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PubMed1991

Alterations in the energy metabolism of the isolated perfused frog heart during calcium depletion and subsequent repletion.

The changes in myocardial energy metabolism of isolated perfused Rana ridibunda hearts subjected to prolonged calcium depletion and reperfusion with calcium-containing medium were studied. Calcium-free perfusion resulted in an increase in the concentrations of glucose, glucose-6-phosphate, alpha-ketoglutarate and malate. The myocardial contents of high-energy phosphates were maintained while concentrations of key amino acids were significantly altered. During the reperfusion period the tissue high-energy phosphate content fell abruptly. A marked increase in glycolytic flux and lactate production was observed. The tissue contents of citric acid cycle intermediates and key amino acids decreased. Examination of the activities of marker enzymes during the calcium-free and reperfusion periods showed that only cytoplasmic enzymes are lost during reperfusion, while the activities of other enzymes remained unchanged. The results suggest that the fluxes of both glycolysis and the citric acid cycle are significantly altered during calcium depletion and following repletion in the amphibian heart. The major characteristics of calcium paradox-induced damage in Rana ridibunda heart are the depletion of high-energy stores, the impairment of mitochondrial oxidative metabolism, and a significant increase in anaerobic metabolism.

Animals↗
PubMed1993

Non-insulin-like action of sodium orthovanadate in the isolated perfused liver of fed, non-diabetic rats.

Vanadium compounds exert insulin-like effects on isolated rat adipocytes and skeletal muscle and improve glucose homeostasis in diabetic rats and mice. However, reports on metabolic actions of vanadium in the liver are still contradictory. Thus, the acute effect of sodium orthovanadate infusion on net glucose production was measured in isolated perfused livers of non-fasting, non-diabetic rats. Continuous infusion (0.2 ml/min; 90 min) of vanadate (10-500 mumol/l) rapidly increased hepatic glucose (p < 0.001), but not cyclic AMP output, reaching peak values after 20 min. The cumulative glucose release displayed concentration dependence with a maximal net effect of 394.3 mumol/100 g body weight and an apparent half-maximal effective vanadate concentration of 19.6 mumol/l. The glycogenolytic response to vanadate was almost completely blocked by 100 mU/l insulin (p < 0.005), by 0.1 mmol/l indomethacin (p < 0.05) and in the absence of Ca2+ (p < 0.001). These results indicate that sodium orthovanadate stimulates glycogenolysis in livers of fed, non-diabetic rats by a Ca(2+)-dependent mechanism, which may involve the release of prostaglandins.

Animals↗
PubMed1982

Renal handling of homologous and heterologous insulin in the isolated perfused rat kidney.

1. Renal handling of pig- and rat-insulin was studied in the isolated perfused rat kidney. 2. Metabolic clearance rates of both pig- and rat-insulin exceeded GFR. 3. Peritubular uptake of pig-insulin accounted for 13% of rat-insulin for 31% of the total metabolic clearance. 4. The nonfiltering kidney does not remove insulin from the peritubular circulation. 5. Metabolic clearance rates of pig- and rat-insulin are directly related to GFR. 6. The filtration process seems to be necessary for the uptake of insulin at the peritubular site.

Animals↗
PubMed1987

Comparison of benzo(a)pyrene metabolism in isolated perfused rat lung and liver.

The metabolism of 1 mM benzo(a)pyrene was studied in isolated perfused lung and liver of 5,6-benzoflavone-pretreated rats. Benzo(a)pyrene metabolism by the liver was more rapid than by the lung, but total metabolite formation in the lung at the end of a 120-min perfusion period was comparable to that in the liver. Lung perfusate was characterized by high concentrations of free metabolites, with diols outweighing phenols; in liver perfusate free metabolite concentrations were low, and large quantities of metabolites were found as conjugates in the bile at the end of perfusion. The tissue concentrations of free diols and phenols including the precursors of the main DNA-binding secondary metabolites were higher in the lung than in the liver. These findings explain the similar level of covalent binding in perfused lung and liver previously described (Klaus et al. 1982).

Animals↗
PubMed1988

Effect of diabetes mellitus on pancreatic exocrine secretion from isolated perfused pancreas in rats.

