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PubMed1980

Effects of selective and nonselective beta adrenergic agents on renin secretion in isolated perfused rat kidney.

The effects of selective and nonselective beta adrenergic drugs on the renin secretion rate (RSR) in isolated perfused rat kidneys were studied. Both isoproterenol (Ipr) (nonselective agonist) and salbutamol (Salb) (beta-2 selective agonist) stimulated RSR in a dose-dependent manner. The lowest doses able to induce a significant RSR increase were 5 nM for Ipr and 50 nM for Salb. A 5-fold increase in RSR was induced by 500 nM Ipr and a 3.2-fold increase by 5 microM Salb. Renin stimulation by both agonists was suppressed by propranolol (nonselective) and by acebutolol and its derivative M&B 16,942 (beta-1 selective antagonists). Thus, renin release was stimulated or inhibited effectively by all the drugs tested, regardless of the beta selectivity of agonists and antagonists. There were no consistent relationships observed between changes in renal hemodynamics and in RSR, suggesting that the used drugs affected renin release from in vitro-perfused rat kidney through their direct effects on juxtaglomerular cells. These results indicate that renal beta adrenoreceptors involved in renin release do not fall into two distinct beta subtypes.

Acebutolol↗
PubMed1982

Prostaglandin E1: stimulation of somatostatin and insulin responses to glucose from the isolated perfused rat pancreas.

The effect of prostaglandin E1 (PGE1) on insulin and pancreatic somatostatin release was investigated using the isolated perfused rat pancreas. In the presence of 4.4 mM glucose, PGE1 produced a significant augmentation in somatostatin release, but not in insulin release, compared to the effect of glucose alone. PGE1 also augmented somatostatin and insulin secretion induced by 16.7 mM glucose. These results suggest that PGE1 plays a role in the regulation of not only insulin but also pancreatic somatostatin release.

Alprostadil↗
PubMed1983

Sodium and chloride dependency of dibucaine- and procaine-induced choleresis in isolated perfused rat livers.

The effect of local anesthetics, dibucaine and procaine, on hepatic bile formation was studied in the isolated perfused rat liver. Perfusate Na+ and Cl- were replaced by other ions to define the possible mechanism of action. A single dose (50 mumol) of dibucaine produced an initial cholestasis followed by choleresis. Whereas dibucaine produced only choleresis at a lower dose (10 mumol), only the cholestatic effect was seen at a higher dose (100 mumol). Procaine, on the other hand, produced only choleresis at all doses (1, 10 and 100 mumol); this choleresis was associated with biliary secretion of procaine and its metabolites. Neither dibucaine nor procaine affected the low endogenous bile acid secretion in these studies. The diffusion permeability coefficient of [carboxy-14C]inulin was not altered significantly by dibucaine and procaine, suggesting no significant alteration of biliary permeability. Biliary secretion of Na+ or Cl- declined during cholestasis and increased during choleresis. The initial cholestatic effect of dibucaine was still present when perfusates Na+ and Cl- were replaced by permeable Li+ or NO3-, but declined when Cl- was replaced by relatively impermeable isethionate, suggesting a nonspecific effect. The choleretic effect of both dibucaine and procaine, however, declined significantly when Na+ or Cl- was replaced by Li+, NO3- or isethionate-. These ion-substitutions did not affect significantly the biliary secretion of procaine and its metabolites. The ability to induce biliary secretion of Na+ and Cl- also decreased when Cl- was replaced by NO3- or isethionate and when Na+ was replaced by Li+, respectively. These results suggest that a part of the choleretic effect of both dibucaine and procaine is specifically dependent on Na+ and Cl-. This fraction is thus unlikely to be due to the osmotic effect of the secreted drug. Further studies showed that dibucaine inhibited Na+-dependent hepatic uptake of taurocholate, suggesting possible interference with other Na+-dependent transport processes. It is proposed that although a part of the choleresis is due to the osmotic effect of the secreted drug, the specific dependency of a portion of the choleretic effect on Na+ and Cl- is due to inhibition of Na+-coupled Cl- reabsorption from the canaliculi.

Animals↗
PubMed1980

PGF2 alpha stimulates release of PGE2 and PGI2 in the isolated perfused rat heart.

