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PubMed2000

Transepithelial transport of levofloxacin in the isolated perfused rat kidney.

PURPOSE: The transepithelial transport of levofloxacin was evaluated in the isolated perfused kidney to investigate its renal secretory mechanisms. METHODS: Levofloxacin was instantaneously administered into the renal artery together with inulin and Evans blue-labeled albumin, and the single-pass dilution curves of the renal venous and urinary outflow were determined in the absence or presence of various compounds. Kinetic parameters were computed based on non-compartment moment analysis. RESULTS: The ratio of fractional excretion to filtration fraction (FE/FF) for levofloxacin was 2.99 +/- 0.18, indicating the involvement of tubular secretion. In the presence of cimetidine and quinolones, the FE/FF of levofloxacin was significantly decreased and the transepithelial mean transit time (Tcell) of levofloxacin was prolonged. The Tcell showed a negative correlation with renal secretion of levofloxacin, while the volume of distribution of levofloxacin showed no correlation. CONCLUSIONS: Transport on the brush-border membrane plays a determining step in the renal secretion of levofloxacin, and cimetidine and quinolones interact with levofloxacin transport on the brush-border membrane.

Animals↗
PubMed2000

Lithium has no direct effect on cardiac function in the isolated, perfused rat heart.

To determine if lithium exerts direct cardiac toxicity, using an isolated, perfused rat heart model, paced and unpaced beating rat hearts were perfused with Krebs-Henseleit bicarbonate solution and left ventricular pressures were measured via a balloon-tipped catheter positioned in the left ventricle via the mitral valve. Following a stabilization period, hearts were then perfused with Krebs-Henseleit bicarbonate solution containing 1, 10, and 100 mM ionized lithium chloride or lithium carbonate in an antecedent dose-response protocol and perfused for 10 min. at each dose. To control for the possibility of osmotic effects from the high dose of lithium, an additional group was studied in which hearts were perfused with Krebs-Henseleit bicarbonate solution for an initial stabilization period, then perfused for an additional 20 min. with Krebs-Henseleit bicarbonate solution alone, and finally with Krebs-Henseleit bicarbonate solution containing mannitol (200 mOsm/l) for 10 min. Lithium did not have any effect on left ventricular peak systolic pressure, left ventricular end diastolic pressure, heart rate or coronary haemodynamics at concentrations of 1 or 10 mM. At 100 mM LiCl and Li2CO3, left ventricular peak systolic pressure decreased transiently during the first minute of lithium infusion, but recovered significant function by 10 min. Heart rate decreased significantly by 10 min. of infusion. These effects were also seen in the osmotic controls and thus do not appear to be a direct effect of lithium. At the doses tested, lithium had no direct effect on cardiac function which could not be explained by an osmotic effect.

Analysis of Variance↗
PubMed1993

Functional and biochemical effects of a K(+)-ionophore on the isolated perfused rat heart.

Valinomycin, a K(+)-specific ionophore, influenced function and metabolism of isolated perfused rat hearts in a dose-dependent fashion. At a concentration of 0.05 micrograms ml-1 in perfusion fluid a 50% reduction of heart rate (HR) and a 90% reduction in max dP/dt were observed. These effects were paralleled by a substantial decrease of myocardial energy charge from about 0.80 to 0.20. A 2.5 fold increase in tissue lactate concentration indicated an increased rate of glycolytic activity. Low ATP combined with high ADP and AMP levels as found in these valinomycin-treated hearts is known to promote phosphofructokinase activity and may explain the elevated lactate levels. A significant increase in the concentrations of adenosine, IMP and inosine was observed as well.

Adenosine↗
PubMed1989

Unequal disposition of enantiomers of the organic cation oxyphenonium in the rat isolated perfused liver.