We studied pancreatic exocrine function in response to cerulein and carbamylcholine in isolated perfused pancreas obtained from control, streptozotocin-induced diabetic, and insulin-treated diabetic rats. The time course of pancreatic juice, protein, amylase, and trypsinogen secretion in response to cerulein or carbamylcholine in diabetic rats was similar to that in control rats. Basal as well as cerulein- or carbamylcholine-stimulated output of amylase from diabetic rat pancreas was significantly reduced, whereas that of trypsinogen was similar to the control. Amylase and trypsinogen outputs in response to 620 pM (1.0 ng/ml) cerulein from insulin-treated diabetic rat pancreas were significantly lower than those from control rat pancreas, although the pancreatic contents of these enzymes were similar to or greater than those in control rats. The dose-response curves of pancreatic juice, protein, amylase, and trypsinogen for cerulein and carbamylcholine were biphasic in both control and diabetic rats. The minimal and the maximal release in response to cerulein occurred with higher concentrations in diabetic rats compared with control rats. In contrast, the maximal responses were obtained with 1 microM carbamylcholine in control rats and with 0.1-1 microM carbamylcholine in diabetic rats. The present study demonstrates that the concentration of cerulein required to elicit maximal response was increased, whereas that to carbamylcholine was reduced in diabetic rat pancreas, and that the protein and enzyme outputs in response to cerulein were significantly reduced in insulin-treated diabetic rat pancreas despite restoration of the pancreatic enzyme contents to control levels.

Animals↗
PubMed2005

Effect of exogenous adenosine and monensin on glycolytic flux in isolated perfused normoxic rat hearts: role of pyruvate kinase.

We studied the effect of exogenous adenosine in isolated perfused normoxic rat hearts on glycolytic flux through pyruvate kinase (PK). We compared its effect with that of myxothiazol, an inhibitor of mitochondrial ATP production. Moreover, we tested whether an increase of membrane ionic flux with monensin is linked to a stimulation of glycolytic flux through PK. After a 20-min stabilization period adenosine, myxothiazol or monensin were administrated to the perfusate continuously at various concentrations during 10 min. The contraction was monitored and the lactate production in coronary effluents evaluated. The amount of adenine nucleotides and phosphoenolpyruvate was measured in the frozen hearts. Myxothiazol induced a decrease of the left ventricular developed pressure (LVDP : -40%) together with a stimulation of glycolytic flux secondary to PK activation. In contrast, adenosine primarily reduced heart rate (HR: -30%) with only marginal effects on LVDP. This was associated with an inhibition of glycolysis at the level of PK. The Na+ ionophore monensin affected HR (+14%) and LVDP (+25%). This effect was associated with a stimulation of glycolysis secondary to the stimulation of PK. These results provide new information of action of adenosine in the heart and support the concept of a direct coupling between glycolysis and process regulating sarcolemmal ionic fluxes.

Adenine Nucleotides↗
PubMed1982

Mechanism of action of hyaluronidase in decreasing myocardial ischemia post coronary occlusion in the isolated perfused rabbit heart.

The influence of hyaluronidase (H) on subacute experimental myocardial ischemia was studied in isolated perfused rabbit hearts. Changes in ischemic area were assessed by epicardial nicotinamide adenine dinucleotide (NADH) fluorescence photography, an intrinsic high-resolution display of myocardial ischemia. Computerized determination of ischemic area was made from standardized photographs. Hyaluronidase was begun 20 minutes after coronary artery occlusion at 4 units/ml perfusate. NADH fluorophotographs were taken at 10-minute intervals up to 60 minutes of ischemia. Coronary sinus oxygen tension (PcsO2), myocardial oxygen consumption (MVO2), and coronary flow were determined. After 70 minutes, the hearts were perfused with rhodamine solution to identify areas of myocardial perfusion. In 13 H-treated hearts 54.3% +/- 3.7% (mean +/- SEM) of the nonperfused area (rhodamine stained) was ischemic (NADH fluorescent). In 14 untreated hearts 79.8% +/- 3.2% of the nonperfused area was ischemic (p less than 0.0001) and the ischemic areas were uniform. The distance between perfused and ischemic tissue was 952 +/- 78 micrometers in the H hearts and 504 +/- 35 micrometers in the untreated heart (p less than 0.0001). In the H hearts PcsO2 increased to 155% of the post-ligation control while it decreased to 79% in the untreated hearts (p less than 0.0001). MVO2 decreased in the H-treated hearts to 62%; the untreated hearts had no further change. In the H-treated hearts, coronary flow increased to 146% of the post-ligation control while it fell to 91% in the untreated group (p less than 0.0001). We conclude that H increases coronary flow while decreasing MVO2 during subacute ischemia. In H-treated hearts, significant amounts of myocardium remain normoxic within the nonperfused areas, and may potentially be salvaged after prolonged myocardial ischemia.

