skeletal muscle t tubules and in the heart in extracellular clefts may markedly affect excitation-contraction coupling. 6) Age and state of training together with nutritional state modify muscle K(+) content and the abundance of Na(+)-K(+) pumps. We conclude that despite modifying factors coming into play during muscle activity, the K(+) shifts with high-intensity exercise may contribute substantially to fatigue in skeletal muscle, whereas in the heart, except during ischemia, the K(+) balance is controlled much more effectively. (+info)
Estimation of aqueous distributional spaces in the dual perfused rat liver.
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1. The aim of this study was to estimate the aqueous distributional spaces of the liver as a function of the route of input: portal vein (PV) versus hepatic artery (HA). 2. Studies were performed in the situ single (PV) and dual (PV-HA) perfused rat liver (n = 6-10) using Krebs bicarbonate buffer at constant PV (12 ml min-1) and HA (3 ml min-1) flow rates. An impulse input-output response technique was employed, varying the route of input, using non-labelled erythrocytes (intravascular marker), 125I-albumin and [14C]sucrose (extracellular markers), and [14C]urea and 3H2O (total water markers) as the reference indicators. 3. Distributional spaces were estimated using two different methods, namely standard and specific. The standard method was applied to hepatic outflow data obtained from the single PV perfused liver. The specific method was used when operating in the dual perfused mode to provide an estimate of the excess space perfused solely by the HA input. Specific spaces, interstitial and intracellular volumes, were estimated by difference. 4. The results were evaluated by means of visual inspection of the outflow profiles and comparison of the distributional spaces. Different hepatic effluent profiles obtained as a function of the route of input indicated that these two inputs did not completely mix within the liver. Estimates of the distributional spaces supported this observation, and further suggested that the arterial input perfuses 9-12 % more hepatic tissue than the venous input. 5. The knowledge obtained from the existence of a specific arterial space can be extended to help make predictions about the fate of an eliminated compound following arterial administration. Any difference between the HA and PV in terms of hepatic recovery could be attributed to this excess space and its enzyme density. (+info)
The effect of altered cerebral blood flow on the cerebral kinetics of thiopental and propofol in sheep.
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BACKGROUND: Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption. METHODS: The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data. RESULTS: The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion. CONCLUSIONS: The cerebral kinetics of thiopental and propofol after bolus injection were dependent on cerebral blood flow, despite partial diffusion limitation. Higher flows produce higher peak cerebral concentrations. (+info)
A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog.
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A turnover model for irreversible inhibition of gastric acid secretion by omeprazole in gastric fistula dogs was developed using data from studies with both short- and long-term measurement periods. In the short-term experiments, after stimulation of acid secretion with histamine, the dogs were infused i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profiles and schedule dependence in the inhibitory effect of omeprazole was observed. In the long-term experiments, dogs were given single intraduodenal doses, which inhibited the acid secretion for several days. Combining the short-term and long-term data allowed the observation of a biphasic recovery of acid secretion that was described by the turnover model. Second order association rate constants (k(ome)) for the covalent binding of omeprazole to H(+),K(+)-ATPase were estimated to 11 and 3.0 l/micromol/h for the i.v. and intraduodenal experiments, respectively. The apparent turnover rate constant of the enzyme (k(out)) was 0.013 h(-1) and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as k(out) over k(ome), was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, respectively. Allometric scaling of the model resulted in trustworthy predictions for observations previously done in humans. The model predicted a good correlation between maximal inhibitory effect and exposure (area under the plasma concentration curve). The time dependence in this relation was also predicted by the model. (+info)
Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats.
