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PubMed1988

The electrophysiologic actions of lidocaine and bupivacaine in the isolated, perfused canine heart.

To discriminate between the electrophysiologic and arrhythmogenic effects of lidocaine and those of bupivacaine, isolated, perfused canine hearts were exposed to toxic concentrations of the drugs. The preparations included the sinus node and right atrium, and, in some cases, the AV node and interventricular septum as well. Action potentials were recorded from these areas, and right atrial twitch amplitude and spontaneous rate and rhythm were monitored. Heart rate was depressed in a dose-dependent manner by both drugs, as was atrial twitch amplitude. In the absence of arrhythmias, the spontaneous rate decreased less than 30% with lidocaine up to 50 micrograms/ml, and with bupivacaine up to 5 micrograms/ml. The twitch depression reflected a potency ratio for bupivacaine (mol. wt. 288) to lidocaine (mol. wt. 234) on a mass basis of 8.1:1. The most prominent arrhythmia found was sinoatrial block, which was caused by both drugs with a potency ratio for bupivacaine to lidocaine of 15.4:1 and was reversed by 0.02 microgram/ml norepinephrine. Sinus arrhythmias, block of retrograde conduction from AV node to atrium, and irregular rhythms originating within the AV node were observed with both drugs at concentrations similar to those which produced sinoatrial block. The atrial action potential revealed decreased upstroke velocity, overshoot, and height with both lidocaine and bupivacaine, with potency ratios (bupivacaine:lidocaine) ranging from 15:1 to 26:1. In septal cells, both drugs depressed upstroke velocity, and bupivacaine lengthened action potentials by up to 14%, but lidocaine did not. The major difference between bupivacaine and lidocaine in this study was the higher potency of the former agent with respect to electrophysiologic end-points.

Action Potentials↗
PubMed1998

"Conventional" antihistamines slow cardiac repolarization in isolated perfused (Langendorff) feline hearts.

We examined the effects of "conventional" antihistamines on cardiac repolarization by using the isolated perfused feline heart model. Representative drugs from the major classes of antihistamines were tested. Each of the antihistamines evaluated in this study elicited a dose-dependent slowing of cardiac repolarization, as indicated by the QT prolongations observed from electrocardiogram (ECG) tracings recorded during these experiments. The concentrations of drugs tested ranged from 1 to 30 microM. Of the drugs analyzed, clemastine and hydroxyzine appeared to be the most potent (relative EC50 values, 5.2 and 6.6 microM, respectively), causing the QT to lengthen by as much as 40-50% at a concentration of 10 microM. Brompheniramine, chlorpheniramine, and diphenhydramine displayed intermediate potencies with respect to QT prolongation (relative EC50 values, 11-13 microM), whereas cyproheptadine, chlorcyclizine, and promethazine were the least potent of the antihistamines tested (relative EC50 values, 16-20 microM). It is concluded that the antihistamines evaluated in this study act directly on the heart to slow cardiac repolarization. These findings could have important clinical relevance for patients taking excessive dosages of conventional antihistamines and those at risk of developing cardiac arrhythmias.

Animals↗
PubMed1987

Renal vascular effects of leukotriene C4 in the isolated perfused kidney of the rat.

1 The vascular effects of leukotriene C4 (LTC4) were investigated in the isolated perfused kidney of the rat. 2 LTC4 (6.4 X 10(-10) to 3.2 X 10(-8) mol kg-1 min-1 given over 5 min) resulted in a prompt, dose-dependent increase in renal vascular resistance in a recirculating system, which lasted for more than 60 min. 3 LTC4 was 10 to 20 fold and 1000 to 2000 fold, respectively, less active on a molar basis than noradrenaline and angiotensin II in eliciting renal vasoconstriction. 4 The vascular response to LTC4 was blocked dose-dependently by FPL 55712, an antagonist of slow reacting substance of anaphylaxis. OKY 1581, a specific thromboxane synthetase inhibitor, and indomethacin, a cyclo-oxygenase inhibitor, did not influence the LTC4 response. 5 LTC4 given in a single-pass perfusion system resulted in a short lasting response with baseline values for renal vascular resistance reached after 4 min. 6 These results show that LTC4 is a short acting renal vasoconstrictor with less potency than noradrenaline and angiotensin II. Its pressor effects seem to be mediated by specific leukotriene receptors and independent of cyclo-oxygenase products. The long-lasting effect in the recirculating arrangement, in contrast to the single pass system, is compatible with formation of active metabolite(s).