Animals↗
PubMed1983

Control of pelvic cancer with hyperthermic isolation-perfusion.

Eight patients with refractory pelvic cancer were treated with a technique of hyperthermic pelvic isolation-perfusion (rectosigmoid colon 7, bladder 1). The procedure was successful in achieving regional hyperthermia in all patients. All five patients experiencing severe pelvic pain prior to surgery had resolution of pain, although in one patient this relief was transient. Five patients had additional intraabdominal procedures at the time of laparotomy to control unsuspected foci of recurrent cancer. There were no operative deaths. Five complications occurred in four patients although only one was considered life threatening (fracture of aorta at the time of cross-clamping). Sloughing of necrotic tumor occurred between 1 and 2 weeks postperfusion and at times was dramatic. The efficacy of this technique is impressive and it is suggested that it be utilized earlier in the course of disease in patients with uncontrolled pelvic cancer.

Aged↗
PubMed1987

Hemodynamic effects of different preparations of stroma free hemolysates in the isolated perfused rat kidney.

We have examined the effects of Stroma Free Hemolysate (SFH) solutions in the isolated perfused rat kidney. Three types of SFH, stored for 6 to 8 months at 4 degrees C, were tested: 1) unmodified, 2) glyoxalated and lightly cross linked and 3) pyridoxalated and polymerized. All three SFH solutions, added to the perfusate at a concentration of approximately 420 mg/100ml, increased renal vascular resistance (RVR) and reduced glomerular filtration rate (GFR). Unmodified, glyoxalated and lightly cross linked and pyridoxalated polymerized SFH resulted in a rise in RVR of 55%, 38% and 33% respectively and a fall in GFR of 42%, 57% and 83% respectively. In order to determine whether storage had altered the effect of SFH on renal function, one of the forms of SFH (glyoxalated and lightly cross linked) was studied only 4-6 weeks after preparation. While this preparation caused an increase in RVR of 41% it did not alter GFR; filtration fraction (FF) rose. However, after further storage of this preparation for 6-7 months, the solution resulted in a marked decrease in GFR of 47% as well as a rise in RVR of 23%. We conclude that three different SFH preparations resulted in marked vasoconstriction and reductions in GFR. These deleterious effects on renal hemodynamics were noted at a concentration of hemoglobin well below that necessary to effectively improve oxygen content. Storage of the SFH solutions may cause or contribute to their effects on renal function. SFH solutions intended for use as blood substitutes should be tested for vasoconstrictor activity.

Animals↗
PubMed1989

The isolated perfused porcine skin flap. III. Percutaneous absorption pharmacokinetics of organophosphates, steroids, benzoic acid, and caffeine.

The isolated perfused porcine skin flap (IPPSF) has been developed as an alternative in vitro tool for examining the pharmacokinetics and mechanisms of percutaneous absorption. In this study, dosing solutions of seven 14C-radiolabeled compounds representing three chemical classes--organic acid/base [benzoic acid (B), caffeine (C)], organophosphate (OP) pesticides (diisopropylfluorophosphidate, malathion, parathion), and steroid hormones (progesterone, testosterone)--were prepared in ethanol and applied topically at a surface concentration of 40 micrograms cm-2 to the IPPSF. A three-compartment pharmacokinetic model used to stimulate mass transfer from the surface (C1), diffusion through epidermis and dermis (C2), and transfer into the capillary perfusate (C3), was developed based on flux through the IPPSF from 0 to 8 hr. This basic model accurately stimulated measured IPPSF fluxes for five of seven compounds, including the OPs and steroids. The model was modified to simulate the shunting of drug to fast and slow release pathways, which occurred for B 3-4 hr postapplication, and to account for flow-dependent flux increases seen for C at 6 hr postapplication. The latter may be due to a direct pharmacologic effect, since C is a known vasodilator. Extrapolated (to 6 days) areas under the curve from the model simulations were compared with in vivo percutaneous absorption estimates, obtained from 6-day excretion studies in pigs. The in vivo-in vitro correlation, based on simple linear regression across compounds, was excellent (R2 = 0.88, R = 0.94, p less than 0.002). These results suggest that xenobiotic penetration in the 8-hr IPPSF experiments is highly predictive of in vivo absorption totals (6-day studies). In addition, since pig and human skin are similar physiologically and pharmacologically, the IPPSF may eventually have applications in formulating human dermal risk assessment models.

