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PubMedDate not supplied

Enhancement of reductive metabolism of p-nitrobenzoate and nitrazepam in isolated perfused rat liver by ethanol.

Reductive metabolism of p-nitrobenzoate (2 mM) was studied in the isolated perfused rat liver, after acute ethanol dosing, with use of a hemoglobin-free perfusion medium. Formation of reduced metabolites under control conditions (0.3 mumol per g of liver per hr) was enhanced fivefold (1.4 mumol/g/hr) in the presence of ethanol (38 mM), thus reaching hepatic reductase activities occurring under anaerobic conditions (1.4 mumol/g/hr). Ethanol failed to increase hepatic nitro reduction when alcohol dehydrogenase was inhibited by pyrazole. Addition of acetaldehyde led to a marked stimulation of nitroreductase activity. Carbon monoxide did not influence the ethanol-mediated enhancement of nitroreductase activity but almost abolished the enhancement caused by anoxia. Reductive azo cleavage of salazosulfamide was not enhanced by ethanol. When nitrazepam was used as the substrate (1 mM) for the isolated perfused rat liver, addition of ethanol (38 mM) led to an enhanced content of 7-amino derivative in the liver and in the perfusate, whereas the formation of 7-acetylamino derivative remained unchanged. The distribution of nitrazepam in liver and perfusate was not altered by ethanol.

Animals↗
PubMed1983

Hyperthermochemotherapeutic in vivo isolated perfusion of the rat liver.

This report describes a system of in vivo isolated perfusion of the rat liver. The effects of perfusion with 5-fluorouracil (5-FU) (0.125-1.5 g/kg) on survival, liver function, and hepatic regeneration are studied. A dose of 0.125-0.25 g/kg of 5-FU produced acceptable toxicity with 0% and 25% mortality rate, but induced liver dysfunction indicated by abnormal biochemical values and severe inhibition of hepatic regeneration. Doses of 0.5 g/kg, 1.0 g/kg, and 1.5 g/kg produced a mortality of 60%, 100%, and 100%, respectively. Regional hyperthermia (37-43 degrees C) achieved by perfusion of the liver with heated saline produced an adverse effect on survival, liver function and hepatic regeneration, which are both temperature- and perfusion time-dependent. Hyperthermochemotherapy using in vivo isolated hepatic perfusion might be acceptable for the treatment of unresectable liver cancer, but should not be utilized as an adjuvant therapy prior to hepatic resection without the use of hepatic growth factors which could reverse the inhibitory effect of hepatic perfusion.

Alanine Transaminase↗
PubMed1993

Platelet-activating factor induces selective pulmonary arterial hyperreactivity in isolated perfused rabbit lungs.

The role of vasoreactivity in PAF-induced pulmonary hypertension (PHT) was assessed in isolated, perfused rabbit lungs. We evaluated the steady-state pulmonary vascular response to five vasoconstrictors: PGF2 alpha, norepinephrine, angiotensin II, PAF, and KCl. Pulmonary arterial pressure and pulmonary vascular resistance (PVR) were significantly greater in lungs of rabbits treated with PAF for 28 days than in control rabbits in response to PGF2 alpha and norepinephrine. When resistance was partitioned by the vascular occlusion method, at baseline the vascular resistance was equally distributed between arterial and venous segments in both experimental groups. Arterial resistance accounted for approximately 76% of PVR during norepinephrine injection and 60% of PVR during PGF2 alpha injection in PAF-treated lungs. Whereas arterial resistance accounted for approximately 63% of PVR during norepinephrine injection and 52% of PVR during PGF2 alpha injection in control lungs, there was no significant difference in the response to angiotensin II, acute PAF, and KCl in lungs from chronic PAF-treated rabbits compared with responses in control rabbit lungs, though the pressor response to acute PAF tended to be blunted in PAF-treated lungs. Chronic PAF treatment results in enhanced pulmonary arterial reactivity to selected autacoids in isolated perfused lungs.

Angiotensin II↗
PubMed1990

Uptake, incorporation and metabolism of (3H)triolein in the isolated perfused rabbit heart.

