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PubMed1979

The determinants of insulin extraction in the isolated perfused rat liver.

The effect of hepatic blood flow and portal insulin concentration on insulin extraction during one passage through the isolated perfused rat liver was studied. The percentage of insulin extracted was constant over the physiological range of blood flows (4 to 28 ml/min). The total amount of insulin extracted increased as the input concentration was raised from 48 to 4860 microU/ml with the highest level of extraction being approximately 700 microU of insulin per gram of liver per minute. When square wave input pulses of 243 to 4860 microU/ml were presented, about 5% of this insulin was retained and then released by the liver for periods up to 15 minutes after the cessation of the input. The possible roles of glucose and glucagon as regulators of insulin extraction were studied. Glucose (300 mg/dl), as compared with no glucose, led to a significant reduction of insulin extraction (22% vs. 38%, p less than 0.001). Glucagon had no effect on insulin extraction in the presence of constant levels of glucose. It is concluded, therefore, that glucose may increase circulating insulin levels not only by its well known stimulation of insulin secretion by the pancreas, but also by inhibiting insulin extraction by the liver.

Animals↗
PubMed1980

The dual effect of alloxan modulated by 3-O-methylglucose or somatostatin on insulin secretion in the isolated perfused rat pancreas.

While alloxan treatment stimulated insulin secretion, alloxan pretreatment reduced arginine and glucose-induced insulin secretion in the isolated perfused rat pancreas. The transient insulin secretion by alloxan was inhibited by 3-O-methylglucose and somatostatin. Diminished insulin response to arginine and glucose induced by pretreatment with alloxan was restored by the addition of 3-O-methylglucose, whereas the addition of somatostatin did not improve the impaired insulin secretion. These results indicate that alloxan induced insulin secretion is not due to an uncontrolled leakage, but that the stimulatory and inhibitory action of alloxan on insulin secretion might be initiated by the binding of alloxan to the hexose transport site.

Alloxan↗
PubMed1979

Effect of glucose/sulfonylurea interaction on release of insulin, glucagon, and somatostatin from isolated perfused rat pancreas.

The effect of a sulfonylurea, glibenclamide, on the release of insulin, glucagon, and somatostatin was studied in the isolated perfused rat pancreas. At glucose concentrations of 1.1 mM or less, the drug stimulated somatostatin release, whereas glucagon release, after 2-3 min of increase, was markedly inhibited. Insulin release was moderately stimulated, and maximal release occurred relatively late. A moderate glucose load (6.7 mM) inhibited glibenclamide-induced release of somatostatin, whereas the two in combination exerted an additive action on insulin release. Greater glucose loads, which by themselves would stimulate somatostatin release, only marginally suppressed glibenclamide-induced somatostatin release. The insulinogenic effect of these glucose levels was not modified by glibenclamide. Glibenclamide may thus stimulate both the alpha and beta as well as delta cells of the pancreas, depending on glucose concentration. We suggest a paracrine (local) interaction of somatostatin with the alpha and beta cells, which has an important role in the kinetics of insulin and glucagon release induced by sulfonylureas.

Animals↗
PubMed2001

Immunoneutralization of somatostatin, insulin, and glucagon causes alterations in islet cell secretion in the isolated perfused human pancreas.

INTRODUCTION: In this study, immunoneutralization of endogenous insulin, glucagon, and somatostatin with specific antibodies was used in an isolated perfused human pancreas (IPHP) model. AIMS: To study intrapancreatic cellular interactions and pancreatic hormonal secretion. METHODOLOGY: Randomized, sequential 10-minute test intervals of single-pass perfusion with each antibody were performed at 3.9 mM or 11.5 mM steady-state glucose concentrations. Somatostatin, insulin, and glucagon levels were measured in the effluent during basal and immunoneutralization intervals. RESULTS: At 3.9 mM glucose concentration, somatostatin antibody (SS-Ab) stimulated insulin and glucagon secretion, insulin antibody (IN-Ab) inhibited glucagon secretion, and glucagon antibody (GN-Ab) stimulated insulin secretion. At 11.5 mM glucose concentration, SS-Ab stimulated insulin secretion, IN-Ab stimulated glucagon and inhibited somatostatin secretion, and GN-Ab stimulated insulin secretion. CONCLUSION: The variation in hormonal responses to immunoneutralization during stimulated and nonstimulated glucose conditions suggests that a dynamic association exists between the pancreatic cells.