Angiotensin II↗
PubMed1992

A method for sequential excision biopsies of rat liver in an isolated perfused system.

We describe a simple method of performing sequential excision biopsies during liver reperfusion in the isolated perfused rat liver. After hepatectomy, four ligatures (5.0 silk) tied with a slip knot are placed around the pedicles of: (1) the inferior and (2) the superior parts of the caudate lobe, as well as (3) the inferior and (4) the superior parts of the right lateral lobe. At the time of biopsy, the prepared 5.0 silk ties are tightened with sufficient force to occlude the vascular pedicle, preventing leakage of circulating perfusate. The procedure provides four biopsies of more than 350 mg each without alteration of perfusate transaminases and tissue ATP contents. The total tissue removed by this method comprises 20-25% of the whole liver weight.

Animals↗
PubMed1987

Trichloroethylene inhibits uptake of 3H-5-hydroxytryptamine but not uptake of 3H-zimeldine or 3H-propranolol in isolated perfused rat lungs.

Pulmonary uptake of 5-hydroxytryptamine (5-HT), zimeldine and propranolol were studied using the isolated perfused rat lung model. The 5-HT uptake was found to be attenuated by approximately 50 per cent in comparison to the control, when the lungs were ventilated with air containing 5,000 p.p.m. trichloroethylene. In experiments in which the active uptake of 5-HT was blocked with the selective 5-HT uptake inhibitor zimeldine (5 X 10(-6) M), the uptake of 5-HT decreased by 70 +/- 1.7 per cent (mean +/- S.E.M.). When trichloroethylene (5,000 p.p.m. and 18,000 p.p.m.) was added, no further decrease in uptake was noted. The uptake of 3H-zimeldine (10(-6) M) and 3H-propranolol (10(-6) M) was unaffected by ventilating the lungs with trichloroethylene. It is concluded that trichloroethylene inhibits the active uptake of 5-HT from the pulmonary circulation, but that it has no effect on the uptake of zimeldine or propranolol, which are taken up predominantly by passive diffusion.

Animals↗
PubMed1986

The disposition of pyrimethamine in the rat isolated perfused liver: the effect of suramin.

The pharmacokinetics of pyrimethamine (0.5 mg) were determined in the rat isolated perfused liver in the presence of suramin (17.75 mg). The clearance, half life, area under the curve, and volume of distribution of pyrimethamine were unaffected by the concurrent administration of suramin, as was the hepatic sub-cellular disposition of the drug. This report is of relevance to the future concurrent administration of suramin and pyrimethamine in West Africa.

Animals↗
PubMed1980

Direct measurement of microvascular pressures in the isolated perfused dog lung.

Microvascular pressures in the pulmonary circulation were measured under the pleural surface of the isolated perfused dog lung by the servo-null technique. Strong glass micropipettes with short beveled tips were used, with a suction ring to stabilize the lung's surface. Of the total vascular resistance, 45 percent was in the alveolar wall capillaries themselves. Most of the remaining resistance was in the arterioles. There was negligible pressure drop in venules with diameters larger than 20 micrometers.

Animals↗
PubMed1983

Influence of adenosine triphosphate on the isolated perfused mesenteric artery of the rabbit.

