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PubMed2001

Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver.

1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 microg NAP equivalents ml perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t 1/2) of 13.4 +/- 4.4h. No metabolites were detected in perfusate, while NAG was the only metablolite present in bile in measurable amounts (3.9 +/- 0.8% of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t 1/2 in perfusate = 57 +/- 3 and 75 +/- 14 min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.

Acylation↗
PubMed1988

Uptake and excretion of vecuronium bromide and pancuronium bromide in the isolated perfused rat liver.

Using the isolated perfused rat liver preparation, the disappearance from the perfusate and the excretion in the bile of vecuronium bromide and pancuronium bromide and their metabolites were followed for 2 h after the addition of 1 mg of either drug to the perfusate. In addition, the rate of change of the hepatic content of these two compounds was calculated by serially subtracting the amount of the compound and the metabolites in the bile and in the perfusate from the dose of drug added to the perfusate. It was found that, whereas the concentration of pancuronium in the perfusate declined slowly and monoexponentially, vercuronium concentration in the perfusate declined rapidly in a biexponential manner. No metabolites of either drug were detected in the perfusate. Approximately 40% of the injected dose of vecuronium was excreted in the bile as unchanged vecuronium and another 30% as the 3-hydroxy metabolite. No other metabolites of vecuronium were found in the bile. In total only about 7% of pancuronium (unchanged) was collected in the bile by the end of the experiment. It is concluded that, in comparison to pancuronium, the rat liver takes up large amounts of vecuronium rapidly, half of which is eliminated as unchanged vecuronium and half as the 3-hydroxy derivative. A small amount of vecuronium or its 3-hydroxy metabolite is returned to the perfusate from the liver. Some possible mechanisms underlying these differences are discussed.

Animals↗
PubMed1998

Effect of cationic drugs on the renal secretion of ranitidine in the rat isolated perfused kidney.

1. The rat isolated perfused kidney (IPK) was used to determine whether the renal tubular secretion of ranitidine is influenced by clinically relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubular secretion. 2. Ranitidine and [3H]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a constant infusion to maintain clinically relevant perfusate ranitidine concentrations in the range 400-700 ng/mL. The renal clearance of ranitidine (CL[R]) was calculated, as was glomerular filtration rate (GFR), from the renal clearance of [14C]-inulin. 3. A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 min. In four control IPK, no drug other than ranitidine was administered. In the remaining IPK, amantadine, pseudoephedrine, triamterene or trimethoprim (n = 4 in each case) were administered to achieve low, medium and high concentrations during the 20-40, 40-60 and 60-80 min periods, respectively. 4. The mean (+/- SD) unbound fraction of ranitidine in the perfusion medium was 0.889 +/- 0.046 and was not altered (P>0.05) by the presence of the other drugs. 5. The CL(R)/GFR ratio for ranitidine in all kidneys was substantially greater than unity and had a mean value of 10.65 or greater in control kidneys, indicating extensive net tubular secretion. 6. The CL(R)/GFR was not affected (P>0.05) by amantadine, pseudoephedrine or triamterene at any concentration or by trimethoprim at the low concentration. However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reductions in CL(R)/GFR of 20 and 28%, respectively (P<0.05). 7. The results indicate that at clinically relevant concentrations the renal tubular secretion of ranitidine is inhibited by trimethoprim, but not by amantadine, pseudoephedrine or triamterene.

Amantadine↗
PubMed1992

Comparison of the effect of a mitochondrial uncoupler, 2,4-dinitrophenol and adrenaline on oxygen radical production in the isolated perfused rat liver.

