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PubMed1990

A physiologically relevant pharmacokinetic model of xenobiotic percutaneous absorption utilizing the isolated perfused porcine skin flap.

A physiologic pharmacokinetic model describing percutaneous absorption of topically applied compounds in the isolated perfused porcine skin flap (IPPSF) is presented. As an extension of a previously reported hybrid physiologically relevant compartmental model of uptake of intra-arterially administered drug in the IPPSF, this percutaneous model should allow experimental results obtained from an in vitro preparation to serve as quantitative input to an in vivo pharmacokinetic system. Model parameters estimated from 8-10-h IPPSF experiments were able to predict 6-day in vivo radiolabel absorptions in pigs for topically applied benzoic acid, caffeine, malathion, parathion, DFP, testosterone, and progesterone. These results compare favorably with those obtained previously using a classical compartmental modeling approach.

Animals↗

PubMed1994

23Na NMR detects protection by glycine and alanine against hypoxic injury in the isolated perfused rat kidney.

Protection against hypoxic injury by supraphysiological glycine and alanine concentrations was investigated in the isolated perfused rat kidney (IPRK). 23Na NMR detects consistent increases in total renal Na in IPRK during hypoxic perfusion. Increasing the concentration of glycine and alanine to 5 mM each produced a 34% (p < 0.001) reduction in the increase in total renal Na following 30 minutes of hypoxia compared to a matched control group supplemented with 5 mM each of serine and glutamine. There was also a trend (p = 0.067) to improvement in the fractional excretion of sodium (FENa) in the glycine plus alanine treated group. Hypoxic alterations of other physiological parameters were not prevented by supraphysiological glycine plus alanine. This suggests that monitoring total renal Na is a more sensitive method of defining renal injury and protection than monitoring changes in FENa, fractional excretion of potassium (FEK) and inulin clearance.

Alanine↗

PubMed1987

Hepatic extraction, metabolism and biliary excretion of doxorubicin in the isolated perfused rat liver.

The hepatic extraction, metabolism, and biliary excretion of doxorubicin (DX) were studied in the isolated perfused rat liver. Three doses of DX equivalent to 2, 20, and 100 mg/kg in rats were studied over a period of 3 h after bolus injection into the reservoir. DX and metabolites concentration in perfusate, bile, and liver were determined by high-pressure liquid chromatography. The hepatic extraction ratio was low (less than 0.24) and decreased progressively over the 3 h. The hepatic extraction and clearance were significantly lower at the highest dose. Doxorubicinol (DX-OL) was the only metabolite detected in the perfusate, accounting for less than 4% of the total AUC. Thirty-one to thirty-three percent of the dose was excreted into bile over 3 h as unchanged DX. This was reduced to 22% at the highest dose. Only 0.35%-1.33% of the dose was excreted as DX-OL. DX aglycones were found only in the liver, where they represented 20%-30% of the total fluorescence at 3 h. In conclusion, in this model DX has a low extraction ratio, is poorly metabolized and extensively excreted into bile.

Animals↗

PubMed1990

Sodium entry routes in principal and intercalated cells of the isolated perfused cortical collecting duct.

Transmembrane sodium transport pathways were studied in principal and intercalated cells of the isolated perfused rabbit cortical collecting duct. Intracellular electrolyte concentrations in individual collecting duct cells were measured by electron microprobe analysis during blockage of basolateral Na-K-ATPase by ouabain and simultaneous inhibition of sodium entry across the apical and/or basolateral cell membrane. In principal cells the ouabain-induced rise in cell sodium concentration could only partially be blocked by amiloride (10(-4) mol/l) in the perfusion fluid. Amiloride (10(-3) mol/l) added to the bathing solution produced a further, significant reduction of sodium influx. In principal cells the ouabain-induced increase in sodium concentration was completely prevented by amiloride in the perfusion solution in combination with omission of sodium from the peritubular bathing solution. In intercalated cells ouabain caused a less pronounced increase in sodium concentration than in principal cells. Neither amiloride in the perfusate, nor amiloride in both bathing and perfusion solution, significantly reduced the ouabain-induced rise in intercalated cell sodium concentration. These results indicate that in principal cells amiloride-sensitive sodium channels constitute the predominant pathway for sodium entry across the apical cell membrane. In addition, substantial amounts of sodium enter principal cells across the basolateral cell membrane, probably via Na-H exchange. Finally, the data suggest that in intercalated cells sodium channels and the Na-H exchange are sparse or even absent.

