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At least 1,531 records · Page 85Linked to original sources
PubMed2003

On the use of R1 and R2* for measurement of contrast agent concentration in isolated perfused rat liver.

We present experimental MRI protocols at 4.7 T for quantitative determination of the Dotarem distribution volume in isolated perfused rat liver. The procedures involved either constant contrast agent (CA) concentration or bolus administration conditions. R1 and R2* effects of the CA in liver and perfusate were measured using gradient echo fast imaging (GEFI) experiments by varying either the excitation angle or the echo time. CA concentrations in liver and perfusate were also measured after MRI by inductively coupled plasma atomic emission spectroscopy, in order to determine in situ relaxivities in the perfusate (r1=4.2 +/- 0.1 s(-1) mm(-1), r2*=17 +/- 2 s(-1) mm(-1)) and in the liver (r1=7.2 +/- 0.2 s(-1) mm(-1), r2*=99 +/- 5 s(-1) mm(-1)). When CA concentrations were estimated from R1 measurements and r1, the CA distribution volume estimations in liver resulting from bolus (0.31 +/- 0.01) and stationary (0.32 +/- 0.05) experiments were not significantly different. In contrast, after a bolus, CA concentrations derived from R2* and r2* were overestimated in liver and even more in perfusate. However, with R1 and R2* being measured before CA bolus administration, zero echo time signal intensities computed from multiple TE measurements during multiple boli yielded good estimations of R1 and thus correct CA concentrations in liver and in perfusate. Under these conditions, a single multi-echo GEFI acquisition should be sufficient to determine the concentration-time curves. Consequently, this protocol should be appropriate to rapidly estimate the distribution volume in vivo when multiple boli have to be avoided.

Algorithms↗
PubMed1995

Toxicokinetics of topical sulfur mustard penetration, disposition, and vascular toxicity in isolated perfused porcine skin.

Sulfur mustard bis(2-chloroethyl) sulfide (HD) is a bifunctional alkylating agent that causes cutaneous vesication. The isolated perfused porcine skin flap is an in vitro model that has been used to study this toxic response. The purpose of this study was to formulate a toxicokinetic model of HD penetration and cutaneous disposition as an aid in correlating critical steps in the pathogenesis of vesication to HD concentrations in different regions of skin. [14C]HD was dosed topically in ethanol at 10.0 mg/ml in a 7.5-cm2 dosing site and venous efflux samples were collected over 2, 4, or 8 hr. At the termination of the experiment, stratum corneum tape strips, core biopsies for serial sections, and the entire skin flap were collected for radioassay. Peak 14C-radiolabel flux occurred within 5 to 60 min in all skin flaps, much earlier than signs of HD-induced toxicity. A toxicokinetic model was used to quantitate the time profile of HD disposition in different skin compartments. Estimates of vascular and extracellular volume changes due to topical HD toxicity were estimated using radiolabeled albumin and inulin infusions. A second toxicokinetic model, with a time-variant distribution rate, was used to simulate volume changes. In order to accurately predict HD disposition, it was necessary to add another compartment as a reservoir for slowly released metabolites of HD. This model provides a quantitative profile of the time course of HD (or metabolites) disposition within skin which would aid in the interpretation of mechanistic studies of vesication as well as in designing interventive antivesicant drug strategies.

Animals↗
PubMed1990

Atrial natriuretic factor has a weak insulinotropic action in the isolated perfused rat pancreas.

The effect of atrial natriuretic factor (ANF; 1, 10, 100, 1000 pmol/l) on insulin release from the isolated perfused rat pancreas was studied. ANF weakly augmented the glucose (10 mmol/l)-stimulated insulin release during the second (controls: 100%; 1 pmol/l: 99%; 10 pmol/l: 149%, P less than 0.05; 100 pmol/l: 111%; 1000 pmol/l 135%), but not the first phase of the secretory response. In contrast, the first, but not the second phase of arginine (10 mmol/l)-stimulated insulin release was significantly enhanced by ANF (1000 pmol/l; controls: 100%; 1000 pmol/l: 235%, P less than 0.05). The hormone did not influence basal insulin secretion. Our data indicate an insulinotropic effect of ANF on the rat pancreas, which is dependent on the utilized background secretagogues.

