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PubMed1992

Oxygen radical scavengers protect against eosinophil-induced injury in isolated perfused rat lungs.

The protective effect of oxygen radical scavengers on lung injury induced by activated eosinophils was examined in isolated perfused rat lungs. Eosinophils were obtained by bronchoalveolar lavage from rats infected with Toxocara canis and activated with phorbol myristate acetate (PMA). There were no changes in pulmonary vascular (RT) and airway (Raw) resistances and only minimal changes in vascular permeability assessed using the capillary filtration coefficient (Kf,c) in PMA control lungs and nonactivated eosinophil-treated lungs. In lungs receiving 3 x 10(6) PMA-activated eosinophils, there were significant increases from baseline of 7.3-fold in RT at 30 min, primarily due to the constriction of small arteries and veins; 3.6-fold in Kf,c at 90 and 130 min; and 2.5-fold in Raw. The lungs also became markedly edematous. Both superoxide dismutase and catalase pretreatment prevented the significant increase in Kf,c and lung wet-to-dry weight ratios and partially attenuated the increase in Raw, but did not significantly inhibit the increase in RT induced by activated eosinophils. Heat-inactivated catalase did not attenuate the eosinophil-induced increases in Kf,c, Raw, or RT. Thus, activated eosinophils acutely increased microvascular permeability primarily through production of oxygen free radicals. The free radical scavengers superoxide dismutase and catalase partially attenuated the bronchoconstriction but had no significant effect on the vasoconstriction induced by activated eosinophils.

Animals↗
PubMed1997

Saturable accumulation and diuretic activity of hydrochlorothiazide in the isolated perfused rat kidney.

The role of tubular accumulation in renal disposition and diuretic efficacy of hydrochlorothiazide was studied in the isolated perfused rat kidney. Hydrochlorothiazide resulted in a dose-dependent increase in the fractional excretion of sodium, chloride and potassium, and in urinary flow and pH. Renal clearance of the drug was low as a result of a low extraction ratio and extensive nonionic back-diffusion. Hydrochlorothiazide was subject to saturable tubular secretion, following Michaelis-Menten kinetics. Parameters obtained after nonlinear regression analysis were a maximum tubular transport velocity of 42 +/- 6 micrograms/min, a Michaelis-Menten constant of secretion of 38 +/- 11 micrograms/ml and a fraction of excreted drug reabsorbed passively of 0.49 +/- 0.03. The thiazide diuretic accumulated extensively in kidney tissue due to active cellular uptake (maximum capacity of renal accumulation of 500 +/- 270 micrograms/g; affinity constant of renal accumulation of 28 +/- 16 micrograms/ml) and passive diffusion. Plots were constructed of the sodium excretion rate versus hydrochlorothiazide perfusate concentration or the renal excretion rate. The perfusate plot could be described by the sigmoid Emax model, while a simplification of the model had to be used for the response curve in urine because a maximum effect was not observed. The apparent maximum effect resulting from the perfusate concentration-response curve and the discrepancy with the renal excretion rate-response curve indicates that the diuretic effect of hydrochlorothiazide is restricted by saturable accumulation and secretion.

Animals↗
PubMed1977

Degradation of parathyroid hormone and fragment production by the isolated perfused dog kidney. The effect of glomerular filtration rate and perfusate CA++ concentrations.

The renal degradation of intact bovine parathyroid hormone (b-PTH 1-84) was studied with the isolated perfused dog kidney. Disappearance of b-PTH 1-84 from the perfusate occurred concomitantly with the appearance of smaller molecular weight forms of immunoreactive parathyroid hormone (PTH). These smaller molecular weight PTH fragments included both carboxyl and amino terminal regions of the PTH peptide. Perfusate from kidneys with lower glomerular filtration rates (GFR) contained b-PTH 1-84 for longer periods of time than kidneys with higher GFRs, and perfusate from kidneys with lower GFRs demonstrated greater accumulation of carboxyl terminal PTH fragments. Perfusate containing high Ca++ concentrations retarded, and perfusate with low Ca++ concentrations accelerated the rate of degradation of b-PTH 1-84 by the kidney. These studies, therefore document the production of PTH fragments during the course of intact hormone degradation by the kidney. They also demonstrate renal clearance of the PTH fragments produced and define the effects of glomerular filtration rate and calcium concentrations on degradation of intact hormone and the clearance of PTH fragments.