Adolescent↗
PubMed1991

Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys.

The effect of variations in plasma protein binding on the renal excretion of cefonicid was assessed by using isolated perfused rat kidneys. Cefonicid exhibits preferential binding ex vivo to human serum albumin (HSA), as opposed to bovine serum albumin (BSA), and is eliminated mainly by tubular secretion, a process that was reported to be dependent on the total drug concentration. This contradicts previous studies with antimicrobial compounds and other drugs of low renal extraction in which the unbound drug concentration was shown to be the driving force for carrier-mediated tubular transport. To clarify this discrepancy, we performed perfusion studies by using 6% BSA at initial concentrations of 200 micrograms/ml (n = 6) and 20 micrograms/ml (n = 9) and in a combination of 4% BSA plus 2% HSA at initial concentrations of 200 micrograms/ml (n = 4). The excretion ratio [ER = CLR/(fu x GFR)] of cefonicid decreased with increasing unbound concentrations, whereas no apparent relationship with the total concentration was evident. At similar total concentrations of cefonicid, the renal clearance remained unchanged; the secretion clearance increased significantly in the 4% BSA-2% HSA experiments, reflecting the reduced unbound fraction and unbound drug concentration of cefonicid. The excretion ratio data were compatible with a model in which Michaelis-Menten kinetics were required to describe active transport and secretion was dependent on the unbound cefonicid concentration. As a result, changes in plasma protein binding as a result of drug interactions or disease states could significantly influence the tubular transport capability of compounds with low renal extraction.

Animals↗
PubMed1978

Secretory effects of secretin on isolated perfused porcine pancreas.

The effect of pure natural porcine secretin on endocrine and exocrine pancreatic secretion was studied in the totally isolated perfused porcine pancreas. The exocrine pancreatic responses to secretin correspond well with those obtained in the anesthetized pig. The lowest concentration of secretin observed to increase pancreatic secretion was 2.8 pmol/liter, whereas the maximum pancreatic responses were obtained at a secretin concentration of 92 pmol/liter. The infusion of secretin in concentrations ranging from 2.8 to 278 pmol/liter in the presence of a constant concentration of glucose (7.5, 5.0, or 3.5 mmol/liter) was without effect on the insulin and glucagon release. Infusion of secretin at a concentration of 834 pmol/liter in the presence of glucose at 7.5 mmol/liter provoked a significant (P less than 0.01) short-lived increase in insulin secretion. However, there was no effect on the glucagon secretion. The results of this study indicate that neither the augmented insulin response nor the suppression of glucagon elicited by oral glucose depend on secretin.

Animals↗
PubMed1981

Effects of starvation and obesity on somatostatin, insulin, and glucagon release from an isolated perfused organ system.

We have studied the effects of starvation and of obesity on somatostatin, insulin, and glucagon release from an isolated perfused organ system in fed and 3- and 5-day fasted Holtzman rats and in obese (fa/fa) and lean (Fa/?) Zucker rats. Fasting for 3 days significantly decreased basal (-71%) and amino acid-stimulated (-62%) somatostatin output. After 5 days of starvation, there was a significant increase over the 3-day level in somatostatin output stimulated by amino acid plus glucose (+540%) and by amino acids plus tolbutamide (+238%). Three and five days of starvation severely depressed insulin output while having no statistically significant effects on glucagon secretion. Somatostatin output from obese Zucker rats was significantly greater than that from lean controls in response to amino acids (41.2 +/- 13.2 vs. 16.3 +/- 10.3 ng/25 min, P less than 0.05). Insulin output was greatly increased from obese compared to lean Zucker rats, whereas there were no statistically significant differences in glucagon output. These data show that fasting decreases and obesity increases both somatostatin and insulin release. They suggest that altered stimulation by nutrients was primarily responsible for changes in somatostatin and insulin release observed in starving and obese rats.

