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F G Russel

Publications and source records attributed to F G Russel.

At least 19 recordsLinked to original sources
PubMed2003

Nitric oxide-mediated vascular tone in the fetal placental circulation of patients with type 1 diabetes mellitus.

Endothelium-derived nitric oxide (NO) plays a key role in the regulation of vascular tone in health and disease. The present study addresses the contribution of NO to the baseline vascular tone in the fetal placental circulation of type 1 diabetic women. To this end, we performed ex-vivo dual perfusions of isolated cotyledons from seven women with type 1 diabetes mellitus and 24 healthy women. The fetal arterial pressure was considered to be a measure of fetal vascular resistance. The contribution of NO to the baseline vascular tone of the fetal placental circulation was quantified by addition of the NO-synthase inhibitor N(G)-nitro-arginine-methylester (L-NAME). Apart from the diabetic state, we studied the influence of exogenous insulin on the response to L-NAME. Mean (+/-SEM) baseline fetal arterial pressure was higher in diabetes (25.7+/-3.4 mm Hg vs 18.0+/-1.7 mm Hg, P<0.05). Maximum perfusion pressure after L-NAME was 87.9+/-7.1 mm Hg in diabetes vs 58.9+/-4.5 mm Hg in controls (P<0.01). The net L-NAME-induced increase in fetal arterial pressure was higher in diabetes (62.2+/-9.1 mm Hg vs 40.9+/-3.5 mm Hg, P<0.05). Although insulin induced a shift to the left of the L-NAME-curve, the net L-NAME-induced increase in fetal arterial pressure was not affected. We conclude that diabetes is associated with an increased baseline vascular tone of the fetal placental vascular bed. This can not be explained by attenuated NO-mediated effects. In contrast, the activity of the NO-pathway seems to be increased in diabetes. The latter observation seems not to be caused by high insulin levels.

Adult↗
PubMed2001

In vivo evidence for K(Ca) channel opening properties of acetazolamide in the human vasculature.

1. The selective carbonic anhydrase inhibitor acetazolamide is known to increase blood flow in several organs. Acetazolamide directly dilates isolated resistance arteries associated with activation of calcium-activated potassium (K(Ca)) channels. We examined both the presence and mechanism of the direct vascular action of acetazolamide in vivo in humans. 2. Forearm vasodilator responses of 30 healthy volunteers to infusion of placebo and increasing doses of acetazolamide (1-3-10 mg min(-1) dl(-1)) into the brachial artery were recorded by venous occlusion plethysmography, before and after local administration of L-NMMA (0.2 mg min(-1) dl(-1), an inhibitor of NO-synthase, n=6), indomethacin (5.0 microg min(-1) dl(-1), an inhibitor of prostaglandin synthesis, n=6), glibenclamide (10 microg min(-1) dl(-1), an inhibitor of K(ATP) channels, n=6), tetraethylammonium (0.1 mg min(-1) dl(-1), an inhibitor of K(Ca) channels, n=6) or placebo (NaCl 0.9%, n=6). Lower dosages of acetazolamide did not affect vascular tone (n=6). 3. Acetazolamide infusions increased forearm blood flow from 2.41+/-0.17 to 2.99+/-0.18, 4.09+/-0.26 and 6.77+/-0.49 ml min(-1) dl(-1) in the infused forearm (P:<0.001), with no significant changes in the non-infused forearm, blood pressure or heart rate. Acetazolamide-induced vasodilation was not inhibited by L-NMMA, indomethacin, or glibenclamide but was significantly attenuated by TEA (vasodilation: 23+/-6, 82+/-19, 241+/-38% versus 27+/-8, 44+/-22, 42+/-35%). 4. We conclude that acetazolamide exerts a direct vasodilator effect in vivo in humans mediated by vascular K(Ca) channel activation. This makes acetazolamide the first drug known that specifically modulates this channel.