Animals↗
PubMed1984

Albumin absorption and catabolism by isolated perfused proximal convoluted tubules of the rabbit.

Overall characteristics and kinetics of tubular absorption of albumin (Alb) were studied in isolated perfused proximal convoluted tubules of the rabbit. The fate of absorbed Alb was determined in tubules perfused with low [Alb]. Alb was labeled with tritium by reductive methylation ( [3H3C]Alb). At [Alb] = 0.03 mg/ml, approximately 80% of the absorbed [3H3C]Alb was released to the peritubular bathing solution as catabolic products. Transcellular transport of intact [3H3C]Alb was negligible. Iodoacetate (IAA, 4 mM) inhibited albumin absorption (JAlb) by greater than 95% and fluid reabsorption (JV) by 55%. At [Alb] = 0.1 mg/ml the absorption rate of a derivatized cationic Alb (pI = 8.4) was fivefold greater (P less than 0.01) than that of anionic Alb. Higher cationic [Alb] had deleterious effects on tubular functions. Overall Alb absorption was of high capacity and low affinity (JmaxAlb = 3.7 ng/min per mm tubule length, apparent Michaelis constant (Km) = 1.2 mg/ml). A low capacity system that saturates at near physiological loads was also detected (JmaxAlb = 0.064 ng/min per mm, apparent Km = 0.031 mg/ml). High [Alb] did not alter the rate of endocytic vesicle formation as determined by the tubular uptake of [14C]inulin. Results show that Alb absorption is a saturable process that is inhibited by high IAA concentrations and is affected by the charge of the protein. Absorbed Alb is hydrolyzed by tubular cells and catabolic products are readily released to the peritubular side. The dual kinetics of Alb absorption may be due to a combination of adsorptive endocytosis (low capacity system) and fluid endocytosis of albumin aggregates (high capacity system). Results indicate that albuminuria occurs much before albumin absorption is saturated. The kinetic characteristics of the process of tubular absorption of albumin helps to explain the concomitance of albuminuria, increased renal catabolic rates of albumin, and renal cell deposition of protein absorption droplets in severe glomerular proteinurias.

Absorption↗
PubMed1991

Effects of human superoxide dismutase on ischemic and reperfused myocardium in isolated perfused rat heart.

The effect of human superoxide dismutase (h-SOD) on the ischemic heart was studied in the isolated perfused working rat heart. Myocardial mechanical function expressed as pressure-rate product decreased and completely stopped within 5 min after the onset of global ischemia, and never recovered after reperfusion following 20 min of ischemia. In the ischemic myocardium, the levels of ATP, ADP, and creatine phosphate decreased, and those of AMP and lactate increased. Reperfusion of the ischemic heart did not restore the level of ATP completely. When the heart was treated with h-SOD, the perfusion medium was switched from the buffer containing no h-SOD to that containing h-SOD at either 100, 300 or 1,000 units/ml 5 min before the onset of ischemia. The pressure-rate products of the heart treated with 100, 300, and 1,000 units/ml of h-SOD were restored by reperfusion to 22%, 59%, and 51% of the preischemic level, respectively. The levels of ATP and creatine phosphate in the reperfused heart with 300 and 1,000 units/ml of h-SOD were significantly higher than those without h-SOD. However, a dose-response relationship was not observed when h-SOD was used in concentrations greater than 300 units/ml. These results indicate that a certain amount of h-SOD has some beneficial effects on the ischemic myocardium.

Adenine Nucleotides↗
PubMed1987

Prostaglandin responses in isolated perfused rat liver: Ca2+ and K+ fluxes, hemodynamic and metabolic effects.

Addition of prostaglandin F2 alpha and prostaglandin E2 to isolated perfused rat liver led to a dose-dependent, transient net Ca2+ release, which was completed within 3 min. Withdrawal of the prostaglandins resulted in a Ca2+ re-uptake over a period of about 10 min. Simultaneously, these prostaglandins induced an increase of portal pressure, stimulated hepatic glucose output and 14CO2 production from [1-14C]glutamate and led to K+ movements across the hepatocyte plasma membrane similar to those observed with other Ca2+-mobilizing agents. With prostaglandin F2 alpha there was a close correlation between the net Ca2+ release and the maximal rate of initial net K+ uptake by the liver (linear regression coefficient r = 0.902; n = 20). Prostaglandin F2 alpha was more effective than prostaglandin E2 or D2. Because prostaglandins are known to be produced by hepatic non-parenchymal cells during stimulation by phagocytosis or by addition of extracellular ATP or UTP, these data suggest an interaction between non-parenchymal and parenchymal liver cells and point to a modulating role of prostaglandins in hepatic metabolism and microcirculation, which is mediated by Ca2+-mobilizing mechanisms.