The purpose of these experiments was to study the uptake and metabolism of exogenous triglyceride in the isolated perfused rabbit heart. When infused into the rabbit heart, [9,10-3H(N)]triolein was retained and incorporated into a lipid fraction that had the chromatographic mobility of authentic triolein. Incorporation of labeled triolein was not likely to be the result of a lipoprotein lipase-mediated lipolysis/resynthesis cycle, since: (i) The distribution of radioactivity following administration of [3H]oleic acid was markedly different from the distribution of radioactivity following the administration of [3H]triolein; (ii) heparin was administered to the rabbits at the time of sacrifice; and (iii) the hearts were perfused with a protein-free buffer for 20 min prior to the labelling period. When isoproterenol was administered to hearts labelled with [3H]triolein, there was an increased output of total radioactivity, composed of labelled free fatty acids, diacylglycerol and monoacylglycerol. In these same hearts, there was an increased output of glycerol in response to isoproterenol. However, following the administration of bradykinin or angiotensin II, neither the radioactivity nor the glycerol content of the perfusate was changed. These data suggest that [3H]triolein is selectively incorporated into the triglyceride pool of the isolated perfused rabbit heart. Furthermore, this [3H]triolein is available to hormonally-activated lipolytic enzymes.

Angiotensin II↗
PubMed1994

Effects of pyridoxalated hemoglobin polyoxyethylene conjugate and stroma-free hemoglobin on renal vascular responsiveness to vasoactive substances in isolated perfused rat kidney.

The effects of pyridoxalated hemoglobin polyoxyethylene conjugate (PHP) and stroma-free hemoglobin (SFH) on vascular responsiveness to various vasoactive substances were examined in isolated perfused rat kidneys. The kidneys isolated from rats were perfused with 6% PHP, 6% SFH, and 6% hydroxyethylstarch (HES) solution at a constant flow rate. Vascular responsiveness to acetylcholine (ACh), nitroglycerin (NG), norepinephrine (NE), and angiotensin-II (ANG-II) was examined by measuring the perfusion pressure (PP). Effects of inhibition of endothelium-derived relaxing factor (EDRF) by NG-monomethyl L-arginine (L-NMMA) on NE-induced and ANG-II-induced renal vascular responses were examined. ACh and NG induced a dose-dependent decrease in perfusion pressure (PP) in all groups. NE and ANG-II induced an increase in PP in all groups, but NE-induced and ANG-II-induced responses in the PHP-perfused and SFH-perfused groups were significantly larger than those in the HES-perfused group. L-NMMA did not alter vascular responsiveness to NE and ANG-II. These results indicate that PHP and SFH do not inhibit EDRF induced by ACh, but hemoglobin moiety per se does augment the vascular responsiveness to NE and ANG-II in the isolated perfused rat kidney.

Acetylcholine↗
PubMed1984

Effect of dihydroergocristine on energy metabolism studied in the isolated perfused rat brain affected by ischemia and in neuroblastoma cells deprived of oxygen and glucose.

The effect of dihydroergocristine on energy metabolism was studied in the isolated perfused rat brain affected by ischemia and in cultivated C-1300 neuroblastoma cells deprived of oxygen and glucose. Creatine phosphate, ATP, ADP, AMP, glucose, glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-diphosphate, pyruvate, and lactate were measured enzymatically. After a perfusion period of 30 min, the cortex of the isolated perfused rat brain exhibited an energy state not different from that in vivo. Dihydroergocristine added to the perfusion medium (5 mumol/L) did not influence these substrate levels under normal perfusion conditions. However, this drug was able to retard the breakdown of high-energy phosphates during ischemia and to accelerate the restoration of the energy state during the postischemic reperfusion period. The perfusion rate was not changed by the drug, and therefore it was assumed that dihydroergocristine could act directly on cell metabolism. This view was supported by the results obtained from experiments using cultivated N-2a neuroblastoma cells. These cells were incubated in a buffered salt solution deprived of glucose and oxygen for 15 min. Under these conditions, dihydroergocristine (2 mumol/L) added to the incubation medium caused changes in the concentrations or the high-energy phosphates similar to those in the isolated brain preparation: It increased the ATP concentration and decreased the ADP concentration significantly.

Adenosine Triphosphate↗
PubMedDate not supplied

Ultrapure polymerized bovine hemoglobin improves structural and functional integrity of the isolated perfused rat kidney.