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Models of leukopenia after chemotherapy are mainly empirical. To increase the derived models' potential of mechanistic understanding and extrapolation, more physiologically based models are being developed. To date, presented models cannot characterize the often-observed rebound of leukocytes. Therefore, a model able to describe the transient decrease and rebound in leukocytes was developed. Three different dosing regimens of 5-fluorouracil were given to rats. One group received a single dose of 127 mg/kg. The other two groups received two and three injections of 63 mg/kg and 49 mg/kg, respectively, with a 2-day interval. Leukocyte counts were followed for 23 to 25 days after the first dose. Plasma concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic and pharmacodynamic models were developed using NONMEM. 5-Fluorouracil showed one-compartment disposition with capacity-limited elimination. The 49-mg/kg dose injected on three occasions produced the lowest leukocyte count (28% of baseline) and the most prominent rebound of the schedules, despite the fact that the fractionated regimens produced only 52 to 56% of the area under the concentration-time curve from time 0 to infinity in the single-dose group. The final semiphysiological model included two 5-fluorouracil-sensitive and two -insensitive transit compartments as well as a compartment of circulating leukocytes. Second order rate constants from the transit compartments and a negative feedback from the circulating leukocytes to the input of the first sensitive compartment characterized the pronounced changes in leukocyte counts. A posterior predictive check as well as predictions into a new data set showed that our model could well predict the schedule-dependent leukopenic effects of 5-fluorouracil. (+info)
Lung function, permeability, and surfactant composition in oleic acid-induced acute lung injury in rats.
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Although acute lung injury (ALI) is associated with inflammation and surfactant dysfunction, the precise sequence of these changes remains poorly described. We used oleic acid to study the pathogenesis of ALI in spontaneously breathing anesthetized rats. We found that lung pathology can occur far more rapidly than previously appreciated. Lung neutrophils were increased approximately threefold within 5 min, and surfactant composition was dramatically altered within 15 min. Alveolar cholesterol increased by approximately 200%, and even though disaturated phospholipids increased by approximately 30% over 4 h, the disaturated phospholipid-to-total phospholipid ratio fell. Although the alveolocapillary barrier was profoundly disrupted after just 15 min, with marked elevations in lung fluid ((99m)Tc-labeled diethylenetriamine pentaacetic acid) and (125)I-labeled albumin flux, the lung rapidly began to regain its sieving properties. Despite the restoration in lung permeability, the animals remained hypoxic even though minute ventilation was increased approximately twofold and static compliance progressively deteriorated. This study highlights that ALI can set in motion a sequence of events continuing the respiratory failure irrespective of the alveolar surfactant pool size and the status of the alveolocapillary barrier. (+info)
Body composition of anorexia nervosa patients assessed by underwater weighing and skinfold-thickness measurements before and after weight gain.
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BACKGROUND: Weight restoration is a crucial element in the treatment of patients with anorexia nervosa. Therefore, the validity of different methods for measuring body composition is important. OBJECTIVE: We tested the concurrent validity of hydrodensitometry (underwater weighing) and anthropometry (12 skinfold thicknesses) and assessed body composition and subcutaneous fat before and after a refeeding program and a multifaceted program of therapy in a specialized inpatient unit for eating disorders. DESIGN: The body composition of a large sample of anorexia nervosa patients (97 restricting type, 33 binging-purging type) was studied by using 2 methods both before and after weight gain. We applied a behavioral contract for weight restoration with a minimum weekly gain of 700 g and a maximum of 3 kg. Bland-Altman analysis of agreement, Pearson correlation analysis, t tests, and analysis of covariance were used. RESULTS: There was good agreement between the results obtained by underwater weighing and by skinfold-thickness measurement (r = 0.76, P < 0.001); the results produced by the 2 methods did not differ significantly. On average, a significant weight gain (11.9 kg) was observed, composed of 6.6 kg fat and 5.3 kg fat-free mass. CONCLUSIONS: Body fat estimation by skinfold-thickness equation appeared to be as accurate as underwater weighing. The refeeding program led to a significant increase in body weight, of which 55.5% was body fat. The mean ratio of fat-free mass to fat mass at the end of the treatment was 3.4:1. (+info)