Amino Acids↗
PubMed1979

Cardiac performance of isolated perfused hearts from alloxan diabetic rats.

Acute alloxan diabetes (3 days) in the rat resulted in a decreased ability of the isolated perfused working heart to respond to increased atrial filling pressure with normal systolic (aortic) pressure development, using a physiologic concentration of glucose (5 mM) as substrate. The diabetic heart also exhibited impaired cardiac output, which could be attributed entirely to decreased aortic output without any apparent effect on coronary flow. This decrease in ventricular performance was accompanied by a 40% reduction in glucose uptake and a 20% reduction in tissue ATP concentrations even though perfusate glucose levels remained at or near physiologic levels. Perfusion of hearts with 5 mM glucose plus 10(-8) M insulin, with 10 or 30 mM glucose, or 1 mM octanoate reversed the diabetes-related decrease in systolic pressure development, cardiac output, and tissue ATP content. These data demonstrate that the defect in cardiac performance with increased work loads associated with acute insulin deficiency is due to the relative inability of the heart to utilize physiologic concentrations of glucose as substrate for energy production.

Adenosine Triphosphate↗
PubMed1994

Multiple factors contribute to acetylcholine-induced renal afferent arteriolar vasodilation during myogenic and norepinephrine- and KCl-induced vasoconstriction. Studies in the isolated perfused hydronephrotic kidney.

Acetylcholine (ACh) elicits vasodilation by releasing a number of endothelium-derived relaxing factors (EDRFs). We used the isolated perfused hydronephrotic rat kidney to examine the characteristics of ACh-induced vasodilation of renal afferent arterioles during different types of underlying vasoconstriction. Basal arteriolar tone was increased by either elevating perfusion pressure to 180 mm Hg (myogenic), administering 0.3 mumol/L norepinephrine (NE), or elevating medium potassium concentration to 30 mmol/L (KCl). ACh (10 mumol/L) completely reversed myogenic and NE-induced vasoconstriction and reversed KCl-induced vasoconstriction by 80 +/- 5%. However, whereas ACh produced a sustained vasodilation during KCl- and NE-induced vasoconstriction, only a transient reversal of myogenic vasoconstriction was observed, and myogenic tone recovered within 5 to 10 minutes. ACh-induced vasodilation of arterioles preconstricted with KCl was markedly inhibited by either indomethacin (100 mumol/L) or nitro-L-arginine (100 mumol/L) and was completely abolished by pretreatment with both inhibitors. In contrast, indomethacin and nitro-L-arginine had no effect on the transient response to ACh observed during pressure-induced vasoconstriction. In vessels preconstricted with NE, nitro-L-arginine converted the normally sustained response to ACh to a transient vasodilation, which was refractory to both nitric oxide synthase and cyclooxygenase inhibition. Since this component was not observed during KCl-induced vasoconstriction, it may reflect the actions of an, as yet unidentified, endothelium-derived hyperpolarizing factor (EDHF). Our findings thus suggest that prostanoids, nitric oxide, and EDHF all contribute to ACh-induced renal afferent arteriolar vasodilation and that the relative contributions of these individual EDRFs depends on the nature of the underlying renal vascular tone.

Acetylcholine↗
PubMed1988

Different antagonistic effects of bunazosin and ketanserin on the norepinephrine-induced vasoconstriction in isolated, perfused canine and simian skeletal muscle arteries.

Blocking activities of bunazosin and ketanserin on norepinephrine (NE)-induced vasoconstrictions were investigated in isolated, perfused canine and simian skeletal muscle arteries. NE caused an increase in perfusion pressure in a dose-related manner to almost the same extent in both canine and simian arterial preparations. Bunazosin and ketanserin inhibited NE-induced vasoconstrictions much more readily in simian arteries than in canine arteries. The mechanisms for the different adrenolytic activities of alpha 1-antagonists between these two arteries were discussed.

Animals↗
PubMed1992

The metabolism of acitretin and isoacitretin in the in situ isolated perfused rat liver.