Animals↗
PubMed1978

Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas.

The release of pancreatic polypeptide (PP) by gut hormones, acetyl choline and adrenaline was investigated in an isolated perfused pancreas preparation. PP was potently released by 1 nmol/1 caerulein (186 +/- 12%, p is less than 0.001) and gastric inhibitory peptide (GIP) (211 +/- 31%, p is less than 0.005) as well as by 1 mumol/1 acetyl choline (1097 +/- 59%, p is less than 0.001). A significant two-fold release of PP was also evoked by 1 nmol/1 vasoactive intestinal peptide (VIP) (129 +/- 38%, p is less than 0.02 and gastrin (108 +/- 25% p is less than 0.01). Insulin release, induced by high glucose concentration was enhanced by both GIP (210 +/- 38%, p is less than (0.01) and VIP (48 +/- 5%, p is less than 0.001). In addition GIP enhanced the release of glucagon by 179 +/- 18% (p is less 0.001) at 1.4 mmol/1 glucose and by 127 +/- 24% (p is less than 0.005) at 8.3 mmol/1 glucose. Thus no simple inter-relationship appears to exist between the control of the three circulating islet hormones.

Acetylcholine↗
PubMed1991

Influence of nocloprost on the vascular responses to various stimuli in the isolated perfused rabbit kidney.

Nocloprost, a new synthetic prostanoid, elicited a vasodilator action when given through the renal artery of the isolated perfused rabbit kidney. Lower concentrations of the compound inhibited the pressor response to sympathetic stimulation or to angiotensin II, but potentiated the pressor effect of exogenous noradrenaline. These results were taken as an evidence that nocloprost prevents the release of neurotransmitter by a presynaptic mechanism.

Angiotensin II↗
PubMed1996

Tubular transport mechanisms of quinapril and quinaprilat in the isolated perfused rat kidney: effect of organic anions and cations.

The clearance mechanisms of quinapril and quinaprilat were probed using an isolated perfused rat kidney model. Sixty-four experiments were performed with drug in the absence and presence of classic inhibitors of the organic acid (i.e., probenecid and p-aminohippurate) and organic base (i.e., tetraethylammonium and quinine) transport systems of the proximal tubule. Initial perfusate concentrations of quinapril and quinaprilat were approximately 2.36 microM (or 1000 ng/ml), and transport inhibitors were coperfused at 100-10,000 times the drugs' initial microM concentrations. Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a reversed-phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. Perfusate protein binding was determined using an ultrafiltration method at 37 degrees C. Overall, the clearance ratios of quinapril (total renal clearance divided by fu x GFR) and quinaprilat (urinary clearance divided by fu. GFR) were significantly reduced, and in a dose-dependent manner, by the coperfusion of organic acids but not organic bases. The data demonstrate that the organic anionic secretory system is the primary mechanism by which quinapril and quinaprilat are transported into and across renal proximal cells.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Oxidant-antioxidant balance: some observations from studies of ischemia-reperfusion in isolated perfused rat hearts.

Alteration in oxidant-antioxidant balance is a key feature of many common vascular diseases. Using an isolated perfused heart model, we found that (a) xanthine oxidase-derived oxygen radicals contributed to ischemia-reperfusion injury; (b) addition of antioxidants within or outside erythrocytes decreased injury following ischemia-reperfusion; (c) endotoxin pretreatment increased myocardial catalase activity and decreased injury following ischemia-reperfusion; (d) interleukin pretreatment increased myocardial glucose-6-phosphate activity and decreased ischemia-reperfusion injury, and (e) neutrophils mediated tolerance to a subsequent oxidative stress by causing a small oxidant stress that in turn increased antioxidant protection mechanisms.

