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PubMed1985

Phagocytic function in the isolated perfused rat liver. An experimental model.

An experimental model for measuring the phagocytic function of the isolated perfused rat liver is described. A progressive rise in phagocytosis was observed with increasing liver blood flow. This is due to an increase in total particle uptake by the liver with no alteration in the rate constant for phagocytosis except at the highest flow rate. Phagocytosis is substantially greater in the livers of 100-day-old rats than in 21-day-old rats, but the number of particles ingested per unit weight by the older rats is significantly less. Liver phagocytosis is shown to be both temperature- and oxygen-dependent, but independent of nutritional status and animal gender. This model may be useful for assessing the effects of drugs and toxins on hepatic phagocytosis.

Age Factors↗
PubMed1974

Nitrogen metabolism in the isolated perfused rat liver. Nitrogen balance, redox state and rates of proteolysis.

Nitrogen balances were measured in isolated perfused rat livers in the presence and absence of nitrogen donors. In all instances the balance apparently was incomplete. The expression [alanine][alpha-oxoglutarate]/[pyruvate][glutamate] remained fairly constant under the metabolic conditions studied, indicating that it may be at near-equilibrium. The source of the extra nitrogen seems to be derived from increased hepatic proteolysis. The addition of a nitrogen donor to the perfusate arrested proteolysis, as did the addition of pyruvate. The free mitochondrial [NAD(+)]/[NADH] ratio, calculated from the glutamate dehydrogenase and beta-hydroxybutyrate dehydrogenase reactants, showed similar values and exhibited parallel changes under most metabolic situations studied. These results suggest that, under the reported experimental conditions, both dehydrogenases share a common mitochondrial NAD pool. Glutamate dehydrogenase plays an important role in hepatic nitrogen metabolism in vivo.

Alanine↗
PubMed1996

Possible involvement of muscarinic M1 and M3 receptor subtypes mediating vasodilation in isolated, perfused canine lingual arteries.

1. Using the cannula insertion method, muscarinic receptor subtypes were analysed in isolated, perfused canine lingual arteries preconstricted with phenylephrine. 2. Both acetylcholine and McN-A-343 induced a profound vasodilation in a dose-related manner. Acetylcholine-induced dilations were approximately 1000-times more potent than McN-A-343-induced dilation. 3. Acetylcholine-induced dilations were abolished after removal of the endothelium by intraluminal treatment with 1 mg saponin. 4. Acetylcholine-induced dilations were markedly inhibited by an M1/M3 receptor antagonist, 4-DAMP. Moreover, they were slightly, but significantly, inhibited by an M1 antagonist, pirenzepine, but never influenced by an M2 antagonist, AF-DX 116. Mc-N-A-343-induced vasodilations were inhibited by both 4-DAMP or pirenzepine. 5. These results suggest that there are abundant functional M3 and a few M1 receptors in the canine lingual artery that mediate vasodilation and that this vasodilation is dependent on the presence of an intact endothelium.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1990

Myocardial uptake of lignocaine: pharmacokinetics and pharmacodynamics in the isolated perfused heart of the rabbit.

1. The uptake kinetics and pharmacodynamics of lignocaine were studied in isolated perfused heart of the rabbit. 2. Six hearts were perfused with increasing concentrations of lignocaine in a modified Krebs-Henseleit buffer. The effluent concentration together with the increase in QRS duration were measured during lignocaine infusion and during 20 min after cessation of lignocaine infusion. 3. Lignocaine disposition and elimination were best described by a two-compartment open model. Terminal half-life was 11.0 +/- 2.9 min. The unidirectional transfer was slower from central to peripheral compartment than from peripheral to central compartment (T1/2.12 = 42.6 +/- 10.5 min whereas T1/2.21 = 10.7 +/- 2.8 min). The myocardium/perfusate concentration-ratio was 4.7 +/- 0.4. 4. The pharmacodynamic effect was best described in the central compartment by using the Hill equation. Calculated maximum QRS duration (Emax) was 77 +/- 8 ms. Emax was also directly measured in four additional rabbits by infusing ten times the dose of lignocaine used in the main experiment: the value of Emax measured in these conditions was 92.5 +/- 9.6 ms, i.e. a QRS widening of 150%. The steady-state perfusate concentration producing half the effect (C50) was 15.7 +/- 7.6 micrograms ml-1. 6. In conclusion, the specific lignocaine binding leading to increase in QRS duration appeared to be more closely related to the vascular stream than non specific binding leading to a deeper accumulation process.