Amiloride↗

PubMed1978

The interaction of rifamycin SV with hepatic transport of taurocholic acid in the isolated perfused rat liver.

The effect of rifamycin SV on hepatic transport of taurocholic acid was investigated using isolated perfused rat liver technique. In all experiments, the perfused liver was maintained at taurocholic acid steady state by infusing constant amount of taurocholic acid. Infusion of rifamycin SV at various rates decreased biliary secretion of bile acids in a dose-dependent manner. Replacement of rifamycin SV by perfusion medium reversed this effect. To determine the site of action of rifamycin SV, kinetic experiments with 14C-taurocholic acid were undertaken. Rifamycin SV elevated the half-life of the medium disappearance of 14C-taurocholic acid. Furthermore, the antibiotic delayed the biliary appearance of 14C-taurocholic acid. The analysis of the results gave indications that the antibiotic interferred with hepatic uptake as well as biliary secretion of taurocholic acid.

Animals↗

PubMed1982

Compartmentation of citrate in relation to the regulation of glycolysis and the mitochondrial transmembrane proton electrochemical potential gradient in isolated perfused rat heart.

Subcellular fractionation of tissue in nonaqueous media was employed to study metabolite compartmentation in isolated perfused rat hearts. The mitochondrial and cytosolic concentrations of citrate and 2-oxoglutarate, total concentrations of the glycolytic intermediates and rate of glycolysis were measured in connection with changes in the rate of cellular respiration upon modulation of the ATP consumption by changes of the mechanical work load of the heart. The concentrations of citrate and 2-oxoglutarate in the mitochondria were 16- and 14-fold, respectively, greater than those in the cytosol of beating hearts. The cytosolic citrate concentration was low compared with concentrations which have been employed in demonstrations of the citrate inhibition of glycolysis. In spite of the low activities reported for the tricarboxylate carrier in heart mitochondria, the cytosolic citrate concentration reacted to perturbations of the mitochondrial citrate concentration, and inhibition of glycolysis at the phosphofructokinase step could be observed concomitantly with an increase in the cytosolic citrate concentration. The delta pH across the inner mitochondrial membrane calculated from the 2-oxoglutarate concentration gradient and the mitochondrial membrane potential calculated from the adenylate distribution gave an electrochemical potential difference of protons compatible with chemiosmotic coupling in the intact myocardium.

Animals↗

PubMed1979

The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium. II. Activation by the isolated perfused rat liver.

In this investigation Salmonella typhimurium strain TA 1530 and TA 1535 were combined with isolated perfused rat liver. Samples of perfusate and bile produced were tested for mutagenicity after treatment with 1,2-dichloroethane (DCE), 1,2-dibromoethane (DBE) or 2-chloroethanol. The results are in good agreement with our previous experiments which indicate that both DEC and DBE are activated through conjugation with glutathione (GSH). Most GSH conjugates are normally excreted in bile. Following liver perfusion the bile was highly mutagenic after DCE and DBE treatments, while 2-chloroethanol did not have this effect. The highest mutagenic effect was seen 15--30 min after the addition of DCE or DBE. The production of mutagenic bile also occurred in mice treated in vivo with DCE. One possible metabolic endproduct of a GSH conjugate is the corresponding mercapturic acid. Thus synthetic N-acetyl-S-(2-chloroethyl)-L-cysteine was tested on TA 1535 and found to be as mutagenic as S-(2-chloroethyl)-L-cysteine in the concentration range 0.2--0.6 mumol/plate. Differences and similarities in the metabolism of DCE and vinyl chloride are discussed on the basis of these results.

Animals↗

PubMed1979

Structural specificity of nucleotides for insulin secretory action from the isolated perfused rat pancreas.