Using the isolated perfused rat liver, we examined the effect of stimulation of mitochondrial respiration by 2,4-dinitrophenol (2,4-DNP) and adrenaline on reactive oxygen species (ROS) production, liver damage and lipid peroxidation. ROS production was monitored by luminol- and lucigenin-enhanced chemiluminescence and oxygen uptake was measured simultaneously. Liver damage and lipid peroxidation were evaluated by measuring hepatic lactate dehydrogenase (LDH) and thiobarbituric acid reacting substances (TBARS) release. Tissue ROS level decreased and oxygen uptake increased soon after 2,4-DNP infusion. On termination of 2,4-DNP infusion, there was a sharp increase in lucigenin-enhanced chemiluminescence, which declined slowly, but luminol-enhanced chemiluminescence did not change prominently. Hepatic LDH and TBARS release increased gradually during 2,4-DNP infusion and were manifested by termination of the infusion. Allopurinol did not affect ROS production and TBARS release, but delayed increases in LDH release after termination of 2,4-DNP infusion. Adrenaline, which stimulates mitochondrial respiration without uncoupling caused similar but smaller ROS changes observed in 2,4-DNP. LDH and TBARS release were not affected significantly by adrenaline infusion. These results indicate that uncoupling of oxidative phosphorylation decreases ROS production and restoration of oxidative phosphorylation enhances ROS production and liver damage. Xanthine oxidase is unlikely to contribute to enhanced ROS production after termination of 2,4-DNP but has some protective effect during uncoupling.

2,4-Dinitrophenol↗
PubMed1963

Norepinephrine synthesis from tyrosine-C-14 in isolated perfused guinea pig heart.

The isolated, perfused guinea pig heart contains all the catalysts required to form norepinephrine from the dietary precursor, tyrosine. The conversion of tyrosine-C(14) to norepinephrine in the perfused heart occurred at a rate comparable to that estimated for this conversion in vivo. To account for the maintenance of norepinephrine stores in the normal heart, it is not necessary to postulate that the hormone is extracted from the blood.

Guinea Pigs↗
PubMed1992

Arg-Gly-Asp (RGD) peptides alter hepatic killing of Candida albicans in the isolated perfused mouse liver model.

The isolated perfused mouse liver model was used to study the effect of Arg-Gly-Asp (RGD)-containing peptides on hepatic trapping and killing of Candida albicans. After extensive washing, 10(6) C. albicans CFU were infused into mouse livers. At the time of recovery, 63% +/- 2% (mean +/- standard error of the mean) of the infused C. albicans CFU were recovered from the liver and 14% +/- 1% were recovered from the effluent for a total recovery of 77% +/- 2%. This indicates that 86% +/- 9% of the original inoculum was trapped by the liver and that 23% +/- 2% was killed within the liver. Prior to their infusion into livers, 10(7) CFU of C. albicans were incubated at 37 degrees C for 30 min in the presence of various RGD peptides (0.1 mg/ml). Repeatedly, more than 90% of the infused RGD-treated C. albicans was trapped by the perfused liver. In comparison with the 23% killing rate observed in control livers, perfused livers killed approximately 40 to 50% of the infused C. albicans treated either with fibronectin, PepTite 2000, RGD, or RGDS. Hepatic killing of C. albicans treated with PepTite 2000 or fibronectin was dose dependent. Treatment of C. albicans with GRGDTP, GRGDSP, GRADSP, or GRGESP did not alter the ability of the perfused liver to kill C. albicans, suggesting that a degree of specificity for RGD peptides is associated with an increased ability of liver to kill RGD-treated C. albicans. Together, the data suggest that RGD peptides bind to a receptor on the surface of C. albicans, thereby increasing hepatic, and presumably Kupffer cell, killing of C. albicans. Natural or synthetic RGD peptides may serve as opsonins promoting C. albicans killing by Kupffer cells.

Amino Acid Sequence↗
PubMed1977

Prostaglandins in adrenergic transmission of isolated perfused rat pancreas.