Animals↗
PubMed1985

Biliary elimination of beta-lactam antibiotics by the isolated perfused rabbit liver.

Biliary elimination of 15 beta-lactams was studied using a model of isolated perfused rabbit liver. During the perfusion period, the main liver functions were well preserved. The highest biliary concentrations were reached by antibiotics of the penicillin group, and the highest biliary recovery was observed with metampicillin, apalcillin and mezlocillin (46.5, 30.7 and 20.3%, respectively, of the dose administered). This technique was also suitable for estimating the degree of bio-transformation in the liver of the antibiotics studied.

Animals↗
PubMed1984

Isolated perfused rabbit coronary artery and aortic strip preparations: the role of endothelium-derived relaxant factor.

Isolated perfused coronary arteries and aortic ring preparations of rabbits were studied, both with intact endothelium and with endothelium removed by K-rich solution and friction respectively. Constrictor dose-responses to histamine, acetylcholine, phenylephrine and 5-hydroxytryptamine (5-HT) were measured. They were greatly depressed by the presence of endothelium in coronary preparations. In aortic preparations endothelium affected dose-responses relatively little, depressing the response to acetylcholine but apparently increasing the responses to the other three agents. Acetylcholine relaxed pre-constricted coronary or aortic preparations but only when endothelium was present. This relaxation was inhibited by quinacrine or hydroquinone. Aortic preparations had resting tone which could be increased by hydroquinone if endothelium was present, suggesting continual release of endothelium-derived relaxant factor (EDRF) at rest. When allowance was made for basal EDRF activity in aortic preparations, the maximal constrictor response to acetylcholine remained lower in the presence of endothelium, consistent with acetylcholine stimulation of EDRF, but maximal constrictor responses to the other three agents were the same with and without endothelium, suggesting that the direct constrictor response overrides EDRF activity.

Acetylcholine↗
PubMed1989

Glucocorticoid receptor activation in isolated perfused rat hearts.

The formation of unactivated and activated glucocorticoid receptor complexes was studied in intact, isolated, perfused rat hearts in the presence of [3H]triamcinolone acetonide. Receptor activation, as quantified by the DNA-cellulose-binding assay, began to increase within 30 s of perfusion and reached a final steady-state level (t 1/2 = 4.6 min) with 46% of the steroid-receptor complexes bound to DNA-cellulose. With the use of a linear potassium phosphate (KP) gradient (5-400 mM), unactivated receptors eluted from DEAE-cellulose anion exchange columns at approximately 250 mM KP. Two activated receptor forms appeared, which eluted either in the wash fraction (binder IB) or between 50 and 100 mM KP (binder II) and occurred with half times of 1.3 and 2.7 min, respectively. Postperfusion cytosol preparation did not markedly influence the results as receptor binding was reduced by 10% or less when a 100-fold excess of unlabeled triamcinolone acetonide was included in the homogenizing buffer. We conclude from these results that glucocorticoids are able to exert a direct effect on the heart through binding to their own receptor in the absence of endogenous hormones. The time dependency of receptor activation supports a physiological role for this process. However, activation rates, determined from conformational changes associated with altered DEAE-cellulose elution profiles and appearance of activated receptor forms, occur earlier and may not be coordinated with the rate of activation as quantified by DNA-cellulose binding.

Adrenalectomy↗
PubMed1978

Secretory effects of VIP on isolated perfused porcine pancreas.