The study concerned the effects of variuos nucleotides on the insulin secretion from the isolated perfused rat pancreas. ATP, the first nucleotide studied, increased the insulin release induced by glucose 1.5 g/l. There was a first immediate peak followed by a second significant and durable increase. The log dose-response curve was linear for concentrations ranging from 0.825 microM to 330 microM. The effects of natural adenine derivatives (ATP, ADP, 5' AMP, cAMP and adenosine) were compared. ATP was the most active compound; ADP had nearly the same activity as ATP (relative potency ATP/ADP = 3.2); 5' AMP, cAMP and adenosine displayed a very weak activity (about 100 fold less active). Adenylimido-diphosphate (AMP-PNP), a non-phosphorylating structural analogue of ATP, clearly stimulated insulin secretion and its effect was concentration-related. It was about 10 fold less active than ATP. The comparison of triphosphorylated derivatives from various purine nucleosides (ATP, GTP, ITP) or pyrimidine nucleosides (CTP and UTP) showed that only the purine derivatives had a strong insulin secretory effect with, in order of decreasing activity: ATP greater than GTP greater than ITP. These results show that certain structural features (purine basis and di- or triphosphate groups) are essential to elicit an insulin secretory effect.

Adenine Nucleotides↗

PubMed1982

Forskolin stimulates renin release from the isolated perfused rat kidney.

Forskolin, a novel receptor-independent adenylate cyclase activator, stimulated renin release from the isolated perfused rat kidney twofold at 10(-7) M and threefold at 10(-6) M. This stimulation was blocked by angiotensin II but not by the beta-adrenoceptor antagonist atenolol. These findings strengthen the concept that an intracellular increase of 3',5'-cyclic AMP by adenylate cyclase activation can induce stimulation of renin release.

Adenylyl Cyclases↗

PubMed1986

Iloprost (ZK 36374) prevents angiotensin I conversion in the isolated perfused rat lung against anoxia.

The tissue protective effect of iloprost against anoxia was studied in the isolated perfused rat lung. The change in angiotensin converting enzyme activity was taken as a sign of the biochemical activity of pulmonary vascular endothelium and was measured by bioassay of the vasoconstrictor effects of angiotensin I and angiotensin II. A significant decrease in angiotensin converting enzyme activity was observed in the lungs incubated with Krebs alone and exposed to anoxia for 2 h. The decrease in angiotensin converting enzyme activity following anoxia for 2 and 24 h was prevented by prior pretreatment with iloprost. The pulmonary vasoconstrictor effect of angiotensin II was significantly enhanced following anoxia and iloprost prevented this potentiation. The prevention by iloprost of the decrease in angiotensin converting enzyme activity and increase in the pressor response to angiotensin II was attributed to damage of pulmonary vascular endothelium during anoxia. Possible underlying mechanisms are discussed.

Angiotensin I↗

PubMed1995

Effect of the pyrrolizidine alkaloid, monocrotaline, on bile composition of the isolated, perfused rat liver.

Monocrotaline is a hepatotoxic pyrrolizidine alkaloid, releasing high levels of metabolites into bile of isolated, perfused liver. Although perfusion of rat liver with 0.5 mM monocrotaline does not affect bile flow over a 1 hr study period, it markedly affects bile composition. Biliary release of conjugated and free GSH increases 30-fold. Marked increases are also observed in the biliary concentration of the related sulfur-containing substances, cysteine and cysteinylglycine. However, biliary release of the sulfur amino acids, taurine and methionine, is unaffected. Only two amino acids show mildly increased releases, 23% for glycine and 46% for aspartate. Release of bile acids, cholesterol and phospholipids also decrease, both in terms of mM concentration in bile and in terms of nmol secreted per g liver. Thus, exposure to monocrotaline causes disturbances in sulfur metabolism in the liver and in the composition of bile. The consequences of the digestive properties of bile and gastrointestinal toxicity remain to be established. As sulfhydryl compounds are involved in detoxification of monocrotaline metabolites, these findings indicate a mutual interaction of pyrrolizidine toxicity and sulfur metabolism. This suggests that dietary sulfur amino acid intake may influence susceptibility to pyrrolizidine poisoning.

Amino Acids↗

PubMed1985

Release of mast cell mediators, vasoconstriction and edema in the isolated, perfused head of the rat following intracarotid infusion of neurotensin.

