Search PubMed⌕ Search

Biomedical subjects

E Scholtens

Publications and source records attributed to E Scholtens.

At least 37 records · Page 2Linked to original sources
PubMed1987

Captopril-induced increase in coronary flow: an SH-dependent effect on arachidonic acid metabolism?

The effect of captopril (80 micrograms/ml) on coronary flow in the isolated rat heart was compared with the effects of a non-sulfhydryl-converting enzyme inhibitor, ramipril (15 micrograms/ml), and of a sulfhydryl-containing compound with no converting enzyme-inhibiting properties, glutathione (112 micrograms/ml). Drug concentrations were equipotent in their effect on angiotensin I pressor response and equimolar with respect to the sulfhydryl group. Cyclooxygenase products or their stable metabolites (TXB2, 6-keto-PGF1 alpha and PGE2) were measured in the coronary effluent. Furthermore, the effect of mepacrin (1 microM), indomethacin (1 microM), and FPL 55712 (10 microM) on the changes in coronary flow induced by captopril was studied. Both captopril- and glutathione-treated hearts showed a significant increase in coronary flow already after 5 min treatment. After 60 min treatment, coronary flow was further increased to 185 +/- 9% for captopril-treated hearts and to 210 +/- 11% for glutathione-treated hearts when compared to saline treatment. Ramipril treatment resulted in a slower increase in coronary flow, which was significant after 20 min treatment. After 60 min treatment, this increase was 122 +/- 3% when compared to saline-treated hearts. This effect of ramipril was associated with a significant increase in 6-keto-PGF1 alpha overflow when compared to saline-treated hearts. Captopril and glutathione had no significant effect on overflow of the measured cyclooxygenase products. The effect of captopril and glutathione on coronary flow appeared to be dose dependent in an equimolar range. Simultaneous mepacrin treatment diminished the effect of captopril on coronary flow; indomethacin had no effect, and FPL 55712 potentiated the effect of captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Glucuronidation and sulfation in the rat in vivo. The role of the liver and the intestine in the in vivo clearance of 4-methylumbelliferone.

The role of the liver in the conjugation of 4-methylumbelliferone (4MU), mainly glucuronidation, was investigated in the rat in vivo. The liver extracted 4MU almost completely (97%) during steady-state infusion, as measured by the difference between 4MU concentration in portal and hepatic venous blood. Previously, it was shown that the intestinal region extracts 40% of the 4MU of the incoming arterial blood. The liver and the gastrointestinal region are so efficient that their conjugation activity can account for total body clearance of 4MU (50-60 ml/min per kg). These results and other evidence on extrahepatic conjugation of phenolic substrates suggest that glucuronidation may be limited to the liver, (the kidney) and the gastrointestinal region, while sulfation may occur more widespread throughout the body. Protein binding studies showed the sulfate conjugate to be even more protein-bound than unconjugated 4MU, while 4MU glucuronide was much less bound to rat plasma proteins.

Animals↗
PubMed1984

Extrahepatic sulfation and glucuronidation in the rat in vivo. Determination of the hepatic extraction ratio of harmol and the extrahepatic contribution to harmol conjugation.

The phenolic compound, harmol, is metabolized by sulfation and glucuronidation in the rat in vivo. In the present study, various harmol infusion rates into the jugular vein were used to delineate first-order conditions whereby total body clearance was maximal and constant; at low infusion rates the steady state harmol concentration in blood varied proportionally with the infusion rate. At infusion rates of 167 nmole/min and below, the steady state clearance of harmol was 60 ml/min or 200 ml/min/kg. Because this value for total body clearance greatly exceeded the value for hepatic blood flow rate (20 ml/min for a 300 g rat), considerable extrahepatic conjugation of harmol was suggested. At higher harmol infusion rates the total clearance decreased. Since an intraportal infusion of 167 nmole/min to the rat yielded, during steady state, the same arterial harmol blood concentration as a 52 nmole/min jugular infusion, the hepatic extraction ratio of harmol in vivo was 0.7. Extrahepatic clearance, therefore, constituted about 77% of total body clearance (after taking the difference between total body clearance and hepatic clearance). Total sulfation clearance was 52 ml/min, and greatly exceed the value for hepatic clearance (14 ml/min). Extrahepatic clearance for sulfation (at least 38 ml/min) therefore accounted for a major proportion of the sulfation activity. Blood platelets did not seem to contribute to sulfation or glucuronidation in vivo.