In the isolated, perfused rat pancreas, prostaglandins (PGs) E1 and E2 1-5 ng/ml, reduced the vasoconstrictor responses to periarterial nerve stimulation and variably affected those to injected norepinephrine. Prostaglandin F2alpha had no consistent effect on the vasoconstrictor responses to both adrenergic stimuli. Stimulation of adrenergic nerves or administration of norepinephrine released a PGE-like substance from the perfused pancreas which was abolished by inhibitors of PG synthesis, acetylsalicylic acid, indomethacin, meclofenamate, and eicosa-5,8,11,14-tetraynoic acid. The latter three agents did not potentiate, but rather reduced the vasoconstrictor responses to both adrenergic stimuli. Arachidonic acid that was converted by the pancreas into PGE2 and PGF2alpha inhibited the vasoconstrictor responses to adrenergic stimuli. The latter effect of arachidonic acid was not altered by the simultaneous infusion of PG synthetase inhibitors. Although these results, which could be attributed to a direct effect of inhibitors of PG synthesis and arachidonic acid on adrenergic neuroeffector junction, fail to establish the role of endogenous PGs in modulating adrenergic responses in rat pancreatic vessels, they emphasize the differences in the effect of PGE1 and PGE2 on adrenergic responses in various vascular beds of the rat.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1982

Determinants of biliary secretion in isolated perfused skate liver.

In the isolated perfused liver of the little skate, Raja erinacea, bile flow averaged 5.07 +/- 0.58 (mean +/- SE) microliters.h-1.g liver-1 in 21 experiments at a perfusion pressure of 5.0 cm Ringer compared to 3.79 +/- 0.32 in 38 experiments at 2.5 cm (P less than 0.05). [14C]inulin readily entered skate bile. Bile-to-plasma [14C]inulin ratios corrected for delay in transit time, averaged 0.46 +/- 0.07 at 1 h and rose to 0.74 +/- 0.06 by 4 h, although bile flow remained constant. In experiments in which [14C]inulin reached equilibrium between bile and plasma, the bile-to-plasma ratio conformed to the theoretical relationship between bile flow, solvent drag, and inert solute diffusion predicted at extremely low bile flows, but demonstrated that the skate biliary tree is more permeable to inulin than that of the rat. Electron microscopic studies demonstrated that ionic lanthanum could traverse the tight junctions. However, freeze-fracture studies of junction structure did not differ qualitatively from similar studies in the rat. Partial dependence of bile flow on perfusion pressure, high bile-to-plasma inulin ratios, and permeability of the canalicular tight junctions to ionic lanthanum all suggest that the paracellular pathway may be an important component of bile formation in the skate.

2,4-Dinitrophenol↗
PubMed1983

Intracellular chloride activities in the isolated perfused shark rectal gland.

The isolated, perfused shark rectal gland secretes Cl when stimulated with adenosine 3',5'-cyclic monophosphate (cAMP). To investigate the mechanism of secretion, we used Cl-selective and conventional (KCl-filled) microelectrodes to measure the intracellular Cl activity (aClc). Under nonsecreting conditions, the electrical potential difference across the basolateral membrane (psi b) was -78 m V and aClc was 57 mM, a value seven times greater than predicted for electrochemical equilibrium across the basolateral membrane. When theophylline and 8-bromo-cAMP were added to the perfusate, the transglandular electrical potential difference doubled and the rate of fluid secretion increased 20-fold; however, neither psi b nor aClc changed. During both nonsecreting and secreting conditions the intracellular accumulation of Cl results in an electrochemical potential difference favoring Cl exit across the apical cell membrane. The constancy of aClc despite the variation in secretion rate suggests that stimulation is associated with an equivalent enhancement of net Cl movement across both the apical and basolateral membranes. When stimulated glands were perfused with Na-free (choline) Ringer, secretion was abolished and aClc fell toward the value predicted for electrochemical equilibrium. These findings suggest that the "uphill" step in Cl secretion lies at the basolateral membrane, where cellular Cl accumulation probably involves secondary active transport; i.e., Cl entry is driven by an inwardly directed electrochemical potential difference for Na.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1976

Lack of glucose effect on the induction of 5-aminolevulinate synthetase and tyrosine aminotransferase in the isolated perfused rat liver.