This paper describes the results of pharmacokinetic experiments in the rat isolated perfused liver with enantiomers of oxyphenonium. The study was performed with the [14C]methyl labelled compounds. In this preparation both metabolism and biliary excretion were significantly different for the (+)- and the (-)-isomer. Hepatic uptake rate was similar, but total biliary excretion (including metabolites) of the (-)-isomer was only 55% compared with the excretion of the (+)-isomer. In line with these data, after 2 h only 30% of the dose of the (+)-isomer and over 50% of the dose of the (-)-isomer was still found in the liver, predominantly in the form of metabolites. The metabolic profile was investigated using ion pair TLC. At least two metabolites were detected in bile for both enantiomers. However, unchanged (-)-oxyphenonium persisted for longer in bile, indicating either a more rapid canalicular transport of the (+)-isomer and/or a more rapid metabolism of (+)-oxyphenonium to cholephilic metabolites.

Animals↗
PubMed1982

Redox state of cytochrome aa3 in isolated perfused rat kidney.

Optical spectroscopy was used to evaluate mitochondrial anoxia in the isolated perfused rat kidney by determining the percentage of cytochrome aa3 in the reduced state. Despite high levels of plasma flow (greater than 20 ml . g-1 . min-1) and venous PO2 (greater than 300 mmHg), 25--40% of cytochrome aa3 appeared to be in its reduced form. Agents that alter metabolism or transport primarily in renal cortex had little or no effect on the redox state of cytochrome aa3. These included 3-mercaptopicolinate, an inhibitor of gluconeogenesis; 2-tetradecylglycidic acid, an inhibitor of fat metabolism via carnitine-fatty acyltransferase, and acetazolamide. In contrast, a decrease in medullary transport induced by the loop diuretics bumetanide or furosemide produced an increase in cytochrome aa3 oxidation consistent with a decrease in transport-related oxygen consumption in the hypoxic area. The results suggest that substantial portions of the kidney, particularly in the renal medulla, may normally operate on the brink of anoxia despite high PO2 in artery and vein.

Animals↗
PubMed1986

N1-methylnicotinamide transport by isolated perfused snake proximal renal tubules.

N1-methylnicotinamide (NMN) transport was studied in isolated perfused snake (Thamnophis spp.) proximal renal tubules. Unidirectional lumen-to-bath (Jl----bNMN) and bath-to-lumen (Jb----lNMN) fluxes saturated. Although Jl----bNMN and Jb----lNMN were similar, mean Jl----bNMN tended to exceed mean Jb----lNMN at all concentrations studied. Direct measurements confirmed a net reabsorptive flux equal to the difference between the unidirectional fluxes. This transport, opposite in direction to tetraethylammonium (TEA) transport, was not inhibited by TEA. Transport into the cells across both the luminal and peritubular membranes during flux measurements was apparently down an electrochemical gradient by a mediated process that was sodium dependent. Inhibition with NMN analogues suggested that transport into the cells across the luminal membrane during Jl----bNMN was more specific than transport into the cells across the peritubular membrane during Jb----lNMN. Transport out of the cells across both the luminal and peritubular membranes during flux measurements was apparently against an electrochemical gradient.

Animals↗
PubMed1987

Bicarbonate and ammonia transport in isolated perfused rat proximal straight tubules.

Bicarbonate, ammonia, and fluid transport were studied in isolated perfused proximal straight tubules from rats. The mean rate of fluid absorption (0.77 nl X min-1 X mm-1) and the mean rate of total CO2 absorption (42 pmol X min-1 X mm-1) exceeded corresponding rates measured previously in rabbit proximal straight tubules. The limiting total CO2 concentration when the tubules were perfused at slow flow rates was 5 mM, a value similar to those reported previously for rat proximal convoluted tubules and thick ascending limbs. When rat proximal straight tubules were perfused and bathed with solutions containing 1 mM total ammonia at slow perfusion rates, the measured total ammonia concentration in collected fluid rose to a level predicted by the diffusion trapping model of ammonia secretion in the absence of a luminal disequilibrium pH. We conclude the proximal straight tubule of the rat can absorb bicarbonate at a rate that can account for a large portion of the bicarbonate absorption measured in vivo between the late proximal convoluted tubule and the early distal tubule, the rat proximal straight tubule is capable of transepithelial ammonia secretion, most likely by NH3 diffusion down a concentration gradient generated by luminal acidification, and the rat proximal straight tubule apparently does not generate a luminal disequilibrium pH despite the occurrence of proton secretion, implying the presence of endogenous luminal carbonic anhydrase.