Acetazolamide↗
PubMed2001

Role of multidrug resistance protein 2 (MRP2) in glutathione-bimane efflux from Caco-2 and rat renal proximal tubule cells.

1. The multidrug resistance protein 2 (MRP2) has been shown to play an important role in the transport of glutathione conjugates in the liver. Its importance in renal excretion, however, is still uncertain and other organic anion transporters may be involved. The objective of the present study was to characterize glutathione conjugate efflux from rat kidney proximal tubule cells (PTC), and to determine the contribution of Mrp2. 2. We used isolated PTC in suspension, as well as grown to monolayer density. For comparison, transport characteristics were also determined in the human intestinal epithelial cell line Caco-2, an established model to study MRP2-mediated transport. The cells were loaded with monochlorobimane (MCB) at 10 degrees C. MCB enters the cells by simple diffusion and is conjugated with glutathione to form the fluorescent glutathione-bimane (GS-B). 3. In primary cultures of rat PTC, no indications for a transporter-mediated mechanism were found. The efflux of GS-B from Caco-2 cells and freshly isolated PTC was time- and temperature-dependent. Furthermore, GS-B transport in both models was inhibited by chlorodinitrobenzene (CDNB), with an inhibitory constant of 46.8+/-0.9 microM in freshly isolated PTC. In Caco-2 cells, the inhibitory potency of CDNB was approximately 20 fold higher. Finally, efflux of GS-B from freshly isolated PTC from Mrp2-deficient (TR(-)) rats was studied. As compared to normal rat PTC, transport characteristics were not different. 4. We conclude that in freshly isolated rat PTC glutathione conjugate excretion is mediated by other organic anion transporters rather than by Mrp2.

ATP-Binding Cassette Transporters↗
PubMed2001

Nephrotoxicants induce endothelin release and signaling in renal proximal tubules: effect on drug efflux.

We previously used killifish proximal tubules, fluorescent substrates, and confocal microscopy to demonstrate that transport mediated by the multidrug resistance protein (Mrp2) and by P-glycoprotein was reduced by nanomolar concentrations of endothelin-1 (ET), acting through a basolateral B-type ET receptor and protein kinase C (PKC). Here we show that representatives of two classes of nephrotoxicants decrease transport by activating the endothelin-PKC signaling pathway. Exposing tubules to radiocontrast agents (iohexol, diatrizoate) or aminoglycoside antibiotics (gentamicin, amikacin) reduced Mrp2-mediated fluorescein methotrexate (FL-MTX) transport from cell to tubular lumen. Pretreating the tubules with an ET(B)-receptor antagonist or with PKC-selective inhibitors abolished these effects. The nephrotoxicants activated signaling by inducing release of ET from the tubules, because adding of an antibody against ET to the medium abolished the effects. Elevating medium Ca(2+) also reduced FL-MTX transport; this reduction was abolished when tubules were pretreated with an ET antibody, an ET(B)-receptor antagonist, PKC-selective inhibitors, or the Ca(2+) channel blocker, nifedipine. None of these drugs by themselves affected FL-MTX transport. Importantly, nifedipine also blocked the ET(B)-receptor/PKC-dependent reduction in FL-MTX transport caused by gentamicin and diatrizoate. These results for two classes of structurally unrelated nephrotoxicants suggest that Ca(2+)-dependent ET release and subsequent action through an autocrine mechanism may be an early response to tubular injury.

Animals↗
PubMed2000

Expression and immunolocalization of multidrug resistance protein 2 in rabbit small intestine.

Multidrug resistance protein 2 (MRP2) is an ATP-dependent transporter of anionic drugs and conjugates. It functions as an efflux pump in the apical membranes of liver and kidney cells, but its membrane localization in small intestine has not yet been defined. The present study demonstrates exclusive localization of Mrp2 to the brush-border (apical) membrane of villi, decreasing in intensity from the villus tip to the crypts. In immunoblot analysis of crude membranes of various rabbit tissues, Mrp2 was only found in small intestine, kidney and liver. These results are in-line with the supposed function of Mrp2 in drug excretion.