Alkaloids↗
PubMed1983

A simple method of obtaining multiple blood samples from the portal vein and the hepatic vein in the rat in vivo.

A very simple and rapid technique for inserting a catheter in the portal vein and the hepatic vein in the anesthesized rat in vivo is described. The pointed, saline-containing PE tubing is frozen in liquid nitrogen, whereupon it is used as a 'needle' to insert the catheter into the blood vessel. Multiple blood samples can be obtained from the portal and the hepatic vein at the same time, so that in situ extraction of drugs by the liver can be measured in vivo, since hepatic blood flow is uninterrupted.

Animals↗
PubMed1983

Effects of variation in the dietary supply of cysteine and methionine on liver concentration of glutathione and "active sulfate" (PAPS) and serum levels of sulfate, cystine, methionine and taurine: relation to the metabolism of acetaminophen.

Amounts of the sulfur-containing amino acids methionine and cysteine in synthetic diets were decreased from 22.8 mmol methionine (= 100 Met) and 26.4 mmol cysteine (= 100 Cys) per kilogram diet in the control group to (Met/Cys) 100:0, 75:0, 50:0, 25:0 and 25:25, respectively, in experimental diet groups, in order to evaluate effects of limiting sulfur supply on the availability of cosubstrates for conjugation. Below a Met level of 22.8 mmol/kg growth rates decreased. Urinary excretion of inorganic sulfate decreased to 10-20% of control values in all groups. Feeding diets 100:0 and 75:0 for 14 days resulted in a decrease of the concentration of inorganic sulfate in serum; on diets 25:25 and 25:0 an increase was found. A decreased content of methionine/cysteine resulted in an increase in cystine, a decrease in taurine and no change in methionine concentration in serum. In all experimental groups the glutathione concentration in the liver diminished to about 20% of control values, and the hepatic concentration of "active sulfate" (PAPS: adenosine 3'-phosphate 5'-phosphosulfate) decreased in most rats. At the lowest methionine supply, sulfate conjugation of acetaminophen decreased to 50% of control. The formation of the acetaminophen glutathione conjugate remained unaffected, in spite of a decreased hepatic glutathione availability.

Acetaminophen↗
PubMed1983

Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activities of harmol in the perfused rat liver preparation.

The role of zonal distributions of metabolic activities (sulfation and glucuronidation) in the liver on the kinetics of harmol conjugation was investigated. A computer simulation approach was adopted to better understand the effects of distributions of these conjugation activities in competition for a common drug substrate. Several distributions of the sulfation and glucuronidation systems were defined with respect to the flow path of blood; the conjugation activities along the flow path were in turn translated as time elapsed after entry of the substrate via blood into the organ. Realistic values of Km and Vmax for the sulfation and glucuronidation systems were assigned in the simulations. Directional flow, namely, normal vs. retrograde delivery of substrate was used as an additional variable. When the "center" of distribution of the sulfation system was anterior to that for glucuronidation, the steady-state hepatic extraction ratio of harmol (E) would increase, whereas the ratio of the steady-state rates of formation of harmol sulfate to harmol glucuronide (S/G ratio) would decrease when harmol was presented in a reversed direction (via retrograde perfusion), as compared with normal directional flow to the liver. The converse was true for an anterior distribution of the glucuronidation system; E would decrease, whereas S/G would increase with retrograde perfusion. To evaluate such zonal differences experimentally, perfusion studies were conducted in livers of male Wistar rats. A constant concentration of harmol (50 microM) was delivered under constant hepatic flow rate (10 ml/min/liver) by normal and retrograde perfusions to the same rat liver preparation. The steady-state hepatic E was higher (P less than .005) during retrograde perfusion than during normal perfusion, whereas the S/G ratio was significantly decreased (P less than .0005). The observations suggest an intercellular difference in the distribution of the two conjugating systems and are consistent with the view of the center of distribution for the sulfation system being anterior to the center of distribution for the glucuronidation system along the normal flow path of blood in the liver.

Alkaloids↗
PubMed1982

The dependence of the rate of sulphate conjugation on the plasma concentration of inorganic sulphate in the rat in vivo.

