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PubMed1991

Exaggerated response to electrical nerve stimulation of angiotensin II release in isolated perfused hind legs of spontaneously hypertensive rats.

Previously we reported that a large amount of immunoreactive angiotensin II (Ang II) was released from isolated perfused rat hind legs at steady rates for several hours. In view of a recent intriguing hypothesis that the vascular renin-angiotensin system plays an important role in the maintenance of high blood pressure in certain forms of experimental hypertensive models, the release of immunoreactive Ang II from isolated hind legs of spontaneously hypertensive rats (SHR) was examined in comparison with normotensive rats of Wistar-Kyoto strain (WKY) by using a Sep-Pak C18 cartridge directly connected to the perfusion system. We also examined effect of electrically-induced nerve stimulation on the release of immunoreactive Ang II in the two strains. High performance liquid chromatography demonstrated the presence of Ang II in the perfusate. The spontaneous release of immunoreactive Ang II was as high as about 300 to 500 pg/30 min, tended to be higher in SHR rats (435.0 +/- 68.2 pg/30 min) than in WKY rats (342.1 +/- 65.1 pg/30 min), and stable up to 3 hours of perfusion for both strains. Periarterial nerve stimulation elicited a significant increment in the release of immunoreactive Ang II in either SHR (p less than 0.02) or WKY rats (p less than 0.05); however, the amount of released immunoreactive Ang II evoked by nerve stimulation was significantly greater in SHR than in WKY rats (781.3 +/- 89.6 vs 498.8 +/- 54.6 pg/30 min, p less than 0.05). These results further provide evidence for local generation and release of Ang II in peripheral vascular tissues, and are consistent with the hypothesis that the vascular renin-angiotensin system is one of important factors responsible for the maintenance of blood pressure.

Angiotensin II↗
PubMed1993

Bacterial endotoxin rapidly stimulates prolonged endothelium-dependent vasodilatation in the rat isolated perfused heart.

1. The effects of bacterial lipopolysaccharide (Escherichia coli 0111-B4; LPS) on coronary vascular tone were examined in the isolated perfused heart of the rat. The role of nitric oxide and/or prostaglandin products of the cyclo-oxygenase pathway in mediating the actions of LPS were also investigated. 2. Coronary vascular tone was raised and maintained by a continuous perfusion of the thromboxane-mimetic U46619 (5 nM). LPS perfusion (0.1-100 micrograms ml-1) caused a concentration-dependent fall in coronary tone without any significant change in the force of cardiac contractility. 3. At 5 micrograms ml-1, LPS reduced perfusion pressure by 38 +/- 9 mmHg. This effect was rapid in onset, maximal within the first 5 min and sustained for 90 +/- 10 min (n = 6). 4. The vasodilatation induced by LPS was dependent on the presence of an intact endothelium and abolished following endothelial damage caused by air embolism. 5. NG-nitro-L-arginine methylester (L-NAME; 50 microM) or NG-nitro-L-arginine (L-NOARG; 50 microM) blocked the vasodilatation induced by LPS (5 micrograms ml-1). The inhibition caused by these arginine analogues was partially reversed by 1 mM L- but not D-arginine. 6. The vasodilator action of LPS was also completely blocked by the glucocorticoid, dexamethasone (10 microM) but unaffected by indomethacin (10 microM). 7. These results suggest that LPS evokes rapid release of nitric oxide (NO) in the microvasculature of the rat isolated heart presumably via activation of the constitutive L-arginine-NO pathway in the endothelium. Furthermore, the lack of effect of indomethacin suggests that prostaglandins released via the cyclo-oxygenase pathway are not involved in mediating this action of LPS.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1972

Physical properties of isolated perfused renal tubules and tubular basement membranes.