Animals↗
PubMed1987

The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite.

The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 +/- 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 +/- 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 +/- 182 ml) and (+)PQ (930 +/- 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life (-)PQ 54 +/- 29 min; (+)PQ 123 +/- 33 min) and smaller area under the curve to infinity (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 +/- 0.26 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 +/- 0.02 ml min-1 and 0.14 +/- 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites (0.24 +/- 0.13 ml min-1 and 0.29 +/- 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.

Animals↗
PubMed1996

Enhancing effects of vasoconstrictors on bile flow and bile acid excretion in the isolated perfused rat liver.

The effects of vasoconstrictors on bile flow and bile acid excretion were examined in single-pass isolated perfused rat livers. Administration of norepinephrine (NE), 4 nmol/min, plus continuous infusion of taurocholate (TC) (1.0 mumol/min) rapidly increased bile flow in 1 min, and from min 5 until the end of NE administration (late period) bile flow remained above the basal level (111.7 +/- 2.2%), as did bile acid output (114.6 +/- 1.8%). Without TC infusion, administration of NE produced no increase in the late period. Administration of NE plus taurochenodeoxycholate (1.0 mumol/min) increased bile flow and bile acid output in the late period to 121.9 +/- 7.0 and 137.1 +/- 6.8%, respectively. With NE plus taurodehydrocholate, the respective values were only 105.4 +/- 1.6 and 104.1 +/- 4.0%. When horseradish peroxidase (HRP) (25 mg) was infused over 1 min with continuous NE, the late peak (20-25 min) of HRP elimination into bile significantly exceeded that of untreated controls (P < 0.01). These observations suggest that vasoconstrictors enhance biliary excretion of more hydrophobic bile acids, in part by stimulating vesicular transport.

Animals↗
PubMed1986

Antagonism of thromboxane actions in the isolated perfused rat heart.

The effects of SQ-29,548, a novel thromboxane A2 (TxA2) receptor antagonist, were studied in the isolated perfused rat heart. SQ-29,548 at concentrations of 2.5 to 50 ng/ml antagonized the increase in coronary perfusion pressure (CPP) in response to the thromboxane agonist, 9,11-methanoepoxy PGH2. Increases in CPP induced by arginine vasopressin and leukotriene D4 were not altered by SQ-29,548. We conclude that SQ-29,548 is a very potent and specific TxA2 receptor antagonist in the coronary vasculature of the rat heart.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1980

Characterization of the inhibitory effect of somatostatin upon insulin and glucagon release in the isolated perfused canine pancreas: evidence for interaction with calcium.

Somatostatin is a potent inhibitor of insulin and glucagon release from the isolated perfused canine pancreas. The present investigation was undertaken to characterize the pancreatic effects of somatostatin by studying its ability to influence insulin and glucagon release from the same perfusion preparation in response to various well-known stimuli and modulators. Somatostatin inhibited insulin and glucagon release in all test situations chosen but one. Thus, somatostatin inhibits pancreatic hormone secretion irrespective of whether it is modulated by (1) a primary initiator of insulin release--glucose (1.3 or 8.3 mM), leucine (4.1 mM), tolbutamide (2.6 mM); (2) a potentiator of insulin release, i.e., a substance that requires the presence of glucose--arginine (1 mM); (3) substances known to increase the level of cyclic AMP (cAMP) in the islets--glucagon (2 ng/ml), cAMP (1 mM), theophylline (1 mM); (4) an autonomic agent--epinephrine (2 ng/ml), acetylcholine (10 microM); or (5) alpha and beta adrenergic antagonists--phentolamine (1 microM), propranolol (1 microM). In contrast, high Ca++ concentrations (4.8 and 8.2 mM) abolished the inhibitory action of somatostatin on both insulin and glucagon release. These findings lend support to the hypothesis that somatostatin acts at a stage of secretory processes, possibly related to Ca++ inactivation, late in the chain of events leading to hormone release.