Animals↗
PubMed1983

A possible mechanism of vasoactive agents on plasminogen activator release in isolated perfused pig ears.

The mechanism of vasoactive agents on plasminogen activator (PA) release was studied in isolated perfused pig ears. In the perfusion with atropine (3 microM)-containing Tyrode's solution, the enhancement of PA release caused by acetylcholine (1.0 micrograms) was completely inhibited; however, increases caused by other potentiators, namely, bradykinin (1.0 micrograms), histamine (1.0 micrograms), dilazep (30 micrograms), and thrombin (6 U) were not affected. In the case of mepyramine (10 microM), the increase of PA release caused by histamine (1.0 micrograms) was completely inhibited; and that caused by dilazep (30 micrograms) was partially inhibited, however, increases caused by acetylcholine, bradykinin, and thrombin were not influenced. Papaverine (30 microM) which could completely abolish the hypertensive effect of norepinephrine (1.0 micrograms) exerted a partial inhibition of the enhancement of PA release caused by dilazep; however, it did not affect those caused by other agents. Quinacrine (50 microM) and indomethacin (100 microM) did not have any effects on the enhancements of PA release caused by the five potentiators.

Acetylcholine↗
PubMed1982

Cardiac effects of prostaglandins during global ischemia in isolated perfused cat hearts.

Prostaglandin E1,PGD2, and 16,16 dimethyl prostaglandin E2 were studied in an isolated perfused cat heart preparation during normal conditions and in myocardial ischemia. Under ischemic perfusion, prostaglandin E1 showed some protective action on the release of creatine kinase into perfusate during ischemia, but none of the prostaglandins studied prevented increases in perfusate creatine kinase after reperfusion. Prostaglandin E1 also showed significant membrane stabilizing activity reducing the rate of lysosomal hydrolase release from cat liver lysosomes. Prostaglandin E1 may be beneficial in myocardial ischemia due to its membrane stabilizing action and perhaps to other effects but it did not exert significant protective effects on reperfusion injury of the ischemic myocardium under conditions of these experiments.

16,16-Dimethylprostaglandin E2↗
PubMed1983

Urea metabolism in isolated perfused lungs of the laboratory rat and of a desert rodent, Notomys alexis.

1. Using the isolated perfused lung preparation we have demonstrated a low-activity ureolytic enzyme present in rodent lung tissue. The enzyme shares four characteristic features with jack bean urease (EC 3.5.1.5). 2. Ureolytic activity was inhibited by fluoride ions and methionine hydroxamic acid; using the latter inhibitor, the I50 value and maximum inhibition were similar to those reported for jack bean urease. The apparent Km for rat lung urease was similar to the plasma urea level. 3. The low level of urease activity in the rat lung and in that of Notomys alexis, a desert rodent, suggests that the enzyme is not involved in urea excretion, rather that pulmonary ammonia production may influence fluid balance at the alveolus.

Animals↗
PubMed1979

Regulation of carbohydrate metabolism in mouse liver. Effect of glucagon on gluconeogenic/glycolytic flux in isolated perfused livers.

1. Glucagon stimulated gluconeogenesis from both [U-14C]lactate and [14C]xylitol in isolated perfused mouse liver. 2. Addition of cyclic AMP also stimulated gluconeogenesis from [U-14C]lactate. 3. Glucagon caused a rapid (2.5 min) 12-fold increase in hepatic cyclic AMP but not cyclic GMP concentration. 4. Glucagon caused a rapid and stable decrease in hepatic fructose 1,6-diphosphatase activity measured in vitro. 5. The results are interpreted to indicate that glucagon stimulates hepatic gluconeogenesis in mice via cyclic AMP by two different mechanisms: (a) increased substrate uptake (i.e. utilization) and (b) increased gluconeogenic efficiency (i.e. inhibition of alternate substrate fates).

Animals↗
PubMedDate not supplied

Effect of fasting, induction, sex and age on clearance of benz(a)anthracene and chrysene by isolated perfused rat liver.

Hepatic clearances of benz(a)anthracene (B(a)A) and chrysene (Ch) by isolated perfused liver of female rats were similar when measured with hydrocarbons singly (B(a)A 4.3 ml/min, Ch 5.1 ml/min) or in a mixture (4.7 resp. 5.3 ml/min). Clearance of both isomers by livers from 24 h fasted donors was approximately halved. In vivo pretreatment with B(a)A (22.8 mg per kg for 2 days) significantly increased elimination of both hydrocarbons. Hepatic clearance of B(a)A was significantly higher in male rats than in females of the same age (8 weeks). Elimination of both hydrocarbons was significantly lower in 2 year-old males.