The effect of prostaglandin F2 alpha on the release of PGI2 and PGE2 was investigated in isolated perfused rat heart. PGF2 alpha at concentrations of 1.7 nmoles liter-1 or higher increased the release of PGI2 and PGE2 alpha. The release of PGI2 was highest after 3 to 4 min of perfusion with PGF2 alpha. This phenomenon may be of physiological significance and might explain the observed variable effects of PGF2 alpha on vascular resistance.

Animals↗
PubMed1982

Effect of Ni2+, Co2+, Zn2+, Fe2+, Cd2+, Hg2+, Cu2+ and VO-3 on coronary vascular resistance in the isolated perfused rat heart.

The coronary vascular effect of various divalent cations and of sodium-metavanadate was compared in isolated perfused rat hearts. Their order of activity was as follows (the concentrations (microM) evoking a half-maximum increase of coronary resistance are indicated (in parentheses): Ni2+ (0.03) greater than Co2+ (0.1) greater than Hg2+ (0.16) greater than VO-3 (0.2) greater than Cu2+ (15) greater than Zn (50). Iron (Fe2+) and cadmium (Cd2+) were ineffective. The order of coronary vasoconstrictor potency of these metal ions differs from the order of their other physico-chemical properties indicating that their coronary action cannot be explained as being singly a consequence of ion-membrane interaction. In contrast to Ni2+, the effect of Hg2+ was totally inhibited by phenoxybenzamine (10(-5)M) indicating that coronary vasoconstriction induced by mercury ions is mediated by alpha-receptors. Coronary vasoconstriction induced by sodium-meta-vanadate was resistant to verapamil while removal of external Ca2+ potentiated its effect. These data suggest that in contrast to Ni2+ and Hg2+, vanadate increases coronary resistance by mobilizing intracellular Ca2+ in vascular smooth muscle cells.

Animals↗
PubMed1981

Nonlinear pharmacokinetics of misonidazole and desmethylmisonidazole in the isolated perfused rat liver.

Dose-dependent elimination of misonidazole (MISO) and its metabolite desmethylmisonidazole (DESMISO) were investigated in the isolated perfused rat liver and saturation kinetics were observed for both compounds. The simplest model which accurately described the DESMISO clearance from the perfusate consisted of a saturable elimination pathway (Vmax 3 = 32 nmol/min, Km3 = 11 micro M) in parallel with a first-order pathway [CL5 (clearance) = 0.21 ml/min]. A similar model was constructed for MISO (Vmax2 = 110 nmol/min, Km2 = 10 micro M, CL4 = 0.36 ml/min), but required an additional saturable pathway (Vmax1 = 226 nmol/min, Km1 = 1850 micro M) to characterize the generation of DESMISO, as suggested by in vitro microsomal studies. A good correlation was demonstrated between DESMISO perfusate concentrations (generated during the course of MISO perfusion) and simulations based on the MISO model which included the microsomal data. The MISO and DESMISO models demonstrate that the relative contributions of the different pathways for MISO and DESMISO elimination are strongly concentration-dependent and that the MISO leads to DESMISO pathway is a minor route. A qualitative similarity in saturation kinetics was observed in the disappearance curves for both MISO and DESMISO from the liver perfusate. MISO In combination with an excess of DESMISO resulted in a marked decrease in the clearance rate of MISO from the liver perfusate. This observation suggest that MISO and DESMISO are metabolized along similar pathways.

Animals↗
PubMedDate not supplied

Mechanisms of time-dependent kinetics of diltiazem in the isolated perfused rat liver.