The vascular effects of adenosine triphosphate (ATP) were examined in the isolated perfused mesenteric arteries of the rabbit. Bolus injections of ATP (1 X 10(-8) to 10(-6) mol) induced a dose-dependent vasoconstrictor response at resting perfusion pressure, while continuous perfusion with ATP briefly elicited a vasoconstrictor response which was not maintained. Perfusion with phentolamine (2.65 X 10(-6) M, an alpha-adrenergic receptor blocker), indomethacin (8.37 X 10(-6) M, an inhibitor of cyclooxygenase), atropine (1 X 10(-7) M, a muscarinic receptor blocker), and hydralazine (2 X 10(-4) M, a vascular smooth muscle inhibitor) for a period of 1 h had no effect on vasoconstrictor responses to ATP. However, pretreatment with reserpine (2 mg X kg-1 X day-1 for 2 days), an agent which depletes catecholamines, potentiated responses to ATP. On the other hand, when vascular tone was increased with an isoosmotic 60 mM K+ depolarizing Krebs bicarbonate solution, bolus injections of ATP elicited a prominent dose-dependent vasoconstriction followed by a prominent vasodilation. The degree of vasodilation but not of vasoconstriction elicited by ATP was greater in small terminal arteries with branches (less than 0.5 mm outside diameter (o.d.) ) than in the medium size arteries (less than or equal to 1 mm o.d.) without terminal branches. Both the vasoconstrictor and vasodilator responses were unaffected by a perfusion with atropine, indomethacin, or eicosatetraynoic acid (ETYA, 1 X 10(-4) M) for 1-2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1980

Insulin, glucagon, and somatostatin secretion from isolated perfused rat and chicken pancreas-duodenum.

Insulin, glucagon, and somatostatin secretion were evaluated in the following isolated perfused models: rat pancreas-duodenum (both normal and streptozotocin-diabetic animals) and the chicken pancreas with and without duodenum. Insulin secretion in response to glucose or arginine was greater from the normal rat than either the diabetic rat or the chicken. Glucagon release from both species was suppressed by glucose and stimulated by arginine except that poor inhibition by glucose was found in the diabetic rat. Somatostatin could be measured in the effluent from both normal and diabetic rats, but the responses to glucose and arginine were variable and modest. Clear increases of secretion in the rat were only observed in response to a combination of glucose, arginine, theophylline, and isoproterenol. In contrast, the chicken somatostatin secretion was markedly stimulated by glucose and by arginine. In conclusion, the perfused chicken pancreas-duodenum has been shown to secrete large amounts of somatostatin in comparison to the rat and should prove to be a useful system for the study of D-cell regulation.

Animals↗
PubMed1991

Hormone secretion by isolated perfused pancreas of aging Fischer 344 rats.

This is the first study investigating hormone secretion by the isolated perfused pancreas of the aged Fischer 344 rat. Nutrient-induced release of insulin, glucagon, and somatostatin in overnight-fasted rats aged 2, 10, 18, 24, and 30 mo was studied. After an equilibration period, the pancreas was perfused for 20 min with buffer A (containing 4.2 mM glucose plus a 3.5 mM mixture of amino acids) then for 20 min with buffer B (containing 8.3 mM glucose and 7.0 mM amino acids). When stimulated by buffer B, the amount of insulin secreted increased (P less than 0.05) from immaturity (2 mo) to adulthood (10-18 mo) because of growth of the organ. From adulthood to very old age an equal amount of insulin was released in all groups during the last 19 min of perfusion with buffer B. Fasting blood glucose levels remained constant throughout life, whereas pancreatic insulin stores and plasma insulin levels rose, reaching peak values at 18 mo. The alpha-cell appeared to be deemphasized relative to the beta-cell during development but not thereafter, as indicated by the findings that from immaturity to adulthood pancreatic glucagon stores expanded less than insulin stores and that glucagon release significantly decreased. Only minor changes in somatostatin release from the delta-cells were observed after the rat reached adulthood. We conclude that the endocrine secretory response of the pancreas is well maintained throughout life in the Fischer 344 rat.

Aging↗
PubMed1986

Effects of rifampin and isoniazid on the isolated perfused rat liver.