To study the physical properties of renal tubular basement membranes directly, the epithelial layer of single isolated perfused rabbit proximal convoluted, proximal straight, and cortical collecting tubules was removed with sodium desoxycholate. Tubular segments were perfused using micropipets. The distal end of each segment was occluded in order to simplify the measurement of transmembrane water flow. The relation between outer tubular diameter and applied transmural pressure was identical in intact tubules and their respective isolated tubular basement membranes indicating that the basement membrane determines tubular distensibility. Young's modulus for basement membranes from all tubular segments corresponded to that of tendon collagen. Membrane hydraulic conductivity was measured in two ways: (a) from the rate of transmural flow in response to an applied difference in hydrostatic pressure and, (b) from the rate of transmural flow in response to a difference in colloid osmotic pressure. The hydraulic conductivity of tubular basement membranes was 300-800 times greater than that of the intact epithelial layer. Basement membrane hydraulic conductance was similar to that of peritubular and glomerular capillaries in vivo. The hydrostatic conductance of tubular basement membranes exceeded the osmotic conductance by 3-10-fold owing largely to the fact that the membranes were moderately permeable to the osmotic solute (albumin). In view of these findings we suggest that oncotic and hydrostatic pressure may play an important role in the movement of tubular absorbate from the epithelial compartment into the renal interstitium.

Albumins↗
PubMed1988

Pulmonary hypertension and edema induced by platelet-activating factor in isolated, perfused rat lungs are blocked by BN52021.

The experimental intravenous administration of platelet activating factor (PAF) induces pulmonary hypertension and directly or indirectly increases capillary permeability. Selective PAF antagonists BN52021 and L652-731 have been shown to inhibit the action of PAF in vitro and in vivo. Using a unique isolated perfused rat lung model, we measured the effect of these PAF antagonists on PAF-induced pulmonary hypertension and edema. Isolated rat lungs were perfused with Krebs-Henseleit solution. The right and left pulmonary arteries were dissected so that they could be perfused selectively, permitting the use of one lung as an internal control for a specific pharmacologic challenge. Exposure of one lung to PAF induced an increase of perfusion pressure and wet/dry lung weight ratio in a dose-dependent manner compared with the control lung. The PAF antagonists attenuated the increase in perfusion pressure and wet/dry lung weight caused by PAF (0.75 micrograms) in a dose-dependent manner. In addition, prostaglandin F2 alpha induced an equivalent increase in pulmonary pressure without causing a similar increase in lung edema. PAF-induced pulmonary hypertension and the increase in wet/dry lung weight ratio appear to be PAF receptor-mediated processes, and the use of specific antagonists and this technique may be useful probes to determine the role of PAF in pathophysiologic states.

Animals↗
PubMed1995

The effect of sodium fluoride at prophylactic and toxic doses on renal structure and function in the isolated perfused rat kidney.

To assess the renal effects of fluoride, isolated rat kidneys were perfused in single pass mode for 120 min. Five, 15 and 50, as well as 150, 500 and 1500 mumol NaF were administered 60, 80 and 100 min after starting the perfusion, respectively. Kidneys were perfused with constant pressure (100 mmHg). The perfusate consisted of a substrate supplemented Ringer solution containing hydroxy ethyl starch (HES) to produce isoncotic conditions. Concentrations below 500 mumol/l NaF did not induce major changes in the main parameters of renal function. Only upon admixture of the highest concentration of 1500 mumol/l NaF severe changes in renal function could be observed, resulting in complete anuria and a drastic reduction of renal perfusion to 5% of control, associated with a cessation of glomerular filtration. Due to the lack in tubular load, tubular reabsorptive processes inevitably declined to zero. The morphological analysis of kidneys exhibited to 500 mumol/l NaF revealed the occurrence of vesicular material within the urinary space. These vesicles could electron microscopically be identified as membrane enclosed material of podocytic origin. The interstitium was widened. Upon admixture of 1500 mumol/l NaF, kidneys responded with a decrease of the interstitial space. Moreover, epithelial cell swelling, hydropic degeneration of all proximal and distal tubular segments, bleb formation and intraluminal casts were observed frequently. Glomerular capillaries were filled with fine precipitates and their endothelium was severely damaged. The results of our studies in the isolated perfused rat kidney (IPRK) model clearly demonstrate a direct dose dependent acute nephrotoxic effect of NaF only for extremely high doses, which, however, may be reached in human cases of severe fluoride intoxication. On the contrary, for low fluoride doses, especially for those concentrations occurring in human plasma upon cariesprophylactic intake of fluorides, no signs of direct acute nephrotoxic action could be observed in the IPRK model.