The time-dependent mechanisms of diltiazem (DZ) disposition were studied in a single-pass isolated perfused rat liver system. DZ (2-100 microM) was infused continuously until a steady state was achieved. The time required to achieve steady state (Tss) ranged from 15 to 75 min and was inversely related to infusion concentration. Steady-state extraction (E) of DZ decreased from 0.98 to 0.73 as the outlet concentration increased from 0.03 to 26.34 microM. This reduction of E is not related to the saturation of the primary deacetylation and N-demethylation pathways of metabolism. The N-demethylated metabolite went through a characteristic maximum prior to reaching a steady state, indicating enzyme inactivation. During a second DZ infusion, spaced with a 30-min washout period (stop-infusion experiment), the concentration vs. time profile of DZ was similar to that of the first one. Washout data from stop-infusion and [3H]DZ infusion studies showed that DZ and its metabolites were tightly bound to liver proteins. This observation is consistent with the unusually long Tss of DZ. Infusion studies with [3H]DZ showed that 669.5 +/- 156.5 and 974.2 +/- 99.2 nmol of DZ and its metabolites (calculated as DZ) were bound and/or distributed/g of liver at inlet concentrations of 35.5 +/- 3.2 and 67.2 +/- 3.4 microM, respectively. The amounts of DZ and its metabolites bound irreversibly to the whole liver, hepatic microsomal and hepatic cytosolic proteins were not different at the two inlet concentrations studied and were 24.5 +/- 6.6, 48.8 +/- 11.8, and 23.7 +/- 5.8 pmol/mg of protein, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Antidysrhythmic and dose-related hemodynamic effects of manganese in perfused isolated rabbit hearts.

Hemodynamic and antidysrhythmic studies were performed to determine the effects of manganese (Mn) on inotropy and chronotropy in normally perfused isolated rabbit hearts (IRHs), and the efficacy of Mn in suppressing and terminating ventricular dysrhythmias (VDs) in regionally ischemic IRHs. Four groups of eight hearts were perfused with Krebs-Ringer bicarbonate solution (KRB) during the control period, followed by 10 min of perfusion with either KRB, as control, or KRB containing 1.0 mM (A), 0.1 mM (B), or 0.01 mM (C) MnCl2. All hearts were then again perfused, for 10 min, with KRB alone (washout). A caused marked depression of heart rate (HR), peak left ventricular (LV) systolic pressure (PSP) and peak LV dP/dt, B resulted in significant depression of HR alone, and C resulted in significant increases in PSP and dP/dt, with a slight fall in HR. Negative effects of Mn were rapidly reversed during washout. Sustained (greater than 2 min) VDs were induced in five of six by sequential bolus injections of isoproterenol and procaine, following ligation of the left marginal coronary artery. A second group of identically treated hearts developed identical VDs with the same frequency, but were reverted to sinus rhythm by a 2-mol bolus of 10 mM MnCl2, without induction of AV block. In a third group of hearts, treated as described for the two groups above, but perfused with KRB containing 0.1 mM Mn, only one of six developed a sustained VD. These results encourage further work, in ischemic whole animal models, to determine the antidysrhythmic efficacy of manganese.

Animals↗
PubMedDate not supplied

Effect of the peroxisome proliferator perfluoro-n-decanoic acid on glucose transport in the isolated perfused rat liver.

The perfluorinated carboxylic acid, perfluoro-n-decanoic acid (PFDA), is a known peroxisome proliferator which displays toxicity in rodents. Using a paired-tracer first-pass extraction technique, the effect of PFDA on hepatic glucose transport was determined in the isolated perfused rat liver. In brief, livers isolated from PFDA-treated and control rats on day 5 posttreatment were administered the radiolabeled glucose analog, 3-O-[14C]methyl-D-glucose ([14C]3-O-MG) in addition to [fructose-1-3H(N)]sucrose ([3H]sucrose), which served as a measure of extracellular volume. Hepatic glucose transport was calculated from the change in the ratio [14C]3-O-MG/[3H]sucrose during passage through the liver. Data from this study indicate that PFDA inhibits hepatic glucose transport. Percent hepatic glucose extraction is 1.8-fold greater in controls than in PFDA-treated rats. No significant difference in lactate dehydrogenase levels was observed in the liver perfusate from PFDA-treated and control rats. This suggests that the difference in percent glucose extraction between PFDA-treated and control groups is specifically due to the PFDA treatment and is not attributed to differences in liver viability between groups. Although the exact mechanism for this inhibition in hepatic glucose transport is not known, it is hypothesized that PFDA may have a major impact on membrane structure/function which, in turn, may alter glucose transport.

Animals↗
PubMed1986

Hemodynamics of the isolated perfused rat kidney in the absence and presence of kallikrein substrate.

