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PubMed1986

Lysophosphatidylcholine increases airway and capillary permeability in the isolated perfused rat lung.

The effects of lysophosphatidylcholine (lysoPC) on airway and capillary permeability in the isolated perfused rat lung were investigated. We determined the influence of lysoPC on the passage of different-sized (326-722 dalton) polyethylene glycols (PEGs), both from the airways to the pulmonary circulation and from the pulmonary circulation into the lung. We found that 1 mM lysoPC increased the overall passage of PEGs from the airways to the pulmonary circulation, and that 80 microM lysoPC increased the overall passage from the circulation into the lung. In both cases, the passage of the larger (502-722 dalton) PEGs increased more than the passage of the smaller (326-458 dalton) PEGs. We also found that the presence of lysoPC in the circulation increased the pulmonary arterial pressure, whereas deposition of lysoPC in the trachea did not. The pressure increase was blocked by indomethacine, BW755C, and quinacrine, inhibitors of arachidonic acid metabolism. These findings suggest that higher concentrations of lysoPC increase the airway permeability to larger molecules, and that lower concentrations of lysoPC increase the capillary permeability. The increase in capillary permeability may be due to a rise in capillary pressure mediated by arachidonic acid metabolites. The possibility that formation and accumulation of lysoPC is of importance for mediating inflammatory reactions in the lung is inferred.

Animals↗

PubMedDate not supplied

Characteristics of thiamin transport in the isolated perfused guinea pig heart.

The cellular uptake of (14C)-thiamin hydrochloride was studied in the isolated perfused guinea pig heart, using the rapid single circulation, paired-tracer technique, in which D-(3H)-mannitol serves as an extracellular marker. Cellular uptake of this vitamin was estimated by directly comparing venous dilution profiles of (14C) and (3H) radioactivities in the absence and presence of unlabelled thiamin hydrochloride and pyrithiamin hydrobromide. The maximal cellular uptake (Umax) of thiamin was very low (5.31 +/- 1.79%), while in the presence of 10 mM unlabelled thiamin and 1 mM pyrithiamin, Umax was significantly greater (9.71 +/- 1.57% and 12.30 +/- 0.82%, respectively). Our data suggest that there is a saturable mechanism of sarcolemmal thiamin transport out of myocardial cell, while this transport into the cell is unsaturable.

Animals↗

PubMed1991

Possible thromboxane A2 mediated effect of angiotensin II in the rabbit isolated perfused kidney.

Angiotensin II (A II) when given through the renal artery of the rabbit isolated perfused kidney elicited a concentration-dependent increase in perfusion pressure (PP) and urine flow (UF). Noradrenaline (NA) produced similar effect in PP but slightly not significantly increased UF. Addition of UK 38,485, a thromboxane A2 (TXA2)-synthetase inhibitor, to the bathing medium at the concentration of 10(-7) M caused a significant decrease in the pressor effect of A II but significantly enhanced UF. BM 13,177, a TXA2-receptor blocker, in the bathing medium (10(-6) M) produced identical effect in both PP and UF. The responses to NA were not significantly altered by both compounds. A II-induced enhancement of UF in presence of BM 13,177 was significantly lower than that obtained in presence of UK 38,485. These results were taken as an evidence that A II may increase the production of TXA2 in kidney probably originated from vascular bed or tubuli and part of the pressor effect of the peptide is due to this metabolite of arachidonic acid. Enhancement of UF following UK 38,485 is probably due to the shift of the synthesis toward E series of PGs. In addition this effect seems to be specific for A II since no such effect was seen with NA.

Angiotensin II↗

PubMed1985

Furosemide choleresis in isolated perfused rat liver: partial dependency on perfusate sodium and chloride.

The effect of furosemide on hepatic bile formation was studied in isolated perfused rat liver to determine if 1) the observed cholestatic effect at lower dose of furosemide in vivo is a primary effect or a secondary effect due to decreased hepatic blood flow caused by the furosemide-induced volume contraction and if 2) the observed choleretic effect at higher doses can be explained by the osmotic effect of furosemide and its metabolites in bile. A single dose of furosemide (initial perfusate concentration 0.01, 0.1 or 1 mM) produced choleresis, whereas 0.001 mM furosemide did not affect bile flow significantly. Because furosemide failed to produce cholestasis at tested doses, the observed cholestasis in vivo at similar blood concentrations must be a secondary effect. Furosemide choleresis was associated with biliary secretion of furosemide and its metabolites. However, the choleretic effect expressed as microliters per micromole of drug secreted declined with increasing dose and biliary secretion. Furosemide choleresis was also associated with an increase in the net biliary secretion of Na+ and Cl-. The effect of Na+ and Cl- replacement on furosemide choleresis was studied to determine if the choleresis was a result of direct effect of furosemide on hepatic electrolyte transport. Replacement of perfusate Na+ completely by Li+ or partially by choline+ resulted in a 30 to 50% reduction in choleretic effect and furosemide-induced biliary Cl- secretion. A similar decline in choleretic effect and net furosemide-induced biliary Na+ secretion was also observed when perfusate Cl- was replaced by nitrate, acetate or isethionate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1977

Interaction of phenoxybenzamine with angiotensin II in the isolated perfused rabbit kidney. Short communication.