Animals↗
PubMed2000

[Lavage almost never indicated after an autointoxication].

In many Dutch hospitals gastric lavage leaving charcoal and a laxative is the treatment of choice after autointoxication. Gastric lavage is not without risks. No difference has been demonstrated in efficacy and safety of gastric lavage combined with administration of activated charcoal on the one hand and just administration of activated charcoal on the other. In theory, gastric lavage might be useful in patients presenting shortly after the selfpoisoning (up to 2 hours) and in the case of delayed gastric emptying up to 4 hours. Gastric lavage is indicated without doubt in patients presenting shortly after ingestion of toxic substances which are poorly adsorbed by charcoal (for instance lithium). In case of a mild intoxication (for example with benzodiazepines), the risks of drug toxicity do not outweigh those of lavage, regardless of the time elapsed after ingestion. If gastric lavage is applied, it should be performed properly, i.e. with warm water (38 degrees C), with a 36-40 Fr. tube, using aliquots of 200-300 ml. In a minority of the intoxications whole bowel lavage should be employed.

Charcoal↗
PubMed2000

Sulphonylurea drugs reduce hypoxic damage in the isolated perfused rat kidney.

Sulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 microM) and glibenclamide (10 microM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min. Hypoxic perfusions resulted in an increased fractional excretion of glucose (FE % glucose 14.3+/-1.5 for hypoxic perfusions vs 4.9+/-1.6 for normoxic perfusions, mean +/- s.e. mean, P<0.05), which could be completely restored by 200 microM tolbutamide (5.7+/-0.4 for tolbutamide vs 14.3+/-1.5 for untreated hypoxic kidneys, P<0.01). Furthermore, tolbutamide reduced the total amount of LDH excreted in the urine (220+/-100 mU for tolbutamide vs. 1220+/-160 mU for untreated hypoxic kidneys, P<0.01). Comparable results were obtained with glibenclamide (10 microM). In agreement with the effect on functional parameters, ultrastructural analysis of proximal tubules showed increased brush border preservation in tolbutamide treated kidneys compared to untreated hypoxic kidneys. We conclude that glibenclamide and tolbutamide are both able to reduce hypoxic damage to proximal tubules in the isolated perfused rat kidney when applied in the appropriate concentrations.

ATP-Binding Cassette Transporters↗
PubMed2000

Probenecid interferes with renal oxidative metabolism: a potential pitfall in its use as an inhibitor of drug transport.

The anionic drug probenecid has been traditionally used as an inhibitor of renal organic anion transport. More recently the drug was found to inhibit organic cation transport as well, and it is used to retain intracellularly loaded fluorophores. In these investigations it is implicitly assumed that probenecid performs its activity through competition for transport. Here we studied the possibility that probenecid provokes its effect through inhibition of cellular oxidative metabolism. Oxygen consumption was measured in isolated rat kidney cortex mitochondria. At concentrations of 1 mM or higher, probenecid increased the resting state (state 4) and decreased the ADP-stimulated respiration (state 3). A complete loss in respiratory control was observed at 10 mM probenecid. After incubating isolated rat kidney proximal tubular cells (PTC) for 30 min with probenecid a concentration-dependent reduction in ATP content was observed, which was significant at concentrations of 1 mM and higher. Using digital image fluorescence microscopy the membrane potential in PTC was measured with bisoxonol. The mitochondrial effects of probenecid were paralleled by a depolarization of the plasma membrane, immediately after drug addition. All events are likely to be a result of membrane disordering due to the lipophilic character of probenecid, and may explain, at least in part, the various inhibitory effects found for the drug. We recommend to be cautious with applying probenecid in cellular research.

Adenosine Triphosphate↗
PubMed2000

Molecular pharmacology of renal organic anion transporters.