The dependence of the rate of sulphation of harmol [7-hydroxy-1-methyl-9H-pyrido(3,4-b)indole] on the plasma concn of inorganic sulphate was estimated in the rat in vivo. This was done in rats that were fed a low protein diet for 4 days to deplete the pool of inorganic sulphate, which decreased the plasma concn of sulphate from 0.9 mM normally to about 0.15 mM. Infusion of sodium sulphate at a rate that was stepwise increased, yielded a range of constant plasma sulphate levels below and above the physiological concn in plasma. By a constant infusion of harmol (6 mumoles/min/kg body wt), a steady state in the excretion of harmol sulphate could be reached at various plasma concns of sulphate. The apparent Km for inorganic sulphate was approx 0.3 mM. The relevance of these data in the evaluation of the effects of changes in the availability of inorganic sulphate on sulphate conjugation of xenobiotics is discussed.

Animals↗
PubMed1982

Kinetics of sulfation and glucuronidation of harmol in the perfused rat liver preparation. Disappearance of aberrances in glucuronidation kinetics by inhibition of sulfation.

Harmol is conjugated by glucuronidation and sulfation when it is given to the rat in vivo. In the once-through perfused rat liver preparation glucuronidation of harmol shows kinetic aberrances [Pang et al., J. Pharmac. exp. Ther. 219, 134 (1981)]. In order to further delineate the mechanism behind this, sulfation was inhibited to about 10% of control by 2,6-dichloro-4-nitrophenol. The loss of sulfation was compensated by an increase in the rate of glucuronidation, keeping the total clearance by the liver virtually constant in spite of the loss of sulfation. The inhibition of sulfation eliminated the previously observed lag-phase in the kinetics of glucuronidation; the rate of glucuronidation was now almost linear with the input concentration of the substrate harmol. The constant clearance of harmol in spite of inhibition of sulfation, the occurrence of the lag-phase in glucuronidation in the presence of sulfation, and the disappearance of this lag-phase in the absence of sulfation can be explained by either diffusion-limited metabolism of harmol or a heterogeneous sub-lobular distribution of the sulfating and glucuronidating systems. Activation of glucuronidation by harmol at high concentration can be excluded.

Alkaloids↗
PubMed1982

Selective inhibition of sulfate conjugation in the rat: pharmacokinetics and characterization of the inhibitory effect of 2,6-dichloro-4-nitrophenol.

The pharmacokinetics of 2,6-dichloro-4-nitrophenol (DCNP) have been studied in the rat. Upon i.v. injection the plasma decay curve of DCNP showed a rapid distribution phase. After 30 min the plasma concentration reached a value that was constant for at least 90 min, indicating very slow elimination of DCNP. The volume of distribution was 88 ml/kg and a high degree of binding (over, 99%) of DCNP in vitro to bovine serum albumin was found. The concentration of DCNP in the liver was between 30 and 50% of the plasma values. While in vivo the effect of DCNP persisted for a long time, its action was readily reversible in the single-pass perfused rat liver. In vivo, the effect of the dose of DCNP on the inhibition of sulfation of the phenolic compound harmol was investigated. Upon the i.v. injection of 26 mumole DCNP/kg an instantaneous and complete inhibition of sulfation of harmol was found. Using this property of DCNP, the rate of sulfation of harmol in vivo was evaluated in relation to the dose and the time after injection of the substrate. Saturation of sulfation apparently occurred because the consumption of inorganic sulfate was extremely small.

Animals↗
PubMed1982

Cholestatic effect of harmol glucuronide in the rat. Prevention of harmol-induced cholestasis by increased formation of harmol sulfate.

Harmol, a phenolic compound of low molecular weight, is conjugated either with glucuronic acid or sulfate. A clear relationship is observed between the metabolism of harmol and the occurrence of cholestasis: high concentrations of harmol glucuronide in bile induced a complete stop of bile flow, both in the rat in vivo and in the perfused rat liver. Intravenous infusion of harmol (250 mumol/hr/kg b.wt.) in vivo in the rat considerably decreased the availability of sulfate and, consequently, the amount of harmol sulfate excreted in bile and urine; this decrease was compensated for by an increase in glucuronidation, which caused complete cholestasis when the concentration of harmol glucuronide in bile became of the order of 20 mM. A sufficient supply of sulfate by infusion of sodium sulfate prevented the decrease in sulfation and the increase in glucuronidation and no cholestasis occurred. Low sulfate availability in rats fed a low-protein diet decreased the time of harmol infusion required for cholestasis to occur. Alleviation of the cholestasis in low-protein diet-fed rats was observed when after 2 hr of infusion of harmol additional sulfate was supplied. In the single-pass perfused rat liver, cholestasis occurred when large amounts of harmol glucuronide were excreted in bile. When sulfation of harmol was inhibited by 2,6-dichloro-4-nitrophenol, cholestasis occurred at lower infusion rates of harmol. These data indicate that harmol glucuronide is cholestatic when its concentration in bile increases beyond a threshold concentration; the protein content of the diet may profoundly affect the occurrence of this toxic effect.