Aging↗
PubMed1997

Central hemodynamic effects of oxytocin and interaction with magnesium and pregnancy in the isolated perfused rat heart.

OBJECTIVE: Our purpose was to determine the cardiac effects of oxytocin in the isolated perfused rat heart model and to see whether pregnancy or pharmacologic levels of magnesium modifies the hormone's action. STUDY DESIGN: Hearts were excised from 30 female Sprague-Dawley rats (15 pregnant, 15 nonpregnant) and attached to a Langendorf's apparatus. Heart rate, left ventricular systolic pressure, and contractility were measured. Hearts were exposed serially to 2, 4, and 6 mU/ml concentrations of oxytocin. The experiment was repeated in 15 pregnant animals at a magnesium level of 5 mEq/L. RESULTS: Hearts from pregnant rats had lower heart rates than did hearts from nonpregnant animals. Oxytocin exposure diminished heart rate but increased left ventricular systolic pressure and contractility in a dose-dependent manner. Pregnancy did not alter this response. Magnesium levels of 5 mEq/L reversed the effects of oxytocin on contractility and left ventricular systolic pressure. CONCLUSION: Oxytocin is a negative chronotropic and positive inotropic agent in hearts from pregnant and nonpregnant rats. Magnesium reserves the positive inotropic effects of oxytocin.

Animals↗
PubMed1986

Role of cellular energy state and adenosine in the regulation of coronary flow during variation in contraction frequency in an isolated perfused heart.

Regulation of coronary flow as a function of myocardial energy expenditure was investigated in isolated perfused rat hearts electrically paced at the desired frequencies. The sinoatrial node was excised to lower the endogenous heart rate. The main covariants measured were phosphagen, inorganic phosphate, adenosine, inosine and hypoxanthine concentrations in the tissue, washout of nucleosides and hypoxanthine into the perfusate, oxygen consumption and coronary flow. Oxygen consumption was linearly correlated with heart rate and coronary flow, while the correlation between coronary flow and perfusate adenosine was nonlinear. The adenosine concentrations in the tissue and perfusate showed a mirror image curvilinearity reminiscent of a threshold pattern for adenosine washout. The tissue adenosine content had a negative linear correlation with the adenylate phosphorylation potential (long(ATP/ADP X Pi)). Adenosine output was linearly correlated with free AMP concentration in the tissue, the latter being calculated from the equilibrium of the adenylate kinase reaction. The results confirm the correlation between cellular energy state and coronary flow and support the notion that the mediators between the former and the vascular smooth muscle involve the concentration of free AMP in the tissue, suggesting that the formation of adenosine may be limited by the availability of AMP. The results are in agreement with the hypothesis that adenosine is the diffusible extracellular mediator in the energy-linked regulation of coronary flow.

Adenosine↗
PubMed1987

Interstitial fluid of isolated perfused rat hearts: glucose and lactate concentration.

Interstitial fluid (IF) emerging at the ventricular surface of isolated perfused rat hearts was collected and assayed for rate of production, protein content, glucose and lactate concentration. The influence of four perfusion media was investigated during an experimental period of 150 min: Krebs-Henseleit solution (KH) containing glucose (5.5 mM); KH containing glucose and pyruvate (2 mM); Hypoxic KH (20% O2), substrates as 2; KH containing isoprenaline (8 X 10(-9) M), substrates as 2. Interstitial fluid was produced at a rate of 20 to 100 microliters/min/gww and contained proteins (0.5 to 3 g/l). Interstitial glucose concentration was lower than venous concentration by up to 50%. Interstitial lactate concentration was higher by up to 600%. Permeability X surface area products of glucose calculated from transcapillary concentration differences and transfer rates were different depending on experimental conditions, but were within the rather large range of P X S values for molecules of similar size obtained by other authors. Those of lactate were higher by a factor of 3 to 9 and can be interpreted to be influenced by the metabolic activity of the endothelium. The results demonstrate that interstitial substrate concentration can differ very markedly from intravascular concentration and cannot be estimated reliably without assay of the interstitial fluid. Capillary permeability seems to be variable under the experimental conditions of this study.

Animals↗