Animals↗
PubMed1998

Effects of imidazoline derivative RX871024 on insulin, glucagon, and somatostatin secretion from isolated perfused rat pancreas.

The effects of the imidazoline compound RX871024 on arginine-induced insulin, glucagon, and somatostatin secretion in the isolated perfused rat pancreas have been investigated. Arginine induced biphasic insulin, glucagon, and somatostatin release when infused for 20 min at 20 mM concentration and 3.3 mM glucose in the medium. RX871024, at 10 microM, did not influence basal hormone secretion but enhanced arginine-stimulated insulin and somatostatin release. In contrast, glucagon secretion was markedly inhibited by 10 microM imidazoline. RX871024 (1 microM) did not significantly affect arginine-induced insulin and somatostatin secretion but had an inhibitory effect on the second phase of glucagon release. In conclusion, RX871024 exerts a complex effect on the endocrine pancreas challenged by arginine, comprising stimulation of insulin and somatostatin release and inhibition of glucagon release. These effects on hormone release probably constitute the main mechanism of the antidiabetogenic action of the imidazolines.

Animals↗
PubMed1991

Antidiuretic hormone acts via V1 receptors on intracellular calcium in the isolated perfused rabbit cortical thick ascending limb.

The effect of antidiuretic hormone [( Arg]vasopressin, ADH) on intracellular calcium activity [Ca2+]i of isolated perfused rabbit cortical thick ascending limb (cTAL) segments was investigated with the calcium fluorescent dye fura-2. The fluorescence emission ratio at 500-530 nm (R) was monitored as a measure of [Ca2+]i after excitation at 335 nm and 380 nm. In addition the transepithelial potential difference (PDte) and transepithelial resistance (Rte) of the tubule were measured simultaneously. After addition of ADH (1-4 nmol/l) to the basolateral side of the cTAL R increased rapidly, but transiently, from 0.84 +/- 0.05 to 1.36 +/- 0.08 (n = 46). Subsequently, within 7-12 min R fell to control values even in the continued presence of ADH. The increase in R evoked by the ADH application corresponded to a rise of [Ca2+]i from a basal level of 155 +/- 23 nmol/l [Ca2+]i up to 429 +/- 53 nmol/l [Ca2+]i at the peak of the transient, as estimated by intra- or extracellular calibration procedures. The electrical parameters (PDte and Rte) of the tubules were not changed by ADH. The ADH-induced Ca2+ transient was dependent on the presence of Ca2+ on the basolateral side, whereas luminal Ca2+ had no effect. d(CH2)5[Tyr(Me)2]2,Arg8vasopressin, a V1 antagonist (Manning compound, 10 nmol/l), blocked the ADH effect on [Ca2+]i completely (n = 5). The V2 agonist 1-desamino-[D-Arg8]vasopressin (10 nmol/l, n = 4), and the cAMP analogues, dibutyryl-cAMP (400 mumol/l, n = 4), 8-(4-chlorophenylthio)-cAMP (100 mumol/l, n = 1) or 8-bromo-cAMP (200 mumol/l, n = 4) had no influence on [Ca2+]i. The ADH-induced [Ca2+]i increase was not sensitive to the calcium-channel blockers nifedipine and verapamil (100 mumol/l, n = 4). We conclude that ADH acts via V1 receptors to increase cytosolic calcium activity transiently in rabbit cortical thick ascending limb segments, possibly by an initial Ca2+ release from intracellular stores and by further Ca2+ influx through Ca2+ channels in the basolateral membrane. These channels are insensitive to L-type Ca2+ channel blockers, e.g. nifedipine and verapamil.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin.