Since it became evident that organ dysfunctions after acute hemolysis are not induced by hemoglobin per se, but by stroma-contaminated hemoglobin, solutions of ultrapure stroma-free hemoglobins were regarded to be possible substitutes for blood in transfusion medicine. We tested one of the recently developed modified bovine hemoglobins (Ultrapure polymerized bovine hemoglobin 1; UPPBHb1) in the isolated perfused rat kidney (IPRK) model, using a recirculating system. Control kidneys were perfused with a substrate-enriched Ringer solution containing hydroxyethyl starch (HES) to produce isoncotic conditions. In the experimental group HES was substituted in part by UPPBHb1 (34 g/l). For determination of functional parameters, the kidneys were perfused for 180 min. A separate set of kidneys of both groups was perfusion fixed after 80 min of perfusion which is the period of optimal function. Light and electron microscopic analysis revealed major alterations only for the outer medulla of HES kidneys. Only these suffered from a considerable extent of proximal tubular S3 damage, exhibiting condensed tubular epithelia. In the inner stripe of the outer medulla, which is the zone of greatest sensitivity to damage in the isolated perfused kidney, severe hydropic degeneration, cell detachment, and necrotic destruction of the medullary thick ascending limb were seen in the HES-perfused group, too. In the UPPBHb1 group, the medullary thick ascending limb was well preserved, and S3 showed only a minor degree of damage. UPPBHB1 kidneys were further characterized by the occurrence of intracapillary and interstitial precipitates of UPPBHb1 in inner stripe of the outer medulla and inner medulla. The glomerular filtration rate was significantly higher in UPPBHb1-perfused kidneys (870 +/- 80 vs. 630 +/- 55 microliters/min/g kidney weight for HES). Absolute reabsorption of sodium paralleled the behavior of the glomerular filtration rate. The values for renal perfusate flow and urinary flow rate did not differ significantly between both groups. Renal autoregulation was better preserved in UPPBHb1-perfused kidneys (74 +/- 6% of full autoregulatory response) than in HES-perfused controls (42 +/- 4%). Our results suggest that perfusion of isolated rat kidneys with UPPBHb1 improves kidney function and morphology, providing better oxygenation than in control kidneys. UPPBHb1 does not exert additional nephrotoxic effects on the IPRK that will exceed the noxious potential of the method itself. Thus, it must be concluded that UPPBHb1 may be an oxyphoretic blood substitute with nephroprotective characteristics when compared with nonoxyphoretic substitutes. At least, UPPBHb1 seems to be a promising candidate as oxyphoretic additive to perfusates for the IPRK model.

Animals↗
PubMed1994

A comparison of flushing solutions for liver procurement using an isolated perfused porcine model.

There is no agreement on the best technique of in situ flushing of livers prior to storage. In order to study this, porcine livers were stored in the University of Wisconsin (UW) solution for 18 h and then assessed using an isolated perfused porcine model. Livers flushed in situ with UW solution were compared to livers flushed with a non-preservation solution (Hartmann's solution). No statistically significant differences could be found in bile production (18.7 +/- 4.4 vs 17.9 +/- 3.8mL/1000 g per 2 h), aspartate amino-transferase (AST) levels in the perfusate after 2 h of isolated perfusion (687 +/- 101 vs 724 +/- 114 U/L), potassium levels in the perfusate after 2 h on the circuit (5.4 +/- 1.5 vs 5.5 +/- 2.3 mmol/L), weight gain (15.2 +/- 3.7 vs 17.1 +/- 4.0%) or platelet sequestration (41.6 +/- 11.7 vs 37.4 +/- 9.8%) between livers flushed with UW solution as opposed to those flushed with Hartmann's solution, respectively. Of overriding importance was the solution in which the liver was stored, reconfirming the superiority of UW solution over an extracellular solution for preservation. If extrapolated to the clinical situation, these findings would have substantial cost-saving implications.

Adenosine↗
PubMed1986

The rabbit as an experimental model for regional chemotherapy. 2. Isolated perfusion of hindlimbs.

Regional chemotherapy to a tumour is most commonly delivered by intra-arterial infusion. An alternative method of regional drug delivery, isolated perfusion, may be used where anatomical considerations permit. The technique of isolated perfusion in the rabbit hindlimb is described. The use of this model with the implantable rabbit VX2 carcinoma allows estimation of drug uptake by normal tissues, primary tumour and popliteal lymph node metastases. Correlation of such data with blood flow measurements enables targeting of new cytotoxic agents to be evaluated. The effect of perfusate composition on tissue uptake of such an agent, the plant toxin ricin, has been determined.

Animals↗
PubMed1999

The blood perfused isolated heart: characterization of the model.