Rat kidneys were isolated and perfused for 120 minutes at 80 mm Hg with Krebs-Henseleit buffer containing 7 gm% bovine albumin fraction V. Analysis of the bovine albumin revealed the presence of a contaminating kallikrein substrate which exhibited a MW of 55,000 upon gel-filtration on Sephadex G-200, similar to the reported MW of bovine low molecular weight kininogen. The mean values for renal perfusate flow rate (RPF) and glomerular filtration rate (GFR) in kidneys perfused with this bovine albumin depleted of the kallikrein substrate were significantly lower when compared to standard perfusions. In two other groups of isolated kidneys perfused with kallikrein substrate depleted bovine albumin, purified bovine low molecular weight kininogen (bLMWK, 8.5 micrograms protein in 50 microliters per minute) or synthetic bradykinin (Bk, 1 ng in 10 microliters per minute) were infused after the first 30 minute clearance period into the renal artery. The induced hemodynamic changes were similar in that RPF and GFR significantly increased. These studies show that depletion of bovine albumin from kallikrein substrate results in a concomitant decrease of RPF and GFR, while overall renal function is unaffected. Infusion of both bLMWK or BK to kallikrein substrate depleted bovine albumin has similar effects resulting in a simultaneous increase in RPF and GFR. This suggests that endogenous kallikrein from the perfused kidney releases kinin from infused bLMWK and indicates that kinin primarily affects the afferent arterioles.

Animals↗
PubMedDate not supplied

TNF alpha in isolated perfusion systems: success in the limb, developments for the liver credits, debits and future perspectives.

The clinical applicability of Tumor Necrosis Factor-a pi (TNF) is under renewed investigation because of its successful use in the isolated limb perfusion in patients with irresectable soft tissue extremity sarcomas. The high response rate of > 80% with a similarly successful limb salvage rate in this patient population has led to the submission of TNF for registration for this indication in Europe. Similarly, the agent has been shown to be successful in the isolated limb perfusion setting for tumors other than sarcomas, e.g. melanoma, carcinomas. This has caused renewed interest in TNF alpha and in its application in isolated organ perfusions, such as isolated hepatic perfusion. At the Rotterdam Cancer Center a preclinical-clinical interactive development program has been established dedicated to isolated limb, kidney, liver and lung perfusions and the application of new drugs such as TNF and TNF-mutants in these systems. Moreover a program dedicated to reduce the magnitude of surgical procedures by using occlusion balloon catheters is investigating the techniques and pharmacokinetics of procedures such as balloon catheter mediated hypoxic pelvic perfusions (HPP) and isolated hypoxic hepatic perfusions (IHHP). Here we present an overview of these developments.

Animals↗
PubMed1980

[Uptake and incorporation of 3H-orotic acid in isolated perfused rat liver].

3H-orotic acid incorporation into RNA and the level of RNA polymerase activity in isolated rat liver perfused for 5 hrs were investigated. In spite of a dramatic decrease in 3H-orotic acid uptake by liver cells during perfusion, a constant rate of RNA synthesis was observed. Moreover, RNA polymerase I and II activities were not affected by a 5-hr perfusion. It is suggested that isolated perfused rat liver can be used to study direct effects of hormones and drugs on RNA synthesis.

Animals↗
PubMed1975

Metabolism of delta1-tetrahydrocannabinol by the isolated perfused dog lung. Comparison with in vitro liver metabolism.

The metabolism of (-)-delta1-tetrahydrocannabinol (delta1-THC) has been studied in the isolated perfused dog lung. After intravascular administration of [3H]-delta1-THC there was an overall biotransformation of 12%. Two major metabolites were isolated and identified as 3'-hydroxy-delta1-THC and 4'-hydroxy-delta1-THC. 7-Hydroxy-delta1-THC was also present together with small amounts of 6alpha-hydroxy-delta1-THC and 6beta-hydroxy-delta1-THC. An in vitro experiment using a dog liver microsomal preparation was also carried out and showed that the major metabolites were 6beta-hydroxy-delta1-THC and 6alpha-hydroxy-delta1-THC. 7-Hydroxy-delta1-THC and 1,2-epoxy-hexahydrocannabinol were also isolated together with small amounts of 3'-hydroxy-delta1-THC and 4'-hydroxy-delta1-THC. The side-chain hydroxylated compounds are hitherto undescribed metabolites of delta1-THC.

Animals↗
PubMed1993

Preparation and optical characteristics of hemoglobin-free isolated perfused rat head in situ.