We studied the secretion of insulin, glucagon, and the exocrine secretion of the isolated perfused porcine pancreas in response to vasoactive intestinal polypeptide (VIP) in concentrations ranging from 30 to 18,750 pmol/liter at various concentrations of glucose in the perfusion medium. VIP stimulated the insulin and glucagon secretion in a dose-dependent manner. The response pattern was critically dependent on the glucose concentration. In the presence of a glucose concentration of 7.5 mmol/liter, VIP enhanced insulin release without affecting glucagon release. Maximal insulin release was obtained at a VIP concentration of 3,750 pmol/liter. At a glucose concentration of 5.0 or 3.5 mmol/liter, VIP enhanced glucagon release but not insulin release. VIP stimulated the exocrine secretion in a secretin-like manner. The lowest concentration of VIP observed to increase pancreatic exocrine secretion was 30 pmol/liter, whereas the maximal pancreatic exocrine responses were not obtained.

Animals↗
PubMed1988

Phosphorus nuclear magnetic resonance in isolated perfused rat pancreas.

Phosphorus nuclear magnetic resonance spectroscopy was applied to measure phosphorus energy metabolites in isolated perfused rat pancreas. The gland was perfused with a modified Krebs-Henseleit solution at room temperature (25 degrees C). 31P resonances of creatine phosphate (PCr), ATP, ADP, inorganic phosphate (Pi), and phosphomonoesters (PMEs) were observed in all the preparations of pancreas. In different individual preparations, the resonance of PCr varied, but those of ATP were almost the same. The initial levels of PCr and ATP in individual preparations, however, remained almost unchanged during perfusion with the standard solution for 2 h. When the perfusion was stopped, the levels of ATP and PCr decreased, while the levels of PME and Pi increased. At that time, the Pi resonance shifted to a higher magnetic field, indicating that the tissue pH decreased. On reperfusion, the tissue levels of phosphorus compounds and the tissue pH were restored to their initial resting levels. Continuous infusion of 0.1 microM acetylcholine caused marked and sustained increases in the flow of pancreatic juice and protein output. During the stimulation the tissue levels of phosphorus compounds remained unchanged, while the tissue pH was decreased slightly (0.05 pH unit).

Adenine Nucleotides↗
PubMed1984

Monitoring of mitochondrial membrane potential in isolated perfused rat heart.

Optical methods were tested for measuring the membrane potential changes of mitochondria in isolated perfused rat hearts. Safranin was found to be rapidly taken up by the Langendorff-perfused heart, and after loading with the dye there was practically no washout of the stain during perfusion with Krebs-Ringer bicarbonate solution. Staining with safranin induced the appearance of an intense absorption band in the reflectance spectrum of the heart, but the absorbance spectrum changes were not useful for monitoring the mitochondrial membrane potential changes because of interference by endogenous hemoproteins. The fluorescence intensity, however, responded in a manner which indicated that its changes originated from dye attached to the mitochondria. A decrease of the fluorescence was found on energizing the mitochondria by decreasing the cellular energy consumption by arrest induced by 18 mM K+ or by decreasing the beating rate of an electrically paced heart from 5 Hz to the endogenous ventricular frequency of 1.5 Hz. In hearts arrested by Ca2+ depletion, 18 mM K+ did not affect the safranin fluorescence. This was taken to indicate that under these conditions the safranin fluorescence was not sensitive to the plasma membrane potential. The uncoupler carbonyl cyanide m-chlorophenylhydrazone induced an intense enhancement of safranin fluorescence in the perfused heart, demonstrating that the probe is sensitive to mitochondrial membrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

PAH transport and fluid absorption by isolated perfused frog proximal renal tubules.