Intracarotid infusions of neurotensin (NT) into the isolated, perfused head of rats trigger concentration-dependent histamine and 5-hydroxytryptamine (5-HT) release from the perfused organ. The secretory event was accompanied by a concentration-dependent rise in perfusion pressure and facilitation of edema formation. The three NT effects were markedly reduced in heads derived from rats pretreated with high doses of compound 48/80 to produce mast cell depletion. The vasoconstrictor response to NT was greatly attenuated by the 5-HT receptor antagonist methysergide but unaffected by antihistaminic drugs. The results were interpreted as an indication that NT stimulates histamine and 5-HT release from mast cells of the rat perfused head. The results also suggest that the vasoconstrictor response to NT in the rat head is mediated by mast cell 5-HT. The potentiation of edema formation by NT was attributed to the action of mast cell mediators (most likely histamine and 5-HT) released by NT on microvessels.

Animals↗

PubMed1986

Autonomic nervous control of the endocrine secretion from the isolated, perfused pig pancreas.

The effect of electrical stimulation of the splanchnic and the vagus nerve supply to isolated, perfused pig pancreas on the secretion of insulin, glucagon and pancreatic polypeptide (PP) was investigated. Functional integrity of the autonomic nerve supply was assessed by the effect of nerve stimulation on vascular resistance and exocrine secretion. Splanchnic nerve stimulation increased glucagon and PP output (2 to 3-fold) and inhibited insulin output (by 42%). Propranolol abolished the effect on PP and glucagon secretion, but did not affect the inhibition of insulin secretion. Phenoxybenzamine abolished the inhibition of insulin secretion, reduced the effect on glucagon secretion and enhanced the effect on pancreatic polypeptide secretion. Combined alpha- and beta-adrenergic blockade abolished all effects of splanchnic nerve stimulation. Vagus nerve stimulation increased the secretion of all 3 hormones (PP: up to 30-fold, insulin and glucagon: 3 to 5-fold). The effect on insulin and PP-secretion was mimicked by acetylcholine at 10(-7)-10(-6) M, whereas glucagon secretion was inhibited. The effect of vagus nerve stimulation on insulin and PP secretion was augmented by physostigmine, and inhibited (but not abolished) by atropine at 10(-7)-10(-6) M. The effect on glucagon secretion was inhibited by physostigmine and unaffected by atropine. It is concluded that all of the effects of splanchnic nerve stimulation on insulin and PP secretion can be explained by interactions of norepinephrine with excitatory beta-receptors on PP-cells and inhibitory receptors on the insulin cells. Both cell types are also stimulated via muscarinic cholinoceptors, but the partial atropine resistance suggests that other transmitters participate in vagal activation. The nervous regulation of glucagon secretion is complex and may involve the peptidergic innervation of the pancreatic islets.

Animals↗

PubMedDate not supplied

Effects of guinea pig vasoactive intestinal peptide on the isolated perfused guinea pig heart.

The pharmacological effects of guinea pig vasoactive intestinal peptide (VIP) were studied in isolated perfused guinea pig hearts. Bolus injections of VIP produced a dose-dependent tachycardia that was not affected by atenolol. A decrease in amplitude of ventricular contractions occurred in response to all doses of VIP. This response was preceded by a small increase in amplitude in 3 of 6 hearts at the highest dose. VIP produced a decrease in perfusion pressure which was prominent after coronary tone was elevated with [Arg8]-vasopressin. The present findings support speculation that VIP may have a role in the regulation of heart rate and coronary blood flow.

Animals↗

PubMed1985

The role of prostaglandins in aldosterone and corticosterone secretion by isolated perfused rat zona glomerulosa cells.

The effect of PGE2 and PGA1 on aldosterone and corticosterone biosynthesis by isolated perfused rat zona glomerulosa cells has been studied. Incremental doses of each of the prostaglandins tested produced a progressive rise in aldosterone (3-4 fold increase for PGE2 and 2-3 fold increase for PGA1) and corticosterone (4-8 fold for PGE2 and 2-4 fold for PGA1). The cyclo-oxygenase inhibitors indomethacin and meclofenamate however produced no effect on basal steroidogenesis. PGE2 produced a marked potentiation of angiotensin II-induced aldosterone secretion (45.7 +/- 13.6 to 144.3 +/- 19.4 pg/ml with angiotensin II alone and 78.4 +/- 16.6 to 269.9 +/- 39.5 pg/ml with angiotensin II + PGE2). In contrast, there was no effect of PGE2 on ACTH or serotonin-induced aldosterone secretion. These data show that PGE2 and PGA1 can directly stimulate rat adrenal steroidogenesis and suggest that PGE2 may play a role in mediating angiotensin II-induced aldosterone secretion by rat zone glomerulosa cells.