Using a new cannulation method, which completely prevented interruption of circulation to brain tissue during surgical operations, we could prepare a functionally intact hemoglobin-free isolated perfused rat head in situ. The frequency distribution (8-25 Hz) and amplitude of a spontaneous electroencephalogram, EEG (50 microV), were kept within the normal ranges for up to 4 h after the perfusion was started. Our preparation gave characteristic flash-evoked EEG responses through the eyes. The administration of bicuculline elicited an epileptic seizure similar to that in normal rats. Near-infrared difference spectra of the rat head obtained on an aerobic to anaerobic transition were similar to those of cytochrome oxidase in isolated mitochondria as well as in the purified state. Under the aerobic perfusion conditions, both heme a+a3 and copper in cytochrome oxidase were in the fully oxidized states, showing that normoxia was maintained in the brain tissue. The redox behaviors of these two chromophores in the brain were identical to those observed in isolated mitochondria. The usefulness of brain perfusion for bridging in vitro and in vivo studies is well documented.

Animals↗
PubMed1980

Temperature effect on ADH response of isolated perfused rabbit collecting tubules.

The time course of the water permeability response to synthetic arginine vasopressin (AVP) was examined in isolated perfused rabbit collecting tubules. When experiments were conducted at 37 degrees C, addition of AVP in a concentration of 100 microU/ml increased hydraulic water permeability (Lp) from 18 +/- 4 X 10(-7) to 153 +/- 15 X 10(-7) cm x s-1 x atm-1. However, in contrast to results obtained at 25 degrees C, the Lp immediately decreased in spite of the continued presence of AVP, reaching half the peak value in 67 +/- 6 (SE) min. A similar decline was observed at 37 degrees C when a cyclic 3',5'-adenosine monophosphate analogue was added to the bathing medium. Corticosteroids greatly enhanced the peak water absorption but did not stabilize the subsequent response to AVP at 37 degrees C. A decline in diffusional water permeability measured in the absence of a transtubule osmotic gradient excluded the possible roles of cellular hypotonicity, increased cell volume, or osmotic water absorption in the unstable response to hormone. The peritubular membrane remained highly permeable to water, independent of AVP and temperature. Duration of exposure to 37 degrees C was more important than AVP in determining the unstable response. On the basis of these studies we conclude that isolated rabbit cortical collecting tubules progressively become insensitive to AVP at 37 degrees C, possibly due to alterations in the responsiveness of the urinary plasma membrane to cAMP.

Aldosterone↗
PubMed1986

Selective biliary lipid secretion at low bile-salt-output rates in the isolated perfused rat liver. Effects of phalloidin.

At high bile-salt-secretion rates the biliary secretion of phospholipids and cholesterol is dependent on that of the bile salts. However, at low bile-salt outputs some secretion remains. Isolated perfused rat livers were used in these experiments in order to study the bile-salt-independent secretion of biliary lipids. The livers were isolated and saline (0.9% NaCl), or phalloidin dissolved in saline, was added to the perfusion fluid after 1 h of liver isolation. The concentration and output of cholesterol was significantly decreased in phalloidin-treated livers compared with the controls, whereas there was no significant decrease in phospholipids; the secretion of cholesterol and phospholipids can thus be uncoupled from each other by the action of phalloidin. These experiments suggest that a proportion of cholesterol gets into bile independently of bile salts and phospholipids. These findings are discussed in relation to the supersaturation of some biles with cholesterol and its relationship to the bile-salt-independent fraction of cholesterol.

Animals↗
PubMed1994

Renal handling of tobramycin in the isolated perfused rat kidney.

The renal handling of tobramycin (TOB), an aminoglycoside antibiotic (AG), was studied using a single-pass isolated perfused rat kidney with moment analysis. In the bolus administration study at tracer concentration (7.4 microM), 32% of the glomerular-filtrated TOB remained in the lumen, but no TOB was found in the vein. This ratio of the luminal uptake was reduced in a dose-dependent manner. Other aminoglycosides such as gentamicin inhibited this uptake, but tetraethylammonium and glucosamine had no effect. In addition, under the alkalinuria condition, TOB uptake was decreased to 67% of the control value. This indicated that TOB has mainly been taken into the renal epithelial cells from their luminal site and that this uptake process was saturable and specific for AGs which have more than one cationic group. The present findings should be helpful in developing a method to reduce the nephrotoxicity of AGs and to identify their toxicity mechanisms.

Animals↗