In the isolated perfused rat liver, both 5-aminolevulinate synthetase and tyrosine aminotransferase were induced by the addition of 3.5 mmol/l allylisopropylacetamide and 58 mumol/l dexamethasone to the perfusion medium. Glucose (40 mmol/l) did not affect either the induction of these enzymes or the intrahepatic level of cyclic AMP. The results suggest that the glucose effect on the induction of 5-aminolevulinate synthetase and tyrosine aminotransferase in vivo is mediated by extrahepatic factors.

5-Aminolevulinate Synthetase↗
PubMed1971

Secretion of glucagon from the isolated, perfused canine pancreas.

Using the isolated, perfused canine pancreas preparation, previously described, the interrelationship of the secretion of pancreatic glucagon and insulin was studied after stimulation with glucose, gastrointestinal hormones, and the amino acid arginine. The results confirm the concept that pancreatic glucagon is a hormone of "glucose need" and suggest that it may be important in a moment to moment control of glucoregulation. The secretion of pancreatic glucagon was stimulated after infusion of gastrin, pancreozymin, and arginine, while no increase was associated with secretin infusion. The magnitude of the increase was closely related to the glucose concentration present in the perfusion medium, being higher and more pronounced during perfusion with low concentrations of glucose (25 mg/100 ml or 50 mg/100 ml). Stimulation of insulin secretion was seen after glucose, gastrin, pancreozymin, secretin, and arginine. The magnitude of the increase was again closely related to the glucose concentration present, this time being higher and more pronounced during perfusion with high glucose concentrations (150 mg/100 ml). Secretion of both pancreatic hormones always followed a biphasic response pattern after the stimuli mentioned, similar to the characteristic release pattern previously described for insulin after an increment in glucose concentration. In order to elucidate whether endogenous pancreatic glucagon possesses an insulinogenic action, as it has been shown to be the case with the administration of exogenous pancreatic glucagon, the time interrelationship of the secretion of pancreatic glucagon and insulin was investigated by determining the initial rise of the hormones after stimulation with gastrin, pancreozymin, and arginine. The rise of glucagon and insulin occurred simultaneously, i.e. inside a 10 sec period. This does not, however, exclude with certainty an insulinogenic role of pancreatic glucagon.

Animals↗
PubMed1978

Cardiac and renal prostaglandin I2. Biosynthesis and biological effects in isolated perfused rabbit tissues.

Both the isolated perfused rabbit heart and kidney are capable of synthesizing prostaglandin (PG) I(2). The evidence that supports this finding includes: (a) radiochemical identification of the stable end-product of PGI(2), 6-keto-PGF(1alpha), in the venous effluent after arachidonic acid administration; (b) biological identification of the labile product in the venous effluents which causes relaxation of the bovine coronary artery assay tissue and inhibition of platelet aggregation; and (c) confirmation that arachidonic acid and its endoperoxide PGH(2), but not dihomo-gamma-linolenic acid and its endoperoxide PGH(1), serve as the precursor for the coronary vasodilator and the inhibitor of platelet aggregation. The rabbit heart and kidney are both capable of converting exogenous arachidonate into PGI(2) but the normal perfused rabbit kidney apparently primarily converts endogenous arachidonate (e.g., generated by stimulation with bradykinin, angiotensin, ATP, or ischemia) into PGE(2); while the heart converts endogenous arachidonate primarily into PGI(2). Indomethacin inhibition of the cyclo-oxygenase unmasks the continuous basal synthesis of PGI(2) by the heart, and of PGE(2) by the kidney. Cardiac PGI(2) administration causes a sharp transient reduction in coronary perfusion pressure, whereas the intracardiac injection of the PGH(2) causes an increase in coronary resistance without apparent cardiac conversion to PGI(2). The perfused heart rapidly degrades most of the exogenous endoperoxide probably into PGE(2), while exogenous PGI(2) traverses the heart without being metabolized. The coronary vasoconstriction produced by PGH(2) in the normal perfused rabbit heart suggests that the endoperoxide did not reach the PGI(2) synthetase, whereas the more lipid soluble precursor arachidonic acid (exogenous or endogenous) penetrated to the cyclooxygenase, which apparently is tightly coupled to the PGI(2) synthetase.