Animals↗
PubMed1992

The effect of hexane on the ventricular fibrillation threshold of the isolated perfused rat heart.

This investigation was conducted to determine the influence of hexane on the ventricular fibrillation threshold of the isolated perfused rat heart and myocardial electrolyte levels. Ventricular fibrillation threshold was measured using the Langendorff perfusion apparatus. Heart rate was measured by a universal digital counter and the cardiac flow by collecting the outflow of the heating chamber below the heart into a graduated measuring cylinder. Magnesium and zinc were measured by atomic absorption spectrophotometry and potassium by flame photometry. Two groups of rats were studied; those in the experimental group were given 0.2 ml of hexane and the control group 0.2 ml olive oil subcutaneously for 90 days. Their hearts were removed under anaesthesia. Half of the experimental and control hearts were mounted on the Langendorff perfusion apparatus and the heart rate, coronary flow and ventricular fibrillation threshold were measured. The hearts of the other half were used to measure myocardial electrolyte levels. In the experimental group the ventricular fibrillation threshold decreased (4.72 (S.D. +/- 1.87) vs 9.48 (S.D. +/- 2.98); P less than 0.001). There was no change in the coronary flow and heart rate in between the groups. The mean myocardial potassium levels (2586 (S.D. +/- 162) vs 2968 (S.D. +/- 218) micrograms/g; P less than 0.001), magnesium levels (164 (S.D. +/- 28) vs 208 (S.D. +/- 18) micrograms/g; P less than 0.001) and zinc levels (19.6 (S.D. +/- 4) vs 33.8 (S.D. +/- 6.8) micrograms/g; P less than 0.001) were significantly lower in the hexane-treated group compared to controls. Hexane, a constituent of glue and benzine, is cardiotoxic; marked derangement in myocardial electrolytes and a reduced ventricular fibrillation threshold, indicating an increased myocardial vulnerability to arrhythmias, was noted in the experimental animals.

Animals↗
PubMed1985

Metabolism and biliary excretion of trimetrexate by the isolated perfused rat liver.

The metabolism and biliary excretion of trimetrexate (TMTX), a lipid soluble antifolate, were examined using a recirculating isolated perfused rat liver system. Elimination of TMTX into perfusate was biphasic and dose-independent, with distribution and elimination half-lives of 2 and 13 min. Two metabolites, M1 and M2, both known to inhibit dihydrofolate reductase activity, were present in perfusate only in small concentrations. However, of the total TMTX dose, approximately 50% was excreted in bile as M1, and 20% as M2. Up to 75% of the total dose was accounted for as TMTX, M1, or M2 in perfusate and bile.

Animals↗
PubMed1977

Effect of porphyrinogenic agents on protein synthesis and bilirubin formation by the isolated perfused rat liver.

We established an isolated rat liver perfusion system for the study of heme catabolism. The liver of rats fasted for 48 h is perfused with an erythrocyte-free medium. Ultrastructural analysis shows integrity of all subcellular organelles with the exception of minor alterations in the rough endoplasmic reticulum. The perfused liver synthesizes serum proteins at a constant rate for 5 h. Albumin is secreted at a mean rate of 17 +/- 2 mg/h per 100 g liver, hemopexin at 5.0 +/- 0.7, haptoglobin at 3.2 +/- 0.6 and transferrin at 5.1 +/- 0.8 mg/h per 100 g liver. The mean ratio of ATP : ADP is 3.5 +/- 0.1, and that of lactate: pyruvate 27 +/- 6. The rate of conversion of heme into bilirubin is comparable to that reported for in vivo studies. A minimal effect on protein synthesis is observed after administration of the porphyrinogenic agents, allylisopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC). Pretreatment of the rats with the iron chelator, Desferal, causes a 3-4-fold increase in hemopexin but not in albumin and transferrin synthesis. A striking 2-3-fold enhancement of bile bilirubin production follows treatment with DDC and Desferal, but not with AIA. The amount of bilirubin formed from heme added to the perfusate is reduced by AIA and DDC and enhanced by Desferal treatment. It is proposed that unavailability of iron in a certain hepatic tissue pool causes protoporphyrin IX accumulation which may serve as an alternate source for bilirubin production.