Renal organic anion transport systems play an important role in the elimination of drugs, toxic compounds, and their metabolites, many of which are potentially harmful to the body. The renal proximal tubule is the primary site of carrier-mediated transport from blood to urine of a wide variety of anionic substrates. Recent studies have shown that organic anion secretion in renal proximal tubule is mediated by distinct sodium-dependent and sodium-independent transport systems. Knowledge of the molecular identity of these transporters and their substrate specificity has increased considerably in the past few years by cloning of various carrier proteins. However, a number of fundamental questions still have to be answered to elucidate the participation of the cloned transporters in the overall tubular secretion of anionic xenobiotics. This review summarizes the latest knowledge on molecular and pharmacological properties of renal organic anion transporters and homologs, with special reference to their nephron and plasma membrane localization, transport characteristics, and substrate and inhibitor specificity. A number of the recently cloned transporters, such as the p-aminohippurate/dicarboxylate exchanger OAT1, the anion/sulfate exchanger SAT1, the peptide transporters PEPT1 and PEPT2, and the nucleoside transporters CNT1 and CNT2, are key proteins in organic anion handling that possess the same characteristics as has been predicted from previous physiological studies. The role of other cloned transporters, such as MRP1, MRP2, OATP1, OAT-K1, and OAT-K2, is still poorly characterized, whereas the only information that is available on the homologs OAT2, OAT3, OATP3, and MRP3-6 is that they are expressed in the kidney, but their localization, not to mention their function, remains to be elucidated.

Animals↗
PubMed2000

Multidrug resistance protein mrp2 mediates ATP-dependent transport of classic renal organic anion p-aminohippurate.

p-Aminohippurate (PAH) is widely used as a model substrate to characterize organic anion transport in kidney proximal tubules. The carrier responsible for uptake of PAH across the basolateral membrane has been cloned and well characterized, whereas transporters mediating PAH excretion across the brush-border (apical) membrane are yet unknown. In this study we investigated whether PAH is a substrate for the apical multidrug resistance protein 2 (Mrp2). Overexpression of recombinant rabbit Mrp2 in Sf9 cells significantly increased ATP-dependent [(14)C]PAH uptake into isolated membrane vesicles compared with endogenous ATP-dependent uptake. The Michaelis-Menten constant and maximal velocity for Mrp2-mediated ATP-dependent [(14)C]PAH transport were 1.9 +/- 0.8 mM and 187 +/- 29 pmol. mg(-1). min(-1), respectively. On the basis of the inhibitory profile, the endogenous ATP-dependent PAH transporter does not appear to be an ortholog of Mrp2. Together, our results show that Mrp2 is a low-affinity ATP-dependent PAH transporter, indicating that Mrp2 might contribute to urinary PAH excretion.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule.

In the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-tubular lumen transport of both fluorescent compounds. These effects were prevented by an ET(B) receptor antagonist but not by an ET(A) receptor antagonist. Immunostaining with an antibody to mammalian ET(B) receptors showed specific localization to the basolateral membrane of the fish tubular epithelial cells. ET-1 effects on transport were blocked by protein kinase C-selective inhibitors, implicating protein kinase C in ET-1 signaling. Finally, the nephrotoxic radiocontrast agent iohexol reduced cell-to-lumen FL-MTX and NBD-CSA transport, and these effects were abolished by an ET(B) receptor antagonist. These are the first results linking ET to the control of xenobiotic transport and the first demonstrating control of renal multidrug resistance-associated protein 2 and P-glycoprotein by a hormone.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Metabolite anion carriers mediate the uptake of the anionic drug fluorescein in renal cortical mitochondria.