Animals↗
PubMed2000

Effects of adrenomedullin on the cardiac performance and coronary flow in an isolated perfused rat heart model.

The effect of adrenomedullin (AM) on the cardiac performance and coronary flow were studied in an isolated perfused rat heart model based on the modified Langendorff method. The heart rate (HR), electrocardiogram (ECG), left ventricular contraction (LVC) (dP/dt), and coronary flow (CF) were measured before and after the application of AM. The effect of AM on the coronary flow was examined in the model with and without endothelial degradation, using different inhibitors such as N(G)-nitro-L-arginine, glibenclamide, and indomethacin. The present results indicated that AM increased HR and CF, but decreased LVC significantly, while it had no effect on ECG. The vasodilatory effect of AM was discussed in views of endothelial-dependence due to nitric oxide and K+ channel activation.

Adrenomedullin↗
PubMedDate not supplied

Uptake and disposition of aldrin and dieldrin by isolated perfused rabbit lung.

The uptake, metabolism, and release of aldrin and dieldrin by the lungs were studied by use of isolated perfused rabbit lungs that were artificially ventilated and perfused through the pulmonary artery. Both recirculating and single-pass experiments were conducted using an artificial medium as perfusate. Aldrin accumulated in the lung from the perfusate through two distinct phases of uptake: a rapid phase involving simple diffusion and nonspecific binding and a slower phase representing its metabolic turnover as dieldrin. Dieldrin was not metabolized but accumulated in the lungs by a saturable and a nonsaturable process. Single-pass experiments with aldrin indicated that the initial velocity of uptake could be fitted to one component and a constant representing the rate of metabolism. Uptake of dieldrin was biphasic: one phase independent of the perfusate concentration and the other saturable with respect to the perfusate concentration. By the application of Michaelis-Menten kinetics, the maximum amount of dieldrin accumulation attributable to the saturable component was calculated to be 0.64 mumol/lung. Our results indicate that the accumulation of these chlorinated xenobiotics takes place through the processes of simple diffusion followed by nonspecific tissue binding. There was no evidence for irreversible binding of aldrin or dieldrin, its epoxide, in the lung. While the lung plays a role in metabolizing aldrin to dieldrin followed by a transient storage, neither substrate has the potential for long-term storage in the lung.

Aldrin↗
PubMed1975

An inhibitor of hepatoma cells multiplication in the efferent fluid from isolated perfused rat liver.

Efferent fluid from isolated rat livers perfused with a synthetic medium, when concentrated, inhibits the multiplication of hepatoma LF 20 cells "in vitro". The inhibitory factor is thermolabile, and is inactivated at a slow rate by proteolytic enzymes. Sephadex and Acrylamide-agarose chromatographic fractionation leads us to assume a molecular weight around 100,000 for the inhibitory factor. The release of the factor by the perfused liver depends on the temperature of the perfusing fluid. Potential role of this factor in the control of liver cell proliferation is discussed.

Animals↗
PubMed1990

Transport of the organic cation N1-methylnicotinamide by the rabbit proximal tubule. II. Reabsorption and secretion in the isolated perfused tubule.

The mechanisms involved in the transport of the organic cation N1-methylnicotinamide (NMN) were investigated in the isolated perfused rabbit S2 proximal tubule. NMN underwent a small reabsorptive transport which appeared to be passive. NMN secretory transport was saturable, inhibited by mepiperphenidol (10(-4) M) and presented a relatively low apparent affinity (apparent Km of 852 microM) for the organic cation transport system, with transport against a concentration gradient being observed only at low flow rates. Acidification of the perfusate, by either buffering it at pH 6.8 with MES, or by bubbling the bath with a mixture of 80% O2-20% CO2, resulted in a decrease, rather than an increase, of NMN secretion. Carbonic anhydrase inhibition with ethoxyzolamide (10(-4) M in the bath) did not modify NMN secretion. Addition of 20 to 40 microM NMN in the perfusate also did not change NMN secretion. Proton or organic cation counterexchange seemed therefore not to play a major role in NMN apical step of secretion, the basolateral step appearing to be the general organic cation system of transport for which NMN shows a low affinity.