We have characterized the aerobic blood-perfused isolated heart model evaluating the hemodynamics and metabolism of both the blood donor animal and the isolated organ. Anaesthesia of the blood donor with sodium pentobarbital (30 mg/kg) increases arterial concentration of non esterified fatty acids (NEFA) from 80 +/- 6 to 452 +/- 70 microM; p < 0.01. Injection of 1,000 U/kg heparin causes a second significant increase from 452 +/- 70 to 1012 +/- 104 microM; p < 0.01. Insertion of the perfusion circuit, without the isolated heart, causes a reduction in blood pressure of the blood donor and a significant increase in norepinephrine from 277 +/- 44 to 634 +/- 130 pg/ml; p < 0.05. Two hours of aerobic perfusion of the isolated heart inserted in the perfusion circuit, decreases arterial pressure of the blood donor with a concomitant increase of plasma norepinephrine from 475 +/- 150 to 841 +/- 159 pg/ml; p < 0.05. Developed pressure, oxygen consumption, glucose and NEFA uptake of the isolated heart remain constant during two hours of aerobic perfusion, NEFA being the preferred substrate. Tissue content of high energy phosphates at the end of the perfusion is high and similar to that observed "in vivo". Despite this, there is a release of lactate and CPK from the isolated heart. We conclude that: 1) the model allows accurate measurement of hemodynamics and metabolism of both the isolated heart and the blood donor animal; 2) the perfusion procedure modifies the substrates concentration of the blood donor animal which, in turn, results in the preferential NEFA utilization of the isolated heart. These changes do not affect the functional parameters of the perfused heart.

Animals↗
PubMedDate not supplied

Effects of PAF on cardiac function and eicosanoid release in the isolated perfused rat heart: comparison between normotensive and spontaneously hypertensive rats.

The aim of this study was (a) in isolated perfused rat heart to characterize the effects of platelet-activating factor (PAF) on coronary flow, ventricular contractility, and eicosanoid release and (b) to determine whether PAF effects are altered in hearts from spontaneously hypertensive rats (SHR). PAF (10(-10)-10(-7) mol) dose-dependently decreased coronary flow and ventricular contractility; concomitantly, coronary effluent concentrations of thromboxane (TX)B2 and prostaglandin F2 alpha (PGF2 alpha) were elevated but not those of prostacyclin. The PAF receptor antagonist WEB 2086 (10(-7)-10(-5) mol/l) concentration-dependently antagonized these PAF effects. In addition; the cyclo-oxygenase inhibitor indomethacin (5 x 10(-5) mol/l) prevented PAF (10(-9)-10(-7) mol) induced eicosanoid release; in the presence of indomethacin PAF caused coronary constriction and ventricular depression only at the highest dose (10(-7) mol) but had no effect at 10(-9) or 10(-8) mol. Moreover, the TXA2 antagonist SQ29,548 (10(-6) mol/l) completely inhibited 10(-8) mol PAF induced ventricular depression but did not effect coronary constriction. In SHR PAF (10(-9)-10(-7) mol) evoked decreases in coronary flow and ventricular contractility did not differ from those in normotensive Wistar-Kyoto rats while PAF induced TXA2 and PGF2 alpha release was markedly enhanced. In addition, decreases in coronary flow and ventricular contractility induced by the TXA2 agonist U 46619 (10(-7) mol/l) were markedly depressed in SHR. We conclude that in isolated perfused rat heart PAF causes coronary constriction and depression of ventricular function mainly indirectly through released TXA2 and/or PGF2 alpha. Moreover, the fact that in SHR the PAF effects on coronary flow and ventricular function are not altered despite markedly enhanced TXA2 and PGF2 alpha release supports the view that in the SHR the receptors mediating TXA2 and/or PGF2 alpha effects are desensitized.

Animals↗
PubMed1994

Transglomerular transport of DEAE dextran in the isolated perfused kidney.