Animals↗
PubMed1981

Effects of two different angiotensin II antagonists on aldosterone secretion by isolated perfused rat zona glomerulosa cells.

Isolated perfused rat zona glomerulosa cells have been used to determine the specificity of the angiotensin II antagonists, [Sar1,Ala8]angiotensin II and [Sar1,Ile8]angiotensin II. Both antagonists inhibited the aldosterone response to angiotensin II but did not affect serotonin- or potassium-induced aldosterone secretion. However, in contrast to [Sar1,Ala8]angiotensin II, [Sar1,Ile8]angiotensin II inhibited the aldosterone response to ACTH. These results suggest that there are differences in the specificity of these two analogs and that studies with [Sar1,Ile8]angiotensin II and its effect on aldosterone secretion should be interpreted with caution.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1985

Dissociation of the alpha-adrenergic inhibitory effects on glucagon- and secretin-stimulated bile volume and on cyclic adenosine monophosphate production in the isolated perfused rat liver.

In the isolated perfused rat liver, glucagon increased glucose, cAMP, and bile production. Secretin increased cAMP in the effluent more and bile volume less than glucagon, but did not increase glucose output. When glucagon and secretin were infused together, the effect on cAMP was additive, but glucose output and bile volume were the same as with glucagon alone. The stimulation of bile production by glucagon was suppressed by phenylephrine but not by oxymetazoline, whereas the glucagon-induced cAMP increase in the effluent was suppressed by oxymetazoline in a dose-dependent manner, but not by phenylephrine. Glucagon-stimulated glucose output was not suppressed even when cAMP in the effluent was significantly suppressed by oxymetazoline. The secretin-induced stimulation of bile production was suppressed by phenylephrine, but not by oxymetazoline. Secretin-stimulated cAMP was suppressed more by oxymetazoline than by phenylephrine. The bile volume was not suppressed by phenylephrine alone either in the presence or in the absence of sodium taurocholate. These results indicate that the cholestatic effect of adrenergic agents is mediated by alpha 1-adrenergic receptors, whereas their cAMP suppressive effect is mediated by alpha 2-adrenergic receptors. The stimulatory effect of glucagon on cAMP production was more resistant to alpha-adrenergic agonists than to that of secretin. The dissociation by oxymetazoline of the effects of glucagon on cAMP production from its effect on glucose production is unexplained, whereas the significance of the secretin-induced increase in cAMP production is uncertain.

Adrenergic alpha-Agonists↗
PubMed2001

Effects of steroidal and non-steroidal antiphlogistic drugs on eicosanoid synthesis in irritated skin: studies with the isolated perfused bovine udder.

Using the isolated perfused bovine udder as an in-vitro model of skin inflammation, the effects of topically administered arachidonic acid on prostaglandin and leukotriene synthesis have been shown previously. In this study, the effects of indometacin (indomethacin) and clobetasol-17-propionate (administered topically) as well as flunixin meglumine and meloxicam (administered via the perfusion fluid) have been studied. Compared with controls, arachidonic acid caused a significant increase in the dermal prostaglandin E2 (PGE2) and peptidoleukotriene (LTC4/D4/E4) concentration. Topical treatment with indometacin (1.6 mg cm(-2)) and clobetasol-17-propionate (90 microg cm(-2)), which were administered 60 min before arachidonic acid administration, inhibited the inflammatory reaction. Flunixin meglumine (1 microg mL(-1) perfusion fluid) was administered 30 min after and meloxicam (3 microg mL(-1) perfusion fluid) was administered 60 min before arachidonic acid application. Three hours after arachidonic acid administration, a significant inhibition of PGE2 synthesis was induced by flunixin. In contrast, meloxicam showed only a slight effect. The effect of flunixin was comparable with in-vivo results. It is known from animal studies that anti-inflammatory effects of meloxicam are obvious within up to 6 h after treatment. Therefore, the incomplete effect of meloxicam may be explained pharmacokinetically. In conclusion, the described in-vitro model seems to be suitable for studies of pharmacological effects on eicosanoid synthesis in the skin.