Adrenal Cortex↗

PubMed1987

Influence of selenium deficiency on glutathione disulfide metabolism in isolated perfused rat heart.

Selenium deficiency causes a fall in rat cardiac glutathione peroxidase activity. As a consequence, isolated perfused selenium-deficient heart does not release increased amounts of GSSG when hydroperoxide is infused. However, the total amount of glutathione measured as intracellular GSH, intracellular GSSG and GSSG released from the heart when hydroperoxide is infused does not equal the total glutathione measured in these pools in untreated hearts (Xia, Y., Hill, K.E. and Burk, R.F. (1985) J. Nutr. 115, 733-742). GSSG can react with protein sulfhydryl groups to form glutathione-protein mixed disulfides (PrS-SG). PrS-SG were measured in perfused selenium-deficient and control hearts infused with t-butylhydroperoxide and were found to account for the previously unmeasured glutathione. The ability of the selenium-deficient heart to transport GSSG was also examined. GSSG was produced non-enzymatically by infusing diamide. The diamide-treated selenium-deficient heart formed GSSG and released it at the same rate as similarly-treated control heart. Thus although selenium deficiency decreases GSSG formation by glutathione peroxidase, it does not affect cardiac GSSG transport.

Animals↗

PubMed1995

Measuring the weight of the isolated perfused rat lung during negative pressure ventilation.

Weight measurement represents a means of quantitating edema formation in isolated lungs and following its time course. During ventilation by negative pressure measurements with commonly used weight transducers are impossible because the pressure changes inside the artificial thoracic chamber affect the weight reading. Therefore, we have developed a weight transducer that can be used during negative pressure ventilation. Its design and applicability for assessing weight gain induced by various agents in the negative-pressure-ventilated isolated perfused rat lung is presented here.

Animals↗

PubMed1999

Role of potassium channels and nitric oxide in the relaxant effects elicited by beta-adrenoceptor agonists on hypoxic vasoconstriction in the isolated perfused lung of the rat.

1. The aims of this study were to compare, in the rat isolated perfused lung preparation, the antagonist effects of a nonselective beta-adrenoceptor agonist (isoprenaline), a selective beta2-adrenoceptor agonist (salbutamol) and a selective beta3-adrenoceptor agonist (SR 59104A) on the hypoxic pulmonary pressure response, and to investigate the role of K+ channels, endothelium derived relaxing factor and prostaglandins in these effects. K+ channels were inhibited by glibenclamide, charybdotoxin or apamin, NO synthase and cyclo-oxygenase were inhibited by N(G)-nitro-L-arginine methyl ester (L-NAME) and indomethacin, respectively. 2. Hypoxic ventilation produced a significant increase in perfusion pressure (+65%, P<0.001) and L-NAME significantly increased this response further (+123%, P<0.01). After apamin, L-NAME, indomethacin, post-hypoxic basal pressure did not return to baseline values (P<0.001). 3. Glibenclamide partially inhibited the relaxant effects of isoprenaline (P<0.05) and salbutamol (P<0.001) but not that of SR 59104A. In contrast, charybdotoxin and apamin partially inhibited the relaxant effects of SR 59104A (P=0.053 and <0.01, respectively) but did not modify the effects of isoprenaline and salbutamol. L-NAME partially inhibited the dilator response of salbutamol (P<0.01) and SR 59104A (P<0.05) but not that of isoprenaline. 4. We conclude that (a) EDRF exerts a significant inhibition of the hypoxic pulmonary response, (b) SK(Ca) channel activation, EDRF and prostaglandins contribute to the reversal of the hypoxic pressure response, (c) the vasodilation induced by isoprenaline is mediated in part by activation of K(ATP) channels, that of salbutamol by activation of K(ATP) channels and EDRF. In contrast, SR 59104A partly operates through BK(Ca), SK(Ca), channels and EDRF activation, differing in this from the beta1 and beta2-adrenoceptor agonists.

Adrenergic beta-Agonists↗