The effect of the antitubercular drugs rifampin and isoniazid on the function of the isolated, perfused rat liver was evaluated by monitoring the rate of bile flow and sulfobromophthalein (BSP) clearance. The effect of rifampin on bile flow was biphasic: rifampin concentration of 100 micrograms/ml increased the flow to 134% of baseline, while 1,000 micrograms/ml decreased the flow to 58% of baseline (p less than 0.01 for both). Rifampin also caused a dose-dependent inhibition of BSP removal from the perfusate and excretion in the bile. Isoniazid had no adverse effect on bile flow and BSP clearance, and the combination of isoniazid and rifampin had the same effects on the perfused liver as rifampin alone.

Animals↗
PubMed1978

Modulation by alloxan of glucagon and insulin secretion in the isolated perfused rat pancreas.

The acute in vitro effect of alloxan on glucagon and insulin secretion from the isolated perfused rat pancreas was examined. Alloxan alone produced transient insulin secretion. Pretreatment with alloxan attenuated both the stimulatory effect of glucose on insulin secretion and the inhibitory effect of glucose on glucagon secretion. Exposure to alloxan in varying doses either partially or completely inhibited insulin secretion induced by arginine in the presence or absence of glucose. On the contrary, pretreatment with alloxan produced complex effects on arginine-induced glucagon secretion. In the absence of glucose, the response of glucagon to arginine infusion was lower in the pancreas exposed to alloxan than in the control experiment. In the presence of glucose, however, an apparently augmented response of glucagon to arginine was observed after exposure to higher doses of alloxan, suggesting an impaired inhibitory effect of glucose on arginine-induced glucagon secretion. These effects of pretreatment with alloxan on glucagon secretion can not be explained by earlier or simultaneous insulin secretion. Therefore, we conclude that alloxan acts not only on beta-cells, but also directly on alpha-cells, although the latter are less sensitive to this agent.

Alloxan↗
PubMed1982

Effects of dilazep on fibrinolytic system in animals. II. Enhancing effect of dilazep on plasminogen activator release in the isolated perfused pig ear.

The influence of drugs on the release of plasminogen activator was studied in the isolated perfused pig ear. The pig ear was perfused with oxygenated Tyrode's solution pH 7 . 4, at 37 degrees C via main artery and perfusate from the veins was collected at 2 min intervals. The drug was injected into a rubber tube connected in the front of arteria cannula, and the fibrinolytic activity of perfusate collected was measured by the fibrin plate method using plasminogen-containing bovine fibrinogen. Under the test condition, dilazep enhanced plasminogen activator release (PA release) in a dose-dependent fashion ranging 10 to 100 microgram, however, it did not affect the perfusion pressure. Hypotensors, namely acetylcholine (0.1-3 microgram), bradykinin (0.1-3 microgram) and histamine (0.1-3 microgram) enhanced also the PA release in a dose-dependent fashion with no effects on perfusion pressure. Vasoconstricting drugs, namely phenylephrine (0.3-10 microgram), norepinephrine (0.1-3 microgram) and serotonin (0.1-3 microgram) exerted hypertensive effects on perfusion pressure in a dose-dependent fashion, however, it did not cause the PA release.

Acetylcholine↗
PubMed1984

The isolated perfused lung.

The unique nonrespiratory functions of the lungs have become more apparent in recent years. The isolated perfused lung model offers many advantages over other methods for the study of pulmonary metabolism, xenobiotic disposition and the influence of interactions among agents of different physical forms. Detailed descriptions of the experimental preparation are elements in evaluating and comparing data from various sources but these are frequently neglected. A discussion and critique of the following elements are provided in this review in order to elucidate the typical problems one might encounter in evaluating data: perfusate type, perfusion method, construction materials, ventilation method, temperature control, surgical procedure, microbiological contamination and evaluation criteria of the preparation. Examples are given where the IPL method has been applied and suggestions are made for future research efforts.

Air Microbiology↗
PubMed1982

Stereospecific reduction of 3- and 7-oxo groups of oxocholanic acids in isolated perfused rat liver.