Interaction of phenoxybenzamine with angiotensin II was studied in the isolated perfused rabbit kidney. Angiotensin II induced a dose-dependent increase in perfusion pressure and urine flow when given through the renal artery. Phenoxybenzamine when added to the perfusion medium caused a decrease in perfusion pressure but an increase in urine flow. Further addition of acetyl salicylic acid to the perfusion medium significantly reversed both agonistic effects of angiotensin II. The possible mechanisms of these findings are discussed.

Angiotensin II↗

PubMedDate not supplied

Glucagon induced functional changes of isolated perfused rat kidney.

The influence of glucagon on renal function and hemodynamics was studied on isolated perfused rat kidneys. During perfusion with solutions containing no vasoactive substances glucagon increased total renal perfusion flow, while the GFR remained unchanged. The autoregulation of blood flow under these conditions was completely abolished. Na-excretion was slightly reduced under the action of glucagon, due to an increased fractional Na-reabsorption. However, increased fractional Na-reabsorption was not due to a direct influence of glucagon on tubular transport mechanism as comparison of TNa at identical Na-loads demonstrated. In presence of angiotensin II renal perfusion flow was markedly reduced and doubled almost after starting glucagon infusion. GFR under these conditions rose by about 100%. It is concluded from the results that changes of kidney function following glucagon infusion are mainly due to a reduced vascular resistance.

Animals↗

PubMed1977

Characterization of methylumbilliferone (mendiaxon r)-induced choleresis in the isolated perfused rat liver.

The influence of the choleretic drug methylumbilliferone on bile formation in the isolated perfused rat liver is characterized. The compound induces rapidly an elevation of bile flow, bile acid secretion and soium excretion. The increased production of bile is of canalicular origin. The choleretic effect was defined as "bile acid like" choleresis due to excretion of the drug into the bile. It is discussed that the excretion of methylumbilliferone can influence the transport of bile in form of a positive cooperation on transport mechanism.

Animals↗

PubMed1976

Substrate metabolism in the isolated perfused dog kidney.

The relationships between substrate utilization and renal work were investigated in an isolated, perfused dog kidney preparation: substrate utilization included free-fatty acid (FFA), glucose, and oxygen, whereas work was assessed by measuring TNa+. The magnitude of TNa+ was varied by altering glomerular filtration rate as a consequence of changing renal blood flow. As the rate of renal blood flow was reduced, both Qo2, and QFFA decreased while Qglucose increased. The reduction in QFFA and Qo2 paralleled the decrease in TNa+. An inverse relationship was noted between QFFA and Qglucose in all experiments. The results suggest that FFA and perhaps glucose may serve as a significant substrate for providing energy for TNA+ in the kidney. Further, since QFFA and Qglucose are inversely related to each other, glucose may substitute for FFA as an energy source at times when QFFA is reduced.

Animals↗

PubMedDate not supplied

Hepatic extraction of renin: quantitation and characterization in the isolated perfused rat liver.

Since the liver is thought to be the major organ for the metabolism of renin, the rate-limiting enzyme in the renin-angiotensin cascade, we examined the kinetics and regulation of renin extraction by the isolated perfused rat liver. Partially purified, hog kidney renin was continuously infused into isolated rat livers perfused in a nonrecirculating manner with serum-free medium. Concentrations of renin in the portal and hepatic veins were measured by radioimmunoassay and first-pass hepatic extraction calculated. In livers from normal rats, steady-state, first-pass hepatic extraction of porcine renin ranged from 12.3 +/- 0.9 to 25.5 +/- 3.9% of the infused dose; at high renin infusion rates, hepatic extraction was saturable. Administration of captopril, a converting enzyme inhibitor, decreased hepatic extraction of renin by approximately 60%; enalaprilat, another converting enzyme inhibitor, had no effect. First-pass hepatic extraction of renin was also inhibited by the bile acid, taurocholate, in a dose-dependent manner. However, bilateral nephrectomy, which reduced endogenous plasma renin activity to unmeasurable levels, had no significant effect on hepatic extraction of renin by livers isolated from nephrectomized rats. These results demonstrate directly that the liver extracts renin in a dose-dependent and saturable manner, although the precise mechanism of uptake remains to be determined.

Animals↗

PubMed1994

Disposition of nifurtimox and metabolite activity against Trypanosoma cruzi using rat isolated perfused liver.