Para-aminohippurate (PAH) transport and fluid absorption were studied in isolated perfused frog (Rana catesbeiana) proximal renal tubules. With 2 X 10(-5) M PAH in the bath, tubule fluid-to-bath (TF/B) concentration ratios averaged 3.0 and net secretion averaged 746 X 10(-15) mol min(-1) mm(-1) in the proximal tubule. Net PAH secretion did not vary with perfusion rate. During PAH secretion, cell water PAH concentration exceeded that in the tubular fluid or bath, suggesting active transport into cells and subsequent diffusion into lumen. In accordance with this concept, luminal membrane permeability (3.8 X 10(-5) cm s(-1) calculated from perfusion studies was about 6 times greater than peritubular membrane permeability (0.66 X 10(-5) cm s(-1)) determined from studies of PAH efflux from tubules with oil-filled lumens. Net transepithelial PAH transport saturated at bath concentration of about 6 X 10(-5) M. Addition of 20 mM urea to PAH bath concentration of 2 X 10(-5) M reduced net PAH secretion by 32%. Fluid absorption in proximal tubules averaged 0.34 nl min(-1) mm(-1). Ouabain (10(-4), 10(-5), or 10(-6) M) added to bath blocked fluid absorption. Fluid absorption was partially restored following removal of ouabain.

Acetates↗
PubMed1982

Anion permeabilities of the isolated perfused rabbit proximal tubule.

Electrophysiologic and isotopic techniques were used to characterize the anion permeabilities of isolated perfused rabbit proximal tubules (S2 segments). Tubules were differentiated into chloride- and sodium-selective populations by electrophysiologic rather than by anatomic criteria. The tubules were studied under conditions that inhibited active sodium transport. The isotopic chloride permeability coefficient was 5.5 +/- 0.6 X 10(-5) cm/s (n = 19) for chloride-selective tubules and 3.2 +/- 0.6 X 10(-5) cm/s (n = 15) for sodium-selective tubules. The isethionate permeability coefficient was 1.1 +/- 0.2 X 10(-5) cm/s (n = 23) and did not vary with sodium or chloride selectivity. The variation of oxyanion permeability (bicarbonate, isethionate, and cyclamate) relative to chloride resulted from changes in chloride permeability, per se, rather than any change in the oxyanion permeability. A consistent relation between bicarbonate and isethionate permeability permitted the permeability of bicarbonate ion to be estimated at 1.3 X 10(-5) cm/s. The mechanism of ion selectivity appears to be different for the two populations of tubules. Chloride-selective tubules appear to hve relatively small pathways that do not contain fixed-charge sites. In contrast, sodium-selective tubules may have permeation pathways that contain fixed negative-charge sites.

Animals↗
PubMed1984

Verapamil and quinidine effects on PAH transport by isolated perfused renal tubules.

The effects of verapamil and quinidine on p-aminohippurate (PAH) transport by isolated perfused snake (Thamnophis spp.) distal-proximal renal tubules were studied. Addition of 5 X 10(-5) M verapamil or 1 X 10(-4) M quinidine to the bath reversibly depressed net PAH secretion (JnetPAH), apparent permeabilities of luminal (PL) and peritubular membranes (Pp) to PAH, and initial rate of PAH transport into cells at the peritubular membrane without affecting net fluid absorption (Jv), but simultaneously produced a threefold increase in cellular PAH concentration ( [PAH]cell). Addition of 5 X 10(-5) M verapamil to the perfusate reversibly depressed JnetPAH and PL without affecting [PAH]cell or Jv. Tetraethylammonium (1 X 10(-3) M) did not alter the effects of verapamil on PAH transport. The data indicate that verapamil and quinidine in the bath inhibit JnetPAH by inhibiting uptake into cells across peritubular membrane and efflux from cells across luminal and peritubular membranes and possibly by producing intracellular binding, verapamil in the perfusate inhibits JnetPAH by inhibiting efflux from cells across the luminal membrane and probably uptake into cells across the peritubular membrane, and the verapamil effects on JnetPAH do not depend on its entry into cells. The effects of verapamil may result primarily from inhibition of calcium entry into cells, but both verapamil and quinidine may have effects on PAH transport independent of effects on calcium.

Aminohippuric Acids↗
PubMed1991

Indometacin: renal handling and effects in the isolated perfused rat kidney.