The metabolism of 3- and 7-oxo groups of oxocholanic acids was studied in isolated perfused rat liver. The metabolites in bile were determined enzymatically using 3 alpha- and 7 alpha-hydroxysteroid dehydrogenases. The 3-oxo group of all the oxocholanic acids tested (dehydrocholate, glycodehydrocholate, taurodehydrocholate, 3,7-dioxocholanate, 3,12-dioxocholanate and tauro-7,12-dihydroxy-3-oxocholanate) was reduced stereospecifically to 3 alpha-hydroxy metabolites. On the other hand the 7-oxo group was excreted partially unchanged (30% of the dose) and partially as 7 alpha-hydroxy metabolites (6-10% of the dose). The remainder of the 7-oxo group was concluded to have been reduced to 7 beta-hydroxy metabolites. These results indicate that the 7-oxo group of oxocholanic acids is reduced predominantly to 7 beta-hydroxy metabolites in rats rather than to 7 alpha-hydroxy metabolites as found in man.

Animals↗
PubMed1975

Inhibitory effects of synthetic rat C-peptide 1 on insulin secretion in the isolated perfused rat pancreas.

The effects of synthetic rat C-peptide 1 on insulin secretion from the isolated perfused rat pancreas was studied. The perfusion technique was according to the procedure described by Grodsky et al (1963) with a few modifications. After about 20 min of stabilization, the pancreas was perfused for 40 min with synthetic rat C-peptide 1 (100 ng/ml), during which (at 20 min) glucose concentration was switched from 2.7 to 16.6 mM. Insulin response to glucose (16.6 mM) was significantly decreased by the addition of the rat C-peptide 1 in advance when compared with those not pretreated with the C-peptide. In other experiments, the pancreas was exposed to glucose infusion (16.6 mM) for 60 min. 20 min after the start of glucose infusion, the C-peptide (100 ng/ml) was interposed for 20 min. The insulin secretion was reduced by the addition of the C-peptide. It is postulated that the C-peptide may have a role in the regulatory mechanism of the insulin secretion.

Animals↗
PubMed1989

The toxicokinetics of (1R, cis)- and (1R, trans)- tetramethrin in the isolated perfused rat liver.

1. The toxicokinetics of cis- and trans-tetramethrin isomers were investigated using the isolated perfused rat liver preparation. 2. The concentration of cis- and trans-tetramethrin decreased rapidly in the plasma perfusate and was initially replaced by N-(hydroxymethyl)3,4,5,6-tetrahydrophthalimide (MTI) and then by 3,4,5,6-tetrahydrophthalimide (TPI). Plasma perfusate concentrations of the intact cis-isomer were higher than those of the trans-isomer. Concentrations of MTI and TPI were higher in livers treated with the trans-isomer. 3. Tetramethrin and its metabolites were rapidly excreted in the bile. Bile from livers perfused with trans-isomer contained higher concentrations of parent isomer and metabolites MTI and TPI, than did bile from livers treated with the cis-isomer.

Animals↗
PubMed1991

Investigations on the biotransformation of mebendazole using an isolated perfused rat gut system.

1. The intestinal metabolism of the benzimidazole, mebendazole (MEB), has been investigated using isolated perfused jejunal segments of rats. Significant absorption and intestinal metabolism of the substance was observed. 2. The metabolites, the reduced alpha-hydroxy-analogue, its glucuronide, and the decarbamoylated 2-amino-analogue, were transported into the resorbate collected at the serosal side or were resecreted into the gut lumen. 3. The intestinal decarbamoylation of mebendazole increased up to 20-fold after pretreatment with 3-methylcholanthrene (MC), and complete re-secretion of this metabolite into the gut lumen led to a total loss of the absorption of mebendazole and metabolites across the gut wall. 4. The results indicate the ability of the gut to metabolize mebendazole by phase I and II reactions. 5. An almost complete loss of bioavailability after induction of the gut enzyme system by MC was observed.

Animals↗