Nifurtimox disposition was investigated using the rat isolated perfused-liver method after administration of 25 micrograms mL-1 nifurtimox, and its disappearance was monitored by analysing the perfusate sample at various times. Biliary excretion was also measured. The drug concentration profile underwent a biexponential decline over the 2-h study period, with a terminal half-life of 62.76 +/- 17.56 min. Nifurtimox is a high clearance compound (15.23 +/- 5.53 mL min-1). The extraction ratio was 0.621 +/- 0.159. Biliary excretion accounted for 0.05% of the dose, the remainder consisting of highly polar metabolites. By 2 h, a minimal fraction of unchanged nifurtimox was recovered from the perfusate. Nifurtimox activity against Trypanosoma cruzi (clone CA-1) during the perfusion was also determined. Epimastigotes isolated from continuous culture were exposed to the samples of perfusate at different perfusion times in a microtitre plate. After an incubation time of 72 h at 27 degrees C, the parasite number in each well was counted under a microscope. From 0 to 75 min after the perfusion, the anti-trypanosomal activity decreased, but an increase in activity was observed at the later times. These findings show that active metabolites are formed during the perfusion.

Animals↗

PubMed1978

Morphological changes in isolated perfused dog lungs after acute hydrostatic edema.

Morphometric data from stable (nonedematous) isolated dog lungs, perfused with nearly cell-free perfusates, were compared to similar stereological evaluations of isolated dog lungs after induction of severe acute hydrostatic edema. In the edematous lungs, capillary surface and volume densities were substantially increased. Alveolar surface density was also increased. Thicknesses of the endothelial and type I epithelial cellular compartments of the air-blood barrier were unchanged. Thickness of the interstitial compartmemt of the air-blood barrier was substantially increased and this, in turn, caused an overall increase in mean thickness of the barrier. Volume densities of the nonparenchymal connective tissue spaces surrounding the extra-alveolar vessels and airways were also increased. In both the endothelial and type I epithelial cells cytoplasmic volume densities of pinocytotic vesicles were increased. In addition, the number of vesicles opening onto the luminal and albuminal cellular surfaces increased signficantly. Transendothelial vesicular passage may contribute to interstitial edema formation, and transepithelial vesicular transport may contribute to alveolar flooding in isolated perfused dog lungs.

Animals↗

PubMed1976

Production of cortisol from cortisone by the isolated, perfused fetal rabbit lung.

Perfusion of the isolated 26 day fetal rabbit lung with 3H-cortisone resulted in its conversion to 3H-cortisol and release into the perfusate. Little conversion of 14C-cortisol to 14C-cortisone occurred. Quantitative study of homogenized fetal rabbit lung revealed the development of both the cofactor and the enzyme for 11beta-hydroxy steroid dehydrogenase activity between 21 and 29 days gestation. These results suggest increasing production of cortisol from cortisone by the fetal rabbit lung as a function of gestational age. This conversion may be of significance with respect to both lung development and parturition, both events being accelerated by cortisol treatment.

Animals↗

PubMed1992

Metabolism of garlic constituents in the isolated perfused rat liver.

The metabolic and kinetic behaviour of different garlic (Allium sativum L., Alliaceae) constituents were investigated in the isolated perfused rat liver, using aqueous extracts of garlic powder as well as isolated allicin, the main product of the enzymatic degradation of alliin. Allicin (allyl thiosulfinate) showed a remarkable first pass effect and passed the liver unmetabolized only at high concentrations which caused considerable cell injuries. Diallyl disulfide and allyl mercaptan were identified as metabolites of allicin, whereby diallyl disulfide probably is the metabolic precursor of allyl mercaptan as shown by perfusion with diallyl disulfide alone. The metabolites diallyl disulfide and allyl mercaptan could be determined in the perfusion medium as well as in the bile and the liver tissue. Other degradation products of garlic were also investigated in this model. Ajoenes and vinyldithiins were detected in perfusion medium after liver passage but no metabolites of them could be identified up to now.

Animals↗

PubMed1997

Role of potassium channels and nitric oxide in the effects of iloprost and prostaglandin E1 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 iloprost, a stable analogue of prostacyclin, and prostaglandin E1 (PGE1) on the hypoxic pulmonary pressure response, and to investigate the possible involvement of KATP and KCa channels and of EDRF (NO) in the effects. In addition, iloprost and PGE1 effects were compared to those of adenosine and forskolin. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21% O2 + 5% CO2 + 74% N2 (normoxia) or 5% CO2 + 95% N2 (hypoxia) and perfused with a salt solution supplemented with ficoll. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) were used to block KATP, KCa channels and NO synthesis, respectively. 3. Iloprost, PGE1, adenosine and forskolin caused relaxation during the hypoxic pressure response. The order of potency was: iloprost > PGE1 = forskolin > adenosine. EC50 values were 1.91 +/- 0.52 10(-9) M, 3.31 +/- 0.58 10(-7) M, 3.24 +/- 0.78 10(-7) M and 7.70 +/- 1.68 10(-5) M, respectively. Glibenclamide, charybdotoxin and L-NAME inhibited partially the relaxant effects of iloprost and forskolin but not those of PGE1. 4. It is concluded that in the rat isolated lung preparation, iloprost and forskolin but not PGE1 dilate pulmonary vessels partly through KATP channels, KCa and nitric oxide release. Furthermore our results suggest that the role of cycli AMP in these effects is not unequivocal.