We have compared the cardiotoxicity of 3 anthracyclines in a model of isolated perfused rat heart using the Langendorff technique. The contractile state and ventricular compliance were studied. Doxorubicin, epirubicin and pirarubicin were perfused at concentrations of 10(-6) and 10(-5) M during 70 min. The cardiac accumulation of the drugs was studied by HPLC. No significant alteration of cardiac functional parameters was observed at 10(-6) M. At 10(-5) M, epirubicin produced a significantly greater alteration of cardiac contractility than doxorubicin, whereas pirarubicin exerted first an inotropic effect followed by a recovery to initial values at the 60th min. Anthracycline accumulation in the heart was dose-dependent; epirubicin accumulated to a 30% greater extent than doxorubicin and pirarubicin heart concentrations were 4-5 times higher than those of doxorubicin at the end of the perfusion. These results suggest that doxorubicin and epirubicin have the same intrinsic cardiac toxicity, and that their distinct clinical cardiotoxicity must be explained by pharmacokinetic differences, whereas pirarubicin is much less cardiotoxic than the other anthracyclines because of different pharmacodynamic properties.

Animals↗
PubMedDate not supplied

Hypoxia-stimulated glycerol production from the isolated, perfused rat heart is mediated by non-adrenergic mechanisms.

Factors controlling hypoxia-induced myocardial glycerol release were studied in isolated, perfused rat hearts. A constant coronary flow rate 10 ml g-1 min-1 was maintained. The perfusion buffer was gassed with O2-N2 mixtures containing 5% CO2. The O2:N2 ratios were normoxia 95:0, hypoxia 30:65, and severe hypoxia 10:85 (v/v). Glycerol and lactate release were stimulated during a 30-min period of either hypoxia or severe hypoxia but remained constant during normoxia. Tissue glycerol-3-phosphate levels were increased after 30 min hypoxia compared with after a similar period of normoxic perfusion (p < 0.01) and further increased after severe hypoxia (p < 0.01 vs hypoxia). beta-Adrenoceptors remained sensitive to isoprenaline during hypoxia, demonstrated by an increase in glycerol release over a 30-min period of isoprenaline infusion from 897 +/- 317 to 1771 +/- 307 nmol g-1 wet weight (p < 0.05). The isoprenaline-induced increase in glycerol release during hypoxia was inhibited by both atenolol and timolol (1 x 10(-5) M). In contrast, beta-adrenoceptor blockade using these drugs failed to reduce glycerol release induced by either hypoxia or severe hypoxia. Both drugs attenuated the rise in glycerol-3-phosphate during hypoxia. Chronic denervation by pretreatment with 6-hydroxydopamine reduced hypoxia-stimulated glycerol release by only 30%. Thus, a major part of hypoxia-induced glycerol release is mediated by non-adrenergic mechanisms. The results of this study bring into question the validity of the use of glycerol production during hypoxia as a reliable measure of myocardial lipolysis.

Animals↗
PubMed1997

Regional proton nuclear magnetic resonance spectroscopy differentiates cortex and medulla in the isolated perfused rat kidney.

Volume-localized proton nuclear magnetic resonance spectroscopy was used as an assay of regional biochemistry in the isolated perfused rat kidney. This model eliminated artifacts caused by respiratory and cardiac motion experienced in vivo. Immersion of the kidney under its venous effluent reduced the susceptibility artifacts evoked by tissue-air interfaces. The rapid acquisition with relaxation enhancement imaging sequence was used for scout imaging. This gave excellent spatial resolution of the cortex, outer medulla, and inner medulla. Spectra were then acquired in 10 minutes using the volume-selective multipulse spectroscopy sequence from voxels with a volume of approximately 24 microL located within the cortical or medullary regions. Spectral peaks were assigned by the addition of known compounds to the perfusion medium and by comparison with spectra of protein-free extracts of cortex and medulla. The medullary region spectra were characterized by signals from the osmolytes betaine, glycerophosphorylcholine, and inositol. The spectra from the cortex were more complex and contained lesser contributions from osmolytes.

Animals↗
PubMed1993

Influence of thyroid hormone administration on hepatic glutathione content and basolateral gamma-glutamyltransferase ectoactivity in the isolated perfused rat liver.