Ammonia↗
PubMed1979

Protein metabolism in lung: use of isolated perfused lung to study protein degradation.

This study investigates the use of the isolated perfused lung to study protein degradation. Proteins were labeled in vivo for 10 min or for 5 h using L-[U-14C]phenylalanine. When prelabeled lungs were perfused in vitro virtually all of the acid-soluble and acid-insoluble radioactivity in the tissue and perfusate remained as phenylalanine. Protein degradation was measured as the accumulation of free [14C]phenylalanine in ther perfusate; during the time this accumulated the amount of intracellular free phenylalanine and the free phenylalanine space remained constant. Proteins labeled during 10 min had a constant rate of degradation between 45 and 90 min of perfusion (about 11%.h-1); those labeled during 5 h had a constant rate of degradation for 90 (about 3%.h-1). The percent dry lung weight did not change during the perfusion. We conclude that measurable rates of proteolysis of "rapid" and "slowly" turning over proteins can be obtained while the lung is virtually free of edema. This system should allow studies on the modulation of proteolysis in intact lung under defined conditions.

Animals↗
PubMed1985

Alveolar transfer of prostaglandin E2 in isolated perfused guinea pig lungs.

Alveolar transfer of prostaglandin E2 (PGE2) was characterized in isolated perfused guinea pig lungs (n = 19) by measuring radioactivity appearing in the venous effluent during 30 min after intratracheal instillation of [3H]PGE2, [14C]-mannitol, and [125I]iodoantipyrine. Recovery of lipid-soluble [125I]iodoantipyrine [91 +/- 3% (SE)] after 30 min was used to estimate total 3H and 14C delivered to the exchanging region of lung at time 0. In seven control lungs, 58 +/- 4% of [14C]mannitol and 16 +/- 4% of [3H]PGE2 was retained 10 min after instillation. Neither perfusion with diphloretin phosphate (10 micrograms/ml; n = 4) nor hypothermia (5 degrees C; n = 5) significantly affected the amount of [14C]mannitol retained; however, [3H]PGE2 remaining in these lungs increased significantly to 36 +/- 4 and 53 +/- 2%, respectively. Addition of unlabeled PGE2 (200 micrograms) to the instilled solution (n = 3) increased retention of both [14C]mannitol (80 +/- 3%) and [3H]PGE2 (65 +/- 4%). Alveolar transfer of [3H]PGE2 was calculated as the difference in percent retention of [14C]mannitol and [3H]PGE2 and normalized to that of [14C]mannitol. After 10 min, alveolar transfer of [3H]PGE2 was 71 +/- 8% in control lungs but was decreased to 26 +/- 7, 10 +/- 5, and 19 +/- 6% by diphloretin phosphate, hypothermia, or unlabeled PGE2, respectively. These data suggest that alveolar clearance of PGE2 involves a saturable drug- and temperature-sensitive process.

Animals↗
PubMed1991

Elastic properties of the isolated perfused porcine duodenum.

The aim was to investigate elastic wall properties of the isolated perfused porcine duodenum using manometry and impedance planimetry. Distension of an intraluminal balloon with definite pressure steps of 0.5, 1.0, 2.0, 3.0 and 5.0 kPa was done with simultaneous recording of balloon pressure and balloon cross-sectional area (Bcsa). Wall thickness of the relaxed intestine was estimated from measurement of tissue density. The elastic wall parameters were calculated from these measurements. Balloon inflation elicited a phase of rapid Bcsa increase followed by an accommodation phase of slow Bcsa increase. At steady state, the circumferential and the radial wall stress increased as linear functions of the applied balloon pressure, while the circumferential and the radial wall strain increased nonlinearly. The incremental elastic moduli increased exponentially. Our model allows the study of passive biomechanical wall properties of the intact duodenum. The duodenal wall showed qualitatively and also quantitatively an elastic nature.

Animals↗
PubMed1992

Sulfur dioxide-induced bronchoconstriction in the isolated perfused and ventilated guinea-pig lung.