The fluorescent organic anion fluorescein (FL) accumulates in proximal tubular cells of the kidney during renal secretion. In freshly isolated and permeabilized proximal tubular cells, the uptake was reduced but still sensitive to probenecid, suggesting a concentrative mechanism that is associated with intracellular compartments. Previous studies have shown that one of these compartments may be mitochondrial. In this study, we further investigated the transport characteristics of FL in isolated rat kidney cortex mitochondria. Mitochondrial uptake of 100 microM FL was rapid, with an initial rate of 60 pmol/mg protein.min, and reached equilibrium after 5 min. To characterize the transport system(s) involved, FL uptake was studied in the absence and presence of substrates or inhibitors specific for the various mitochondrial anion carriers. Phenylsuccinate (10 mM), an inhibitor of the alpha-ketoglutarate carrier, reduced uptake significantly with a maximum inhibition of 33% and an inhibitory constant (-log IC(50)) of 4.0 +/- 0.4 (P <.05). The apparent K(m) for the phenylsuccinate-corrected FL uptake was 1.3 +/- 0.3 mM with a V(max) of 260 +/- 26 pmol/mg protein.15 s. Substrates for the tricarboxylate and glutamate-aspartate carriers significantly reduced the uptake of 100 microM FL with -log IC(50) values of 4.6 +/- 0.4 (citrate), 5.5 +/- 0.3 (glutamate), and 4.1 +/- 0.4 (aspartate). Substrates for the monocarboxylate and dicarboxylate carriers were without effect. The anionic drugs, valproate, indomethacin, and salicylate, significantly reduced FL uptake, whereas cephaloglycin and cephaloridine had no effect. Finally, a combination of phenylsuccinate, glutamate, and citrate reduced the uptake by 66%, indicating that at least three metabolite carriers contribute concomitantly to intramitochondrial FL transport.

Animals↗
PubMed1999

Presence and mechanism of direct vascular effects of amiloride in humans.

Besides an evident diuretic effect, amiloride has been shown to exert direct vasoactivity in various animal experiments, whereas human data on this issue are lacking. Inhibition of Na+/H+ exchange, alpha-adrenergic blockade, and sodium and calcium channel antagonism have been proposed as possible mechanisms of this action. Although the role of Na+/H+ exchange in vascular-tone modulation is not completely clear, various vasoconstrictive agents (e.g., angiotensin II) enhance its activity. We examined the direct effects of amiloride on human arterial vasculature in vivo. Forearm vasodilator responses to the infusion of placebo and amiloride (n = 10; 0.1-100 microg/min/dl) into the brachial artery were recorded by venous occlusion strain-gauge plethysmography. Reduction of forearm blood flow after local administration of noradrenaline or angiotensin II was measured before and after local amiloride administration. Amiloride increased the ratio of the infused/ noninfused forearm blood flow at the highest dosages (10, 30, and 100 microg/min/dl with 14+/-9, 17+/-14, 58+/-23% (p = 0.002, repeated-measures analysis of variance). In contrast to noradrenaline-induced vasoconstriction, the vasoconstrictor response to angiotensin II was significantly attenuated by amiloride (p = 0.02). At high concentrations, amiloride exerts direct vasodilator activity in human arterial vasculature in vivo. This effect appears not to depend on alpha-adrenergic receptor blockade, but shows interaction with angiotensin II, an activator of Na+/ H+ exchange.

Adult↗
PubMed1999

Active lucifer yellow secretion in renal proximal tubule: evidence for organic anion transport system crossover.