Administration, Topical↗
PubMed1985

Beneficial effects of diltiazem on the ischemic derangements of the myocardial metabolism assessed by 31P-NMR in the isolated perfused rat heart.

Using the isolated perfused heart preparations of the rat, effects of diltiazem, a calcium antagonist, on the ischemic derangements of the mechanical function and the energy metabolism of the ventricular myocardium were studied. The myocardial tissue levels of creatine phosphate (CP), ATP, inorganic phosphate (Pi) and pH were determined with 31P-NMR. Global ischemia was induced by cross-clamping of the aortic inflow line for 15 min, which resulted in a fall of CP, ATP and pH and a rise of Pi. The test hearts were perfused with diltiazem-containing solution (10(-7), 10(-6) and 10(-5) M) for 12 min prior to the induction of the global ischemia. A significant dose-related decline of the myocardial mechanical function expressed as (left ventricular pressure) X (heart rate) was observed in diltiazem-treated hearts. In doses above 10(-6) M, diltiazem delayed the onset of the fall of the myocardial CP and pH levels and the rise of Pi induced by ischemia, and there was an excellent correlation between the suppression of the myocardial mechanical function observed before induction of ischemia and the level of the myocardial CP and pH at the initial phase of ischemia, indicating that the improvement of the myocardial energy metabolism was due to the cardiodepressant effects of the compound.

Animals↗
PubMed1976

An isolated perfused rat lung preparation.

An isolated perfused rat lung preparation (IPL) is described and its physiologic status is evaluated. The evaluation includes light and electron microscopy after perfusion and estimations of substrate utilization. ATP content, lactate production, and incorporation of glucose carbons into lipids and CO2. It is concluded that the IPL is useful for short-term metabolic and physiologic experiments and offers some unique advantages in evaluating effects of reactive gases upon lung function.

Adenosine Triphosphate↗
PubMed1991

Effects of lidocaine on ischemic myocardial metabolism assessed by 31P-NMR in the isolated perfused rat heart.

Using an isolated perfused rat heart preparation, the protective effects of lidocaine and diltiazem on ischemic derangements of myocardial energy metabolism were studied with 31P-nuclear magnetic resonance spectroscopy. The hearts were perfused with a solution containing lidocaine (4.27 x 10(-5), 12.80 x 10(-5) M) or diltiazem (2.22 x 10(-7), 2.22 x 10(-6) M) for 15 min prior to the induction of global ischemia. The decrease in myocardial oxygen consumption rate, assessed as the product of heart rate and left ventricular systolic pressure (HR x LVP), was greater in diltiazem-treated than in lidocaine-treated hearts. Diltiazem and lidocaine significantly retarded the fall in myocardial pH during ischemia and improved ATP recovery after reperfusion. There was a good correlation between suppression of HR x LVP observed before induction of ischemia and decreased drop in pH during the early phase of ischemia in the diltiazem-treated groups (r = -0.78, p less than 0.01), but not in the lidocaine-treated groups. These results indicate that the beneficial effects of diltiazem on the ischemic myocardium are due primarily to the cardio-depressant effects. The beneficial effects of lidocaine cannot, however, be explained solely on the basis of the depression of oxygen consumption.

Animals↗