We investigated renal handling and effects of indometacin on renal function in the isolated perfused rat kidney (IPK). Indometacin concentrations less than 2.5 ng/ml did not influence renal function, while higher concentrations caused a decrease in urinary flow and electrolyte excretion. The presence of 133 ng/ml prostaglandin E2 (PGE2) in the perfusate fully opposed these effects on kidney function. Only a small fraction of the filtered indometacin is excreted into the urine, indicating extensive reabsorption of the compound. This is probably a passive process, dependent on the tubular load, urinary pH and urinary flow. Indometacin accumulates extensively in the IPK, causing a kidney to perfusate ratio between 5 and 9. Accumulation decreased with increasing perfusate concentration. This can be explained by active secretion: increasing the perfusate concentration leads to a saturation of the active secretion and a decrease in the relative accumulation. We conclude that indometacin accumulates extensively in the IPK, that it affects kidney function and that this influence is probably caused by the inhibition of PGE2 synthesis.

Animals↗
PubMed2004

Disposition of amphotericin B in the isolated perfused rat liver.

The hepatic disposition and biliary excretion of amphotericin B were investigated in the isolated perfused rat liver (IPRL). Bolus dose of 50 microg, 99 microg and 198 microg amphotericin B in lipoprotein-free perfusate and 198 microg amphotericin B in perfusate with 1 microM high-density lipoprotein (HDL) or 1 microM low-density lipoprotein (LDL) were examined in the IPRL. Amphotericin B concentration in perfusate was measured using a validated HPLC assay. Amphotericin B was eliminated from the perfusate in a biexponential manner. The hepatic clearance (CL(H)) increased in proportion to the dose administered (0.27 +/- 0.05 mL min(-1) at low dose, 0.54 +/- 0.23 mL min(-1) at medium dose and 1.06 +/- 0.24 mL min(-1) at high dose), indicating non-linear hepatic disposition of amphotericin B. The hepatic extraction ratio of amphotericin B was very low (0.066 +/- 0.015). Tissue-to-perfusion partition coefficient, calculated at 120 min, increased 1.5 fold from 9.8 +/- 1.7 at low dose to 15.9 +/- 6.4 at high dose, suggesting the significant uptake and extensive retention of amphotericin B in the liver. Biliary excretion made only minor contribution to amphotericin B elimination in the IPRL, representing around 1-3% of the dose administered. No metabolites were detected in perfusate, bile and liver samples. The hepatic disposition of amphotericin B was not affected by the presence of HDL and LDL in the perfusate. In conclusion, the hepatic disposition of amphotericin B demonstrates restrictive elimination and is concentration-dependent, consistent with carrier-mediated uptake, and lipoproteins do not influence amphotericin B hepatobiliary disposition.

Amphotericin B↗
PubMed1987

Effects of adrenergic agonists and antagonists on glycogenolysis in isolated perfused rat liver.

The effects of adrenergic agonists and antagonists on hepatic glycogenolysis were investigated using isolated perfused rat liver. Comparative studies on the glucose output by various adrenergic agonists and the inhibitory action of various antagonists on epinephrine-induced glycogenolysis indicated that this glycogenolysis was mediated by alpha 1-adrenergic receptors. Epinephrine-induced glucose output from the liver was detected repetitively when epinephrine was repeatedly added to the perfused liver, while the glucose output decreased gradually when epinephrine was infused repetitively to the liver perfused with Ca2+-free buffer. Infusion of epinephrine to the perfused liver caused a release of Ca2+ associated with the glucose output, and a close correlation was found between the amounts of glucose and Ca2+ released from the liver with the infusion of epinephrine at various concentrations. The amounts of glucose production induced by epinephrine in the absence of extracellular Ca2+ were smaller than in the presence of extracellular Ca2+ when the liver received a large or sustained stimulation of epinephrine. These results suggest that the epinephrine mobilizes Ca2+ from the intracellular store to activate glycogenolysis, while entry of extracellular Ca2+ into the cell is required in order to obtain a large or sustained hormonal stimulation of glycogenolysis and to supply the intracellular Ca2+ store.

Animals↗