SO2 exposure (50-500 ppm) of isolated, perfused and ventilated guinea pig lungs, via the air passages, caused a concentration-related reduction in dynamic compliance and conductance. No changes in pulmonary perfusion flow was noted at any SO2 concentration. Formed sulfite was detected in lung lavage fluid as well as in the perfusate. Pretreatment of the lungs with a low concentration of SO2 (10 ppm) for 30 min protected against bronchoconstriction by a high concentration of SO2 (250 ppm). A similar protective effect was noted by pretreatment with sodium sulfite (3 mM) in the lung perfusate.

Air Pollutants↗
PubMed1997

Renin-angiotensin system components in the interstitial fluid of the isolated perfused rat heart. Local production of angiotensin I.

We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the uptake and clearance of exogenous renin, angiotensinogen, and angiotensin I (Ang I) as well as the cardiac production of Ang I. The levels of these compounds in interstitial transudate were considered to be representative of the levels in the cardiac interstitial fluid. During perfusion with renin or angiotensinogen, the steady-state levels (mean +/- SD) in interstitial transudate were 64 +/- 34% (P < .05 for difference from the arterial level, n = 8) and 108 +/- 42% (n = 6) of the arterial level, respectively; the levels in coronary effluent were not significantly different from those in interstitial transudate. Ang I was not detectable in interstitial transudate during perfusion with Tyrode's buffer or angiotensinogen. It was very low in interstitial transudate during perfusion with renin and rose to much higher levels during combined renin and angiotensinogen perfusion. The total production rate of Ang I present in interstitial fluid could be largely explained by the renin-angiotensinogen reaction in the fluid phase of the interstitial compartment. In contrast, the total production rate of Ang I present in coronary effluent and the net ejection rate of Ang I via coronary effluent were, respectively, 4.6 +/- 2.2 and 2.8 +/- 1.3 (P < .01 and P < .05 for difference from 1.0, n = 6) times higher than could be explained by Ang I formation in the fluid phase of the intravascular compartment. Ang I from the interstitial fluid contributed little to the Ang I in the intravascular fluid and vice versa. These data reveal two tissue sites of Ang I production, ie, the interstitial fluid and a site closer to the blood compartment, possibly vascular surface-bound renin. There was no evidence that the release of locally produced Ang I into coronary effluent and interstitial transudate occurred independently of blood-derived renin or angiotensinogen.

Angiotensin I↗
PubMed1981

Effect of insulin on glucose- and arginine-stimulated somatostatin secretion from the isolated perfused rat pancreas.

The effects of exogenous insulin on somatostatin secretion from the isolated perfused rat pancreas have been investigated in the presence of 5.6 mM glucose and when somatostatin secretion was stimulated by either glucose (16.7 mM) or arginine (20 mM). Insulin (15 mU/ml) significantly and rapidly suppressed glucose- and arginine-stimulated somatostatin release. However, at 5.6 mM glucose and, in the absence of other stimulators of somatostatin release, insulin had no effect on the somatostatin secretion rate.

Animals↗
PubMed1991

Amino acids fail to prevent halothane depression of albumin synthesis: studies in the isolated perfused rat liver.

Halothane (1.3 MAC) and ethanol (0.4%) depress albumin synthesis in isolated perfused rat livers (IPRLs). Addition of amino acids prevents depression by ethanol. We have examined the effects of amino acids on albumin synthesis by IPRLs exposed to halothane. Seventeen livers were perfused with a mixture of rat erythrocytes and rabbit plasma. Five were exposed to oxygen/carbon dioxide alone and 12 to oxygen/carbon dioxide with 1.5% halothane. A mixture of 10 essential amino acids was added to the perfusate of six of the halothane-exposed livers to a concentration approximately 10 times the normal rat plasma level. Perfusate concentrations of newly synthesized albumin were measured by radial immunodiffusion, and the rate of synthesis for the 4.25-h study period was calculated. The mean +/- SEM albumin synthetic rate (mg/h per 300-g rat) in the control group (12.13 +/- 1.36) was significantly greater than in the group receiving halothane alone (6.98 +/- 0.92). Amino acid treatment failed to prevent halothane depression of albumin synthesis (8.68 +/- 0.84). Thus, although amino acids block ethanol depression of albumin synthesis, we could show no such effect in rat livers exposed to halothane.