The effect of thyroid hormone administration on liver glutathione (GSH) content and gamma-glutamyltransferase activity in the isolated perfused liver was studied for a period of 1-7 days in fed rats following a single dose of 0.1 mg 3,5,3'-L-triiodothyronine (T3)/kg. T3 elicited an early and transient calorigenic response, together with GSH depletion at 1 day after treatment. Recovery of hepatic GSH content and enhancement in total basolateral gamma-glutamyltransferase activity occurred in parallel 2-3 days after T3 treatment, parameters that were normalized in the 4- to 7-day time interval studied. The increase in total basolateral gamma-glutamyltransferase activity by T3 at early times after treatment was due mainly to increments in its transpeptidation mechanism, and was characterized by increments in the apparent maximum velocities without changes in the apparent Michaelis constant (Km) for the substrate gamma-glutamyl-p-nitroanilide. Data presented suggest that the elevation in sinusoidal gamma-glutamyltransferase activity could be related to the recovery of hepatic GSH content after depletion by T3 treatment, by supplying the precursors for intracellular GSH synthesis, an effect that seems to be mediated by enhanced synthesis of the enzyme.

Animals↗
PubMed1993

Endothelin-1 enhances vasoconstrictor responses to exogenously administered and neurogenically released ATP in rabbit isolated perfused arteries.

Vasoconstrictor responses to ATP were enhanced in a concentration-dependent-manner by endothelin-1 (0.1-1 nM) in isolated perfused segments of rabbit ear artery. Higher concentrations of endothelin-1 (3-10 nM) also enhanced vasoconstrictor responses to ATP. The enhancement of ATP responses by endothelin-1 (0.1-10 nM) was not affected by nicardipine (10 nM). The ATP-mediated component of the vasoconstrictor response to perivascular nerve stimulation in the rabbit jejunal artery was enhanced by endothelin-1 to a similar extent as that to exogenously administered ATP. The enhancement of vasoconstrictor responses to neurogenic ATP was also not affected by nicardipine.

Adenosine Triphosphate↗
PubMed1994

Percutaneous absorption, dermatopharmacokinetics and related bio-transformation studies of carbaryl, lindane, malathion, and parathion in isolated perfused porcine skin.

The percutaneous absorption of topically applied pesticides is a primary route for systemic exposure and potential toxicity. The isolated perfused porcine skin flap (IPPSF) is an in vitro model for studying percutaneous absorption of xenobiotics as well as cutaneous metabolism and toxicity in an anatomically intact viable skin preparation. In the present studies, percutaneous absorption of four different pesticides, carbaryl (C), lindane (L), malathion (M), and parathion (P), was assessed topically in an ethanol vehicle. A 4-compartment pharmacokinetic model was utilized to model their absorption profile. The order of absorption was C > P > L > M for the 8-h experimental period, but C > L > P > M for a model-extrapolated 6-day prediction. Metabolism of C and P was also assessed by high performance liquid chromatography (HPLC). The HPLC results indicate a significant first-pass effect for both pesticides after topical application, with parathion being metabolized to paraoxon and para-nitrophenol and carbaryl to naphthol. In addition, comparison of the metabolic data of P with previous results underscores the difference between non-recirculating and recirculating IPPSF systems in xenobiotic metabolism studies.

Animals↗
PubMed1981

The metabolism of 7H-dibenzo[c,g]carbazole, an N-heterocyclic aromatic, in the isolated perfused lung.

The metabolism of a carcinogenic N-heterocyclic aromatic, 7H-dibenzo[c,g]carbazole, was investigated in an isolated perfused rabbit lung preparation in a rat liver microsomes. A major metabolite produced in both preparation is the 7-hydroxydibenzo[c,g]carbazole. A substantial percentage of this metabolite is found in the tracheabronchi, which would be consistent with the high incidence of respiratory tract tumors due to dibenzo[c,g]carbazole.

Animals↗
PubMed1984

Effects of aconitine and veratrine on the isolated perfused heart of the common eel (Anguilla anguilla L.).

The effects of two alkaloids: aconitine and veratrine have been investigated in isolated perfused heart of the common eel (Anguilla anguilla L.). Low concentrations (less than 10(-6)M) of aconitine induced a decrease of the heart rate where high concentrations (greater than 10(-6)M) produced a tachycardia and finally led to a depolarization of cardiac cells. Veratrine induced a decrease of the heart rate depending on the concentration. A cardiac arrest was observed with high concentrations (greater than 10(-4)M). Removal of aconitine or veratrine from perfusion medium did not reverse the effects of high concentrations. The tachycardia and arrhythmias were triggered or enhanced.