Acetamides↗
PubMed1989

Effects of platelet activating factor (PAF) and its receptor antagonist BN 52021 on isolated perfused guinea-pig heart.

The cardiac effects of PAF and its antagonist BN 52021 have been investigated on the isolated perfused guinea-pig heart maintained at a constant hydrostatic perfusion pressure of 80 cm water. In this model, PAF (1 x 10(-11) to 1 x 10(-7) moles) induced a dose-dependent coronary vasoconstriction, a decrease in heart rate and a fall in contractile force. BN 52021 (1 x 10(-6) to 2 x 10(-4) M) dose-dependently inhibited the vasospasm induced by PAF (1 x 10(-10) moles). BN 52021 also antagonized the decrease in coronary flow and heart rate, but not that of contractile force induced by a high dose of PAF (1 x 10(-7) moles). This dose of PAF also significantly (p less than 0.001) provoked a marked release of TxB2 but did not alter the generation of 6 Keto PGF1 alpha, PGE2 or LTC4. The PAF-induced increase in TxB2 release was completely abolished by BN 52021.

Animals↗
PubMed1983

A rise in cyclic AMP with a lack of glycogenolysis by secretin in the isolated perfused rat liver and its inhibition by epinephrine.

The effects of secretin on glucose output and cyclic AMP from the isolated perfused rat liver were investigated. Secretin 0.1 U/ml increased cyclic AMP in the effluent without an increase in glucose output. Glucose output induced by epinephrine 10(-8)M was not affected by secretin 0.1 U/ml administered simultaneously, whereas the increase in cyclic AMP produced by secretin 0.1 U/ml was inhibited by epinephrine 10(-8)M. The increase in cyclic AMP produced by glucagon 10(-10)M was not affected by epinephrine 10(-8)M. These results suggest that secretin does not affect glycogenolysis in the liver and secretin activates adenylate cyclase through a different receptor from glucagon in the liver.

Animals↗
PubMed2000

Kinetics of propranolol uptake in muscle, skin, and fat of the isolated perfused rat hindlimb.

The tissue distribution kinetics of a highly bound solute, propranolol, was investigated in a heterogeneous organ, the isolated perfused limb, using the impulse-response technique and destructive sampling. The propranolol concentration in muscle, skin, and fat as well as in outflow perfusate was measured up to 30 min after injection. The resulting data were analysed assuming (1) vascular, muscle, skin and fat compartments as well mixed (compartmental model) and (2) using a distributed-in-space model which accounts for the noninstantaneous intravascular mixing and tissue distribution processes but consists only of a vascular and extravascular phase (two-phase model). The compartmental model adequately described propranolol concentration-time data in the three tissue compartments and the outflow concentration-time curve (except of the early mixing phase). In contrast, the two-phase model better described the outflow concentration-time curve but is limited in accounting only for the distribution kinetics in the dominant tissue, the muscle. The two-phase model well described the time course of propranolol concentration in muscle tissue, with parameter estimates similar to those obtained with the compartmental model. The results suggest, first that the uptake kinetics of propranolol into skin and fat cannot be analysed on the basis of outflow data alone and, second that the assumption of well-mixed compartments is a valid approximation from a practical point of view (as, e.g., in physiological based pharmacokinetic modelling). The steady-state distribution volumes of skin and fat were only 16 and 4%, respectively, of that of muscle tissue (16.7 ml), with higher partition coefficient in fat (6.36) than in skin (2.64) and muscle (2.79).

Adipose Tissue↗