Absorption↗
PubMedDate not supplied

Comparative study of direct coronary vascular responses to diltiazem, adrenergic beta-blockers and other vasodilators in isolated, perfused dog and monkey coronary arteries.

The cannula-inserting method was used to examine the vascular responses of the isolated, perfused dog and monkey coronary arteries to a calcium antagonist (diltiazem), adrenergic beta-blockers (propranolol and pindolol), an antianginal drug (nicorandil) and vasodilators (hydralazine and papaverine). Propranolol and pindolol constricted the dog and monkey coronary arteries dose-dependently. Without any precontraction, hydralazine produced a biphasic response--a vasodilatation followed by a vasoconstriction--in the dog coronary artery, although it produced only a vasodilatation in the monkey coronary artery. Nicorandil and diltiazem dilated the uncontracted dog and monkey coronary arteries dose-dependently. The rank order of drug potency for inducing vasodilatation was diltiazem greater than nicorandil greater than hydralazine in both coronary arteries. These results indicate that the cannula-inserting method is useful to investigate the responses of the large epicardial dog and monkey coronary arteries to vasodilating drugs.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Normothermic isolation perfusion with melphalan for advanced melanoma of the limbs.

Eighteen patients with advanced melanoma of the limbs underwent a single isolation perfusion with melphalan under normothermic conditions, i.e. tissue temperatures between 37.0 and 38.0 degrees C. There were no major complications. In 7 patients complete remission was achieved and in 8 the remission was partial, i.e. tumor reduction greater than 50%. No obvious response was seen in the remaining 3 patients. At the time of analysis 4 patients were still in complete remission, 56, 55, 19 and 8 months after perfusion, respectively. One patient died from distant spread, 17 months after perfusion, but without exhibiting new tumor growth in the perfused area. In 2 patients local control was transient with locally recurrent disease 28 and 10 months after perfusion, respectively. In patients with partial remission the duration of remission could not be determined because of supplementary treatment or death. Our results seem to be comparable to those obtained by so-called mild hyperthermic perfusions.

Chemotherapy, Cancer, Regional Perfusion↗
PubMed1987

Dose and flow dependence of 5-fluorouracil elimination by the isolated perfused rat liver.

The influences of dose and hepatic blood flow on the elimination of 5-fluorouracil (FUra) by the isolated perfused rat liver were investigated. FUra was injected into the perfusion reservoir and then serial blood samples were collected over 2-3 h. FUra concentration was determined chromatographically. In some experiments, the conversion of [2-14C]FUra to 14CO2 was also determined. With livers perfused at 20 ml/min, the initial decrease in plasma FUra concentration was linear with time (apparent zero-order kinetics); at concentrations below about 25 microM, the decrease became exponential (apparent first-order kinetics). Semilogarithmic plots of FUra concentration/dose versus time obtained with different doses were not superposable, consistent with saturable (Michaelis-Menten) elimination. Vmax and Km were 6-11 nmol/ml/min and 33-45 microM, respectively. Hepatic clearance during first-order elimination was close to 20 ml/min. About 84% of the dose was converted to CO2, indicating that catabolic metabolism was the principal route of elimination. As hepatic blood flow increased from 10 to 30 ml/min, Vmax was unchanged but Km decreased progressively from 84 to 32 microM, and clearance increased from 12 to 29 ml/min. It was concluded that hepatic FUra elimination is highly dependent upon both dose and blood flow.

Animals↗
PubMed1984

Regional isolated perfusion of high risk melanoma of the extremities with imidazole carboxamide.

Twenty-four patients have been treated by regional isolated perfusion with decarbazine for melanoma of an extremity, with a follow-up period of seven to 72 months. None of these patients had any signs or symptoms of toxicity from the drug. The serum glutamic-oxalacetic transaminase level was elevated by the first postoperative day and returned to normal within the next six days. Fourteen of these 24 patients are free of disease for a follow-up period of 23 to 70 months. Three of the seven patients treated for local or intransit metastases are free of disease for five, 60 and 61 months; a fourth patient had subcutaneous metastases of the trunk develop while remaining disease-free in the perfused extremity for 72 months, and a fifth patient perfused for numerous intransit metastases of a leg had resolution of many of the nodules and remains without new lesions for nine months. Decarbazine is recommended as a safe and valuable drug for the perfusion of extremities with melanoma.