OBJECTIVE: The renal fractional clearance of [3H]DEAE dextran has been widely used to substantiate the charge selective model for renal permselectively, although there has only been one reported study on this type of clearance. This study sets out to examine the fractional clearance and glomerular processing of DEAE dextran. METHODS: Fractional clearance studies were performed using isolated perfused rat kidneys. The glomerular processing of DEAE dextran was assessed by examining the kinetics of DEAE dextran uptake in glomeruli isolated post perfusion. RESULTS: The fractional clearance of DEAE dextran used in the concentration range of 15-150 micrograms/ml in the perfusate of the isolated perfused kidney did not produce the classical in vivo facilitated transport of DEAE dextran as compared to dextran as observed by Bohrer et al. The fractional clearance curve displays retarded clearance of low molecular weight (small radii) DEAE dextran, giving the appearance of a 'flat curve'. Similar results were obtained when an oxygen free radical scavenger cocktail was included in the perfusate. These results may be due to the fact that DEAE dextran binds to the glomeruli (at an order of magnitude greater than dextran sulfate). Perfused kidneys with [3H]DEAE dextran for 1 h followed by a five minute perfusion with unlabelled DEAE dextran revealed no significant change in the glomerular levels of [3H]DEAE dextran (unlike dextran sulfate). Perfusion of rat kidneys with 15 micrograms/ml DEAE dextran produced no changes in the electron microscopical morphology of the glomerulus and no changes in the fractional clearance of dextran. CONCLUSIONS: These results do not support the glomerular charge selectivity model that involves a non-binding electrostatic interaction of the charged dextran with the fixed anion charges of the glomerular capillary wall.

Animals↗
PubMed1992

Enzymatic basis for the non-linearity of hepatic elimination of propranolol in the isolated perfused rat liver.

Propranolol (PL) metabolism was studied in the isolated perfused rat liver under single-pass and steady-state conditions. An attempt was made to predict the data observed in the isolated rat liver perfusion at PL infusion rates of 89-1317 nmol/min using the microsomal kinetic parameters obtained in our previous paper (Ishida et al., Biochem Pharmacol 43: 2489-2492, 1992) and the unbound PL fractions in rat liver microsomes and the perfusion medium. The values of kinetic parameters obtained in rat liver microsomes were corrected for the whole liver. Two groups of cytochrome P450 isozymes having high (Km < 0.5 microM)- and low (Km > 20 microM)-affinities participate in the metabolism of PL and sudan III pretreatment induces the low-affinity enzymes rather than the high-affinity enzymes in control rats. Of high-affinity isozyme(s) PL 4-hydroxylase and 7-hydroxylase made a major contribution to the overall activity, while for low-affinity isozymes PL 4-hydroxylase and N-desisopropylase did. A nonlinear relationship between the PL concentrations entering and leaving the liver was predicted from these corrected kinetic parameters using the venous equilibrium model. The outflow concentrations and the metabolic rates of PL for the predicted curves were over-estimated at higher inflow PL concentrations and under-estimated at higher substrate concentrations, respectively. On the other hand, the prediction for them was successfully carried out for the livers whose intrinsic clearance was altered due to the induction of low-affinity enzymes in PL metabolism by sudan III pretreatment. The outflow rates of 4-hydroxypropranolol showed a downward curvature at lower substrate concentrations, followed a linear rise in the livers from control rats, while the outflow rates of 5- and 7-hydroxypropranolol exhibited their respective limiting values. The outflow rates of 4-hydroxypropranolol and N-desisopropylpropranolol were enhanced markedly with increasing the outflow unbound concentration of PL by sudan III pretreatment. These results indicate that non-linear PL first-pass metabolism is due to the saturation of the reactions for the high-affinity enzymes among enzymes engaging in PL ring hydroxylations.

Animals↗
PubMed1985

Digoxin quinidine interaction: a pharmacokinetic study in the isolated perfused rat liver.

Digoxin-quinidine interaction was studied in the experimental model of isolated perfused rat liver. Neither digoxin nor quinidine were toxic to the isolated rat liver. The clearance of digoxin and quinidine by the liver was directly related to the rate of bile flow and the size of the initial dose of digoxin. In the presence of quinidine, after initial doses of digoxin of 0.5 and 1 micrograms, the concentration of digoxin in the perfusate was increased 2.5 and 3-fold. Its excretion in the bile was reduced by 45% and 20.5%, respectively (all comparisons, p less than 0.01). Digoxin concentration in the liver tissue was calculated and found to be appreciably elevated in the presence of quinidine. A reduction of about 30% (p less than 0.05) in the excretion of quinidine in the bile was observed in the presence of digoxin. Thus, a competition of digoxin and quinidine for biliary excretion was demonstrated as an underlying cause for digoxin-quinidine interaction in the isolated perfused rat liver.

Animals↗
PubMed1984

Regulation of oxygen consumption and microcirculation by alpha-sympathetic nerves in isolated perfused rat liver.