Alkaloids↗
PubMed1981

The oxidation of L- and D-cysteine to inorganic sulfate and taurine in the rat.

Oral administration of L-cysteine to rats (8 mmol/kg body wt.) caused a rapid increase of the concentration of cystine in serum, from less than 5 micro M in controls to about 200 micro M. Concomitantly, the serum concentration of inorganic sulfate increased, reaching a peak 2 h after L-cysteine administration; this level, twice the control level, was maintained for 4 h. Serum sulfate returned to control concentration 23 h after L-cysteine administration. The urinary excretion of inorganic sulfate during the 24 h after administration increased considerably, and 33% of the dose of L-cysteine was recovered as inorganic sulfate in urine. Consumption of comparable amounts of L-cysteine via the food caused the same increase in urinary excretion of sulfate, but did not increase the concentration of sulfate in serum. After oral administration of D-cysteine (8 mmol/kg body wt.), very high cystine levels were reached in serum (mean concentration about 1500 microM); the sulfate concentration was already maximal 30 min after administration. The increase in urinary excretion of sulfate after D-cysteine was also higher than after L-cysteine administration: 55% of the dose. Possible routes for the rapid degradation of D-cysteine to inorganic sulfate are discussed. The administration of L-cysteine also caused an increase the serum concentration of taurine, while methionine was not influenced. D-Cysteine did not increase the serum concentration of taurine, indicating that it is probably not or only slowly converted to taurine.

Administration, Oral↗
PubMed1979

Absorption, serum levels and urinary excretion of inorganic sulfate after oral administration of sodium sulfate in the conscious rat.

The absorption of inorganic sulfate after ingestion was investigated in rats. After oral administration of Na235SO4, 35S radioactivity was measurable in plasma already after 15 min and its plasma concentration reached a peak after about 1.5--2 h. The 35S-radioactivity excreted in urine during 24 h after ingestion of Na235SO4 together with varying amounts of unlabelled Na2SO4 (0.25--5.0 mmol Na2SO4 per rat) indicated an almost complete absorption of inorganic sulfate from the gastrointestinal tract. Determination of the inorganic sulfate concentration in rat serum 2 h after oral administration of 5.0 mmol Na2SO4 revealed a three-fold increase in serum sulfate concentration. The data suggest a rapid and almost complete absorption of inorganic sulfate after oral administration in the rat. Its importance in relation to the sulfate availability for sulfate conjugation of drugs is discussed.

Administration, Oral↗
PubMed1979

Inhibition of sulfation of phenols in vivo by 2,6-dichloro-4-nitrophenol: selectivity of its action in relation to other conjugations in the rat in vivo.

The effect of 2,6-dichloro-4-nitrophenol, an inhibitor of the sulfation of the phenolic compound harmol in vivo, on the sulfation of other phenolic substances and on various conjugation reactions has been studied in the rat in vivo. Compounds chemically related to 2,6-dichloro-4-nitrophenol were also tested as sulfation inhibitors. 2,6-Dichloro-4-nitrophenol inhibited the sulfation of phenol while it had no effect on biliary excretion of dibromosulphthalein, glucuronidation of phenolphthalein, acetylation of procainamide ethobromide or glutathione conjugation of ethacrynic acid. It is concluded that of these conjugation reactions sulfation is inhibited selectively at the dose level used. Some phenols with chloro- or nitro-substituents effectively inhibited the sulfation of harmol but to a lesser extent than 2,6-dichloro-4-nitrophenol. Many other phenols did not affect the conjugation of harmol, which is both glucuronidated and sulfated.

Animals↗