1. The metabolism of acitretin and its 13-cis isomer, isoacitretin, has been investigated in the in situ isolated perfused rat liver in order to differentiate the action of the liver from that of the gut on the metabolism of these isomers. 2. Acitretin undergoes alpha-oxidation, chain shortening O-demethylation, and glucuronidation in the perfused rat liver. 3. Isoacitretin undergoes glucuronidation as the major, almost exclusive, route of metabolism in the perfused rat liver. 4. The difference in the hepatic metabolism of the cis and trans isomers of this retinoid may explain the differences in their pharmacokinetics, and may help in understanding the pharmacokinetics of related retinoids.

Acitretin↗
PubMed1975

The pharmacodynamics of 5-hydroxytryptamine uptake and metabolism by the isolated perfused rabbit lung.

We have investigated the dynamics for the removal of 5-hydroxytryptamine (5-HT) from the circulation using the isolated perfused rabbit lung. 5-HT was removed from the circulation at a constant rate and metabolized completely to 5-hydroxyindoleacetic acid which effluxed from the lung into the circulation. Two methods were developed to determine the constant rate of removal of 5-HT: (1) the constant rate is equal to the difference between the 5-HT concentration flowing into the lung and the 5-HT concentration in the effluent times the flow rate and (2) extrapolation of the rate of appearance of radioactivity in the effluent to zero time. With these methods, we have confirmed the 5-HT is removed by the lung by a carrier-mediated Na+-dependent transport system. Studies of transport systems in perfused organs required an adequate supply of the chemical to the lung. Supply rates less than removal rate will result in erroneous measurements of the constant removal rate. The relationships between the rate of removal, perfusate concentration and perfusion rate were analyzed.

Animals↗
PubMed1992

[Effects of Salvia miltiorrhiza Bunge on isolated perfused liver and portal vein of rats].

The experiment results showed that Salvia miltiorrhiza (SMB) had a protective effect on the isolated perfused liver injured by CCl4 of rats, made the activity of GPT in perfusate of SMB group lower than that of intoxicated groups and relieved the hepato-pathohistologic lesions of SMB group as compared to the intoxicated group. SMB had no significant effects on both the activities of SGPT in vitro and the portal vein of rats.

Alanine Transaminase↗
PubMed1987

Mechanically induced ventricular extrasystoles in the isolated perfused guinea-pig heart. A model to study cardiac arrhythmia and to differentiate antiarrhythmic drugs.

Pressure pulses applied to an isolated perfused guinea-pig heart via underwater hydrodynamic pressure waves during early diastole induce ventricular extrasystoles (VES). Intensity of pulse pressure and number of VES in relation to number of stimuli show a narrow and reproducible relation following a sigmoid function. Thus we were able to establish a pressure dose-response function between hydrodynamic peak pressure and percentage of VES-responses to mechanical stimulation. In overriding the natural heart rate a ventricular rhythm can be maintained for several hours. In the hypoxic or anoxic heart repetitive automatism can be induced by pulse pressure stimulus. In severe ischemia ventricular fibrillation may occur. In this model differentiation between various classes of antiarrhythmic drugs seems possible in setting up pressure dose-response curves for different concentrations of these drugs. The inhibition of VES is limited to class I antiarrhythmic drugs (quinidine, lidocaine) while specific Ca-antagonists (class IV) are ineffective, thus showing that induction of VES is mediated by a Na channel-dependent process. Preliminary data show that these results can be extended to in situ experiments using an external mechanical stimulator.

Animals↗
PubMed1985

The effect of met-enkephalin and naloxone on somatostatin and insulin secretion from the isolated, perfused rat pancreas.

The effect of met-enkephalin and the opiate antagonist, naloxone, on somatostatin and insulin secretion from the isolated, perfused rat pancreas has been studied during perfusion with 300 mg/dl glucose. In response to a gradient of met-enkephalin from 0 to 10(-5) M, release of somatostatin was inhibited at low concentrations and stimulated at high concentrations. However, both low and high concentrations of metenkephalin stimulated insulin secretion. A gradient of met-enkephalin from 0 to 10(-6) M caused only an inhibition of somatostatin release, whereas insulin release was stimulated. The effects of met-enkephalin on somatostatin release were antagonized by naloxone (10(-6) M). The metenkephalin-induced insulin secretion was partially, but not completely, blocked by naloxone. Naloxone (10(-6) M) alone changed the endocrine secretions by decreasing somatostatin release and by stimulating insulin release. Met-enkephalin may, therefore, be a physiologic regulator of pancreatic endocrine secretion.