Arm↗
PubMed1994

Flow dependence of metoprolol elimination in isolated perfused rat liver.

The effect of blood flow rates on hepatic elimination of metoprolol (Met) was studied in a recirculating isolated perfused rat liver system with a constant infusion of Met into the reservoir. This design ensures that, at a steady state, the elimination rate of Met is a constant. The results showed that at flow rates of 10, 20, and 30 ml.min-1, the concentrations of Met entering the liver (Cin) were 7.6, 5.0, and 3.4 micrograms.ml-1 and the concentrations leaving the liver (Cout) were 1.2, 2.0, and 2.7 micrograms.ml-1, while the logarithmic average concentrations in hepatocytes (C) were 3.4, 3.2, and 3.0 micrograms.ml-1, respectively. It is concluded that the hepatic elimination of Met is flow-dependent, which is in accordance with the 'parallel tube' model.

Animals↗
PubMed1996

[Effects of substance P and neurokinin A on pulmonary circulation in the isolated perfused guinea pig lung].

We studied the effect of sensory nerve peptide substance P (SP) and neurokinin A (NKA) in isolated perfused guinea pig lungs. SP and NKA increased pulmonary arterial pressure, capillary pressure, pulmonary venous resistance, and lung weight, but they did not change pulmonary arterial resistance or pulmonary vascular permeability. The effects of SP on pulmonary vascular dynamics were greater than those of NKA. Ozagrel hydrochloride, a thromboxane synthase inhibitor, partially attenuated the effect of SP. This indicates that thromboxane contributes to SP-induced pulmonary vasoreactivity. However, ozagrel hydrochloride did not change the effects of NKA. FK224, an NK-1/NK-2 receptor antagonist, abolished both SP- and NKA-induced pulmonary vasoconstriction. This indicates that SP and NKA acted on the pulmonary vasculature through the NK-1 or NK-2 receptor, or both. Papaverine, a smooth muscle relaxant, abolished the effects of SP. The SP-induced increase in lung weight was caused by a rise in pulmonary hydrostatic pressure, especially that caused by pulmonary venoconstriction.

Animals↗
PubMed1997

[The effects of vasoconstrictors on distribution of ischemic tissue flow in isolated perfused rat liver].

We studied the effects of ATP and epinephrine on distribution of ischemic hepatic tissue flow in the isolated perfused rat liver. Five minutes after clamping both the portal vein and hepatic artery, perfusion was started. Lidocaine was infused into the portal vein, and the concentration of lidocaine in hepatic outflow was measured with FPIA. The oxygen extraction ratio was also measured. Tissue surface blood flow was measured with laser-Doppler flowmetry. We measured the tissue flow at 2 points: one where flow was more than 10 ml.min-1.100 gm liver weight-1 (R), and the other where flow was less than 10 ml.min-1.100 gm liver weight-1 (P). After perfusion pressure had become stable, ATP or epinephrine was infused for 15 minutes. Perfusion pressure increased, and tissue flow of R decreased significantly, while that of P increased (not significantly). The extraction ratio of lidocaine decreased significantly by epinephrine, and that of oxygen decreased (not significantly). We conclude that in the ischemic liver, vasoconstriction results in changes in the distribution of tissue blood flow and alters drug metabolism.

Adenosine Triphosphate↗
PubMed1987

Alpha-human atrial natriuretic peptide (alpha-hANP) prevents pulmonary edema induced by arachidonic acid treatment in isolated perfused lung from guinea pig.

Protective effect of alpha-human atrial natriuretic peptide (alpha-hANP) on pulmonary edema was investigated using an isolated perfused lung model. Infusion of alpha-hANP (1.7 to 22 ng/ml or 0.56 to 7.3 nM) prevented the edema induced in isolated lung from guinea pig by repeated treatment of 50 micrograms of arachidonic acid at 30 min intervals via the pulmonary artery. The antiedematic action of alpha-hANP was considered to be receptor mediated because the effective concentration was close to the Kd value of the binding of the ANP receptors in the lung homogenate.

Animals↗