Amino Acids, Essential↗
PubMed1986

Histamine induces ovulation in the isolated perfused rat ovary.

Ovulatory effects of histamine and specific antagonists were studied in isolated perfused ovaries from immature rats treated with 10 i.u. PMSG to stimulate follicular growth and maturation. Histamine alone, like LH, induced ovulation in all ovaries tested, but the number of follicular ruptures was lower after histamine (7.0 and 2.2 ruptures, respectively, per ovary). The histamine-induced ovulations could be inhibited dose-dependently by the H1-receptor antagonist, pyrilamine, or the H2-antagonists, cimetidine and ranitidine. At the concentrations tested, these antagonists did not, when given separately, reduce the LH-induced ovulations significantly, but pyrilamine and cimetidine in combination lowered the ovulation frequency by 65%. The prostaglandin synthesis inhibitor, indomethacin, was not able to block the histamine-induced ovulations.

Animals↗
PubMed1975

Metabolism of nicotine by the isolated perfused dog lung.

1. Metabolism of [14C]nicotine has been studied in the isolated perfused dog lung. [14C]Nicotine, 50 mug every 30 s for 10 min administered via the pulmonary artery, undergoes first pass metabolism to a small extent. [14C]Cotinine was detected in the venous blood. Of the injected activity, 6 percent was in the lung at the end of experiment; 60 percent being present as [14C]nicotine and 20 percent as [14C]nicotine-1'-oxide. 2. When [14C]nicotine was administered in cigarette smoke a greater degree of metabolism was observed at first pass. Pyrolysis products of [14C]nicotine also were present in the venous blood. Lungs after smoke exposure contained 30 percent of administered radioactivity, with a substantial proportion of [14C]nicotine-1'-oxide. 3. Administration of [14C]nicotine-labelled smoke to lung preparations, on closed circuit, gave significant amounts of [14C]cotinine and other metabolites over a 2 h period. Lung tissue contained approx. 40 percent of injected dose, of which 25 percent only was [14C]nicotine. Large proportions of [14C]cotinine and [14C]nicotine-1'-oxide were present but 45 percent of the activity was present as other unidentified pyrolysis products. [14C]Demethyl cotinine was detected.

Animals↗
PubMedDate not supplied

Uptake and metabolism of endothelin in the isolated perfused rat lung.

The uptake and metabolism of endothelin was studied in the isolated perfused rat lung. 125I-Labeled endothelin (4 x 10(-12) M) was rapidly removed from the lung perfusate. More than 90% of the label was removed by 5 min, and only 4-5% remained in the perfusate after 30 min. In the presence of 10(-9) or 5 x 10(-9) M unlabeled endothelin added 6 min before 125I-labeled endothelin, the radiolabel was more slowly removed, so that after 30 min 19 or 73% of the label, respectively, remained in the perfusate. Although a high level of unlabeled endothelin in the perfusate reduced the uptake of 125I-labeled endothelin, it did not displace radiolabel previously taken up by the lung. Analysis of radiolabel composition showed that endothelin metabolism was less than 15% in both the lung and the perfusate after 30 min of lung perfusion. Autoradiography of the lung indicated that the radiolabel was located primarily within the alveolar wall. These results suggest that circulating endothelin is readily but finitely taken up in the pulmonary microvasculature where it is avidly bound but slowly metabolized.

Animals↗
PubMed1976

[Correlation between lactate output and insulin secretion of the isolated perfused rat pancreas under the influence of high concentrations of phenformin].

On the isolated perfused rat pancreas phenformin at high concentrations (10 mg/1, 50 mg/1 and 100 mg/1) provokes an increase of the insulin and lactate output in the effluent liquid. In no case is glucagon secretion modified by this substance. There exists a statistically significant correlations between the increase in insulin output and the increase in lactate output induced by phenformin.

Animals↗