Aconitine↗
PubMed1997

An isolated perfused human placental lobule model for multiple indicator dilution studies.

We describe a method for multiple indicator dilution studies in the isolated perfused human placental lobule developed to investigate the relationships between changes in pressure and flow and solute clearance. A peripheral lobule of a human placenta is perfused with a tissue culture-based medium and the perfusate oxygen tension, arterial and venous pressures, pH and perfusion temperature continuously monitored by a computerized system. Flow rates are readily changed. Bolus injections of vascular, extracellular and water space markers, and study compounds can be made into either maternal or fetal circulations, and precisely timed outflow fractions can be collected with computer-controlled fraction collectors, allowing simultaneous determination of concentration-time profiles of each marker.

Female↗
PubMed1999

Effects of tumour necrosis factor-alpha on left ventricular function in the rat isolated perfused heart: possible mechanisms for a decline in cardiac function.

1. The cardiac depressant actions of TNF were investigated in the isolated perfused rat heart under constant flow (10 ml min(-1)) and constant pressure (70 mmHg) conditions, using a recirculating (50 ml) mode of perfusion. 2. Under constant flow conditions TNF (20 ng ml(-1)) caused an early (< 25 min) decrease in left ventricular developed pressure (LVDP), which was maintained for 90 min (LVDP after 90 min: control vs TNF; 110 +/- 4 vs 82 +/- 10 mmHg, P < 0.01). 3. The depression in cardiac function seen with TNF under constant flow conditions, was blocked by the ceramidase inhibitor N-oleoylethanolamine (NOE), 1 microM, (LVDP after 90 min: TNF vs TNF with NOE; 82 +/- 10 vs 11 +/- 5 mmHg, P < 0.05). 4. In hearts perfused at constant pressure, TNF caused a decrease in coronary flow rate (change in flow 20 min after TNF: control vs TNF; -3.0 +/- 0.9 vs -8.7 +/- 1.2 ml min(-1), P < 0.01). This was paralleled by a negative inotropic effect (change in LVDP 20 min after TNF: control vs TNF; -17 +/- 7 vs -46 +/- 6 mmHg, P < 0.01). The decline in function was more rapid and more severe than that seen under conditions of constant flow. 5. These data indicate that cardiac function can be disrupted by TNF on two levels, firstly via a direct, ceramidase dependant negative inotropic effect, and secondly via an indirect coronary vasoconstriction.

Animals↗
PubMed1980

The mechanism of ammonia production and the effect of mechanical work load on proteolysis and amino acid catabolism in isolated perfused rat heart.

The effect of mechanical work load on net proteolysis, amino acid catabolism and ammonia production was studied in isolated perfused beating or K+-arrested hearts. Net proteolysis was about 16 mumol/g dry wt. during 1h and was not affected by the mechanical work. The combined catabolic rate of the major amino acids was 7.1 mumol/g dry wt. in the beating heart and 2.1 mumol/g dry wt. in the arrested heart during the 1 h experimental period. The main differences lay in the deamination of aspartate plus glutamate, which was inhibited by 60% during low energy consumption, and in net alanine synthesis, which was increased by 94%. The ammonia production plus its conversion into amide nitrogen was 9.2 and 3.4 mumol/g dry wt. in the beating and arrested heart respectively during 1 h. The decrease in the total adenine nucleotide pool during the 1 h perfusion was very low, 1.0 and 0.5 mumol/g dry wt. in the beating and arrested hearts respectively, and did not contribute significantly to ammonia production. Thus ammonia production is dependent on the cellular energy state, whereas net proteolysis is not. The maximal capacities of the purine nucleotide cycle and the glutamate dehydrogenase reaction towards deamination were much higher than the observed ammonia-production rates. The anaplerotic role of amino acid catabolism in the myocardium is discussed.

Adenine Nucleotides↗