Animals↗
PubMed1984

Lecithin:cholesterol acyltransferase and cholesteryl ester transfer activity from the isolated perfused rabbit liver.

Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester (CE) transfer activity accumulate linearly in the recirculated medium of the isolated perfused rabbit liver. The appearance of both activities in the perfusate was blocked by the addition of 10 microM colchicine, indicating that these two proteins are synthesized and secreted by the liver. CE transfer activity catalyzed the net transport of cholesteryl ester from high density lipoprotein (donor) to very low and low density lipoproteins (acceptor), both in the perfusate medium and in whole rabbit blood plasma. The activity of LCAT in the perfusate was dependent on the presence of the major protein of the high density lipoprotein class, apoA-I. The similar properties of LCAT and CE transfer activity in rabbit liver perfusate and plasma, compared to these same activities in human blood, suggest that the rabbit is an appropriate model for the study of the cholesterol transport system in man.

Animals↗
PubMed1995

Metabolism of allylbenzene 2',3'-oxide and estragole 2',3'-oxide in the isolated perfused rat liver.

The metabolism of allylbenzene 2',3'-oxide, estragole 2',3'-oxide, allylbenzene and estragole was studied in the isolated perfused rat liver. Formation of dihydrodiol and glutathione conjugate metabolites was detected for both epoxides and the presence of dihydrodiol metabolites after perfusion of allylbenzene or estragole indicated the formation of allylic epoxide intermediates in the intact liver. A comparison of elimination kinetics for parent compounds and epoxides indicated that epoxides were relatively rapidly detoxified and probably do not accumulate on formation in vivo. Acute toxicity of epoxides, measured as the release of alanine aminotransferase activity into the perfusate, or genetic toxicity, determined as covalent binding of radiolabeled epoxide to DNA, were not observed. It was concluded that both epoxide hydrolases and glutathione S-transferases can effectively detoxify the allylic epoxides derived from either allylbenzene or estragole and effectively prevent cellular or genetic toxicity of these reactive intermediates. Epoxide hydrolases appear to play the major role in the detoxication of these epoxides in vivo.

Allyl Compounds↗
PubMedDate not supplied

Biotransformation of topotecan in the isolated perfused rat liver: identification of three novel metabolites.

This study evaluates the metabolism of the anticancer drug topotecan (TPT) in the isolated perfused rat liver of male Wistar-rats. Using a sensitive high-performance liquid chromatography method, in bile TPT, its ring-opened hydroxycarboxylate form and three new metabolites could be quantified. Enzymatic hydrolysis of the metabolites with beta-glucuronidase and mass spectroscopy revealed the existence of glucuronidated TPT as well as unconjugated and glucuronidated bidesmethyl TPT. Biliary secretion of glucuronidated N-bidesmethyl TPT was fast reaching a maximum already after 15 min(30.6 +/- 15.1 pmol/g liver.min), whereas secretion of TPT, topotecan glucuronide and N-bidesmethyl TPT was delayed (maximum at 30 min: 431 +/- 19, 6.4 +/- 2.1 and 12.7 +/- 2.7 pmol/g liver.min, respectively). No release of TPT metabolites into the perfusate was detected. The amount of TPT, TPT glucuronide, N-bidesmethyl TPT and N-bidesmethyl TPT glucuronide excreted into bile during 60 min of perfusion was 2.10 +/- 0.483%, 0.031 +/- 0.006%, 0.058 +/- 0.013% and 0.108 +/- 0.012% of TPT cleared from the perfusate over 60 min, respectively. In conclusion we could identify three novel TPT metabolites, however, their overall metabolism in the rat liver is low.

Animals↗