Adenosine↗

PubMed1993

The isolated perfused bovine udder as an in vitro model of percutaneous drug absorption. Skin viability and percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate.

Using udders from slaughtered cows as a new in vitro model of percutaneous drug absorption, the tissue viability and the percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate were studied. The organ was perfused with gassed tyrode solution for up to 6 hr. As shown by measurement of glucose consumption, lactate production, lactate dehydrogenase activity, and pH in the perfusate, the tissue was viable over a 6-hr period. This was confirmed by a histological examination. Determination of the udder skin-fold thickness demonstrated that no edema developed within the perfusion period. A maximum skin penetration of dexamethasone was found after administration of dexamethasone dissolved in acetone with dimethyl sulfoxide, followed by ointment with salicylic acid, ointment without salicylic acid, and acetone solution. Experiments with benzoyl peroxide and etofenamate demonstrated that the perfused udder skin was capable of metabolizing drugs in vitro. In conclusion, the isolated perfused bovine udder is a new in vitro model, which maintains bovine udder skin with an isolated vasculature in a viable state. Using this in vitro model, we note it is possible to compare the dermal penetration, metabolism, and absorption of substances after topical administration of different drug formulations.

Animals↗

PubMed1989

Cyanide release from nitroprusside in the isolated, perfused, bloodless liver and hindlimbs of the rat.

When sodium nitroprusside in artificial medium was perfused through the isolated liver and hindlimbs of a rat at the near physiological flow rate of 8.5 ml min-1, free cyanide was found in the perfusate. The liver reached a steady-state ratio of cyanide released/nitroprusside perfused of about 1.5 (or approximately 30% of the total nitroprusside cyanide) within 15 min, and maintained that rate for about 1.5 hr. In the hindlimbs cyanide was released at a much slower rate (7.5 to 18.8% of the total), and the release did not achieve a steady state even after 1.5 hr. Even after small corrections for cyanide extraction by both tissues, the rate of cyanide release by either tissue was probably more rapid than that resulting from static incubations in blood.

Animals↗

PubMed1988

Excretion of para-aminohippurate in the isolated perfused rat kidney: net secretion and net reabsorption.

1. The excretion of para-aminohippurate (PAH) in the isolated perfused rat kidney was examined over a wide range of perfusate PAH concentrations (15 microM to 6 mM). PAH excretion increased steadily over the range of perfusate concentrations, reaching a maximal excretion rate of 3.28 mumol/min at a free-PAH concentration of 6 mM. 2. Tubular transport of PAH was evaluated from the difference between ultrafiltered PAH and excreted PAH. Net PAH secretion was observed at low perfusate free PAH concentrations. Net PAH transport was zero at a perfusate free PAH concentration of 2.1 mM. Above this level there was progressive net reabsorption. 3. Probenecid (2.5 mM) decreased PAH secretion to 18% of the initial value at 129 microM-free PAH (P less than 0.05). Probenecid had no effect on net reabsorption of PAH at high perfusate levels of the anion. 4. Alanine (5 mM) decreased net PAH secretion by 50% at low free PAH concentrations (P less than 0.05) and decreased net PAH reabsorption by 50% at at a free PAH concentration of 6 mM (P less than 0.05). These effects could not be related to effects of PAH, probenecid or alanine on glomerular filtration rate (GFR), vascular resistance or electrolyte excretion. 5. The results confirm the existence and integrity of the proximal tubular organic anion secretory system in the isolated kidney. In addition, net PAH reabsorption occurs at high perfusate levels.

Absorption↗

PubMed1978

A device for recording left ventricular contraction and electrocardiogram in nonworking isolated perfused rat heart.

Using the isolated Langendorff rat heart preparation perfused at a constant flow rate (about 6 ml.min-1 pro heart) with a modified Krebs-Henseleit solution, methods for recording left ventricular cavity pressure and electrocardiogram (ECG) changes were devised. Stable levels of mechanical activities were reached 60--90 min after start of perfusion and were maintained for at least 4 hr. When either norepinephrine (0.05--0.15 microgram) was injected into the aortic bulb of the heart, sensitive changes in the measurable cardiac parameters were observed and changes in ECG patterns were particularly characteristic. Our results indicate that this experimental model may be useful for evaluating numerous functions of the isolated heart.

Animals↗