Recent studies show that organic anion secretion in renal proximal tubule is mediated by distinct sodium-dependent and sodium-independent transport systems. Here we investigated the possibility that organic anions entering the cells on one system can exit into the lumen on a transporter associated with the other system. In isolated rat kidneys perfused with 10 microM lucifer yellow (LY, a fluorescent organic anion) plus 100 micrograms/ml inulin, the LY-to-inulin clearance ratio averaged 1.6 +/- 0.2, indicating net tubular secretion. Probenecid significantly reduced both LY clearance and LY accumulation in kidney tissue. In intact killifish proximal tubules, confocal microscopy was used to measure steady-state LY uptake into cells and secretion into the tubular lumen. Probenecid, p-aminohippurate, and ouabain nearly abolished both uptake and secretion. To this point, the data indicated that LY was handled by the sodium-dependent and ouabain-sensitive organic anion transport system. However, leukotriene C4, an inhibitor of the luminal step for the sodium-independent and ouabain-insensitive organic anion system, reduced luminal secretion of LY by 50%. Leukotriene C4 did not affect cellular accumulation of LY or the transport of fluorescein on the sodium-dependent system. A similar inhibition pattern was found for another fluorescent organic anion, a mercapturic acid derivative of monochlorobimane. Thus, both organic anions entered the cells on the basolateral transporter for the classical, sodium-dependent system, but about half of the transport into the lumen was handled by the luminal carrier for the sodium-independent system, which is most likely the multidrug resistance-associated protein. This is the first demonstration that xenobiotics can enter renal proximal tubule cells on the carrier associated with one organic anion transport system and exit into the tubular lumen on multiple carriers, one of which is associated with a second system.

Animals↗
PubMed1999

Mechanisms and interaction of vinblastine and reduced glutathione transport in membrane vesicles by the rabbit multidrug resistance protein Mrp2 expressed in insect cells.

The present study examined how the multidrug resistance protein (MRP) 2, which is an ATP-dependent anionic conjugate transporter, also mediates transport of the chemotherapeutic cationic drug vinblastine (VBL). We show that ATP-dependent [(3)H]VBL (0.2 microM) uptake into membrane vesicles from Sf9 cells infected with a baculovirus encoding rabbit Mrp2 (Sf9-Mrp2) was similar to vesicles from mock-infected Sf9 cells (Sf9-mock) but could be stimulated by reduced glutathione (GSH) with a half-maximum stimulation of 1.9 +/- 0.1 mM. At 5 mM GSH, initial ATP-dependent [(3)H]VBL uptake rates were saturable with an apparent K(m) of 1.5 +/- 0.3 microM. The inhibitory effect of VBL on Mrp2-mediated ATP-dependent transport of the anionic conjugate [(3)H]leukotriene C(4) was potentiated by increasing GSH concentrations. Membrane vesicles from Sf9-Mrp2 cells exhibited a approximately 7-fold increase in initial GSH uptake rates compared with membrane vesicles from Sf9-mock cells. Uptake of [(3)H]GSH was osmotically sensitive, independent of ATP, and was trans-inhibited by GSH. The anionic conjugates estradiol-17beta-D-glucuronide and leukotriene C(4) cis-inhibited [(3)H]GSH uptake but only in the presence of ATP. Whereas ATP-dependent [(3)H]VBL uptake was stimulated by GSH, VBL did not affect [(3)H]GSH uptake. Our results show that GSH is required for Mrp2-mediated ATP-dependent VBL transport and that Mrp2 transports GSH independent of VBL.

Animals↗
PubMed1998

Solid-phase extraction of 18beta-glycyrrhetinic acid from plasma and subsequent analysis by high-performance liquid chromatography.

A new method is described for the solid-phase extraction of 18beta-glycyrrhetinic acid from plasma or serum, with subsequent analysis by HPLC. New aspects of the method include the use of commercially available 18alpha-glycyrrhetinic acid as the internal standard and the use of a Bond Elut C2 (ethyl) extraction column, to avoid the need to use large volumes of organic solvent to elute the isolates from the columns. Separation was achieved on a Shandon Hypersil BDS C18 analytical column, with a mobile phase consisting of acetonitrile-0.02 M phosphate buffer, pH 5.7 (55:45, v/v). The column effluent was monitored at 248 nm. Compared with previous methods, the procedure is much easier to carry out, whereas the sensitivity (limit of detection, 10 ng/ml, and limit of quantitation, 50 ng/ml), the precision (0.3-6.2%) and the accuracy (97.2-101.9%) are of the same order of magnitude.

Calibration↗