In isolated rat liver perfused at constant flow with erythrocyte-free Krebs-Henseleit bicarbonate buffer containing 5 mM glucose and 2 mM lactate, perivascular stimulation of the hepatic nerves caused a rapid decrease of oxygen uptake, a decrease of the periportal and, after a transient rise, of the perivenous tissue po2 of surface acini, an increase of portal pressure, and an enhancement of glucose output. Furthermore, nerve stimulation changed the intrahepatic distribution of the perfusate drastically. Infusion of trypan blue 20 s after nerve stimulation resulted in a heterogeneous staining of the liver both at the surface and in cross-sections, while it led to a homogeneous distribution in non-stimulated controls. It is concluded that the major component in the mechanism of the nerve-dependent decrease of oxygen uptake is the microcirculatory change rather than a metabolic effect.

Animals↗
PubMed1987

Characteristics of the action of Crotalus horridus horridus (timber rattlesnake) venom on the isolated, perfused rat heart.

The isolated Langendorff-perfused heart was used to examine the effects of a 4 min infusion of Crotalus horridus horridus venom (3.3-33 micrograms/ml) on various physiological, biochemical and morphological parameters. Venom infusion reduced ventricular contractility in a dose-dependent manner that was not reversible; this response was markedly attenuated by either lowering the temperature from 37 degrees C to 32 degrees C or the perfusate potassium ion concentration from 5.9 to 2.5 mM. The negative inotropic response was not associated with any change in heart rate or coronary flow. Envenomation induced a progressive fall in ECG amplitude without effect on P and Q waves and a variable delayed incidence of premature ventricular complexes. Light microscopy showed localized, patchy areas of degenerating fibres within the ventricular mass by 5 min. Ventricular tissue ATP, ADP and lactate content were not significantly changed at this time. Crotamine was without effect on the heart. Another venom component apparently has a direct effect on the heart to disrupt the integrity of ventricular fibres.

Adenosine Diphosphate↗
PubMed1980

Evaluation of citrate flushing solution using the isolated perfused rat kidney.

The isolated rat kidney perfused at 37 C with dialyzed bovine serum albumin (6.5 g/100 ml) in Krebs-Henseleit buffer was used to examine why a hypertonic citrate flush permits rapid recovery of renal function after storage. The composition of the original hyperosmolar citrate solution was varied so that the roles of osmolality, magnesium, and citrate could be evaluated. All kidneys were flushed with the test solutions and stored for 24 hr in the test solutions at 0 C. The citrate flushing solution requires both the citrate anion and magnesium for efficacy. Hyperosmolality does not enhance its action, an isosmolar solution is more effective. Citrate can be replaced by a nonmetabolizable analogue, tricarballylate, if the solution is suitably buffered. The mechanism of action of citrate is still uncertain, it does not seem primarily to act as a metabolic fuel or inhibitor.

Animals↗
PubMed1991

[Effects of the PAF antagonist WEB 2086 on hypoxia and angiotensin II-induced pulmonary vasoconstriction in the isolated perfused rat lung].

Using isolated blood-perfused lung preparations of rats, we tested the influence of the PAF antagonist WEB 2086 on vasoconstriction triggered by hypoxia or angiotensin II (A II). If a constant flow was pre-set, changes in the prepulmonarily measured pressure were directly related to the changes of resistance in the pulmonary flow. WEB 2086 reduced the hypoxically conditioned vasoconstriction (HPV) when using blood as perfusion medium, the effect being dependent on the dose (ED50 = 127.3 +/- 21.1 mg/l). HPV was lowered on the average by 82% if the full pharmacologic dose of 800 mg/l WEB 2086 was added to the perfusate. The A II response was weakened to a lesser degree (by 45%). If plasma was used as perfusate, the pressure increase in response to hypoxic stimulation or A II was less marked. However, the relative effect of the PAF antagonist was analogous (attenuation by 83% or 53%, respectively). In chronically hypoxic animals (3 weeks at 10% O2) the relative pressure drop in the lesser circulation after application of WEB 2086 (400 mg/l; HPV; blood as perfusate) was definitely more pronounced (p less than 0.001). The fact that WEB partly antagonises the pulmonary vasoconstriction triggered both by alveolar hypoxy and by angiotensin II, seems to indicate that in both constrictive stimuli PAF participates in the complex mediator mechanism or that WEB 2086 exercises a non-specific vasodilatory effect on the pulmonary flow.

Angiotensin II↗