摘要:

The diastereomeric glucuronic acid conjugates are major metabolites of the nonsteroidal anti-inflammatory drug fenoprofen (FEN). Glucuronidation of FEN enantiomers was investigated with liver microsomal preparations from different species (sheep, rabbit, rat and human). The formed R- and S-FEN conjugates can be separated and quantitated directly on a C18 reversed-phase HPLC column using a mixture of acetonitrile and tetrabutylammonium sulfate buffer, pH 2.5, as mobile phase. Applying this analytical procedure, it is possible to characterize enantioselective glucuronidation of FEN. For in vitro procedures, rates of glucuronide formation are substrate (FEN) and cosubstrate (UDP glucuronic acid, UDPGA) dependent with initial rates of glucuronide formation being higher for R- than for 5-FEN. The R/S ratio of the formed products was independent of UDPGA (2.5–15 mmol/l) and substrate concentrations ≧ 0.4 mmol/l. Enantioselective cleavage of the formed FEN conjugates by alkaline hydrolysis and hydrolytic enzymes (R S-glucuronide) can be controlled during in vitro studies by pH adjustment and the addition of enzyme inhibit

ISSN:0031-7012    

DOI:10.1159/000138828

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The urinary bladders of 1-day- and 1-week-old rabbits generate higher intravesical pressures in response to bethanechol and field stimulation than bladders isolated from mature 8-week-old rabbits. Yet the density of cholinergic receptors in the rabbit bladder does not change with maturation (1 day to 8 weeks). In an effort to better understand the molecular mechanisms by which newborn rabbit bladders generate greater pressures than the bladders of adult rabbits, we studied the effect of maturation on the relationship between extracellular calcium and contraction. Our results showed quite clearly that (1) at physiologic concentrations of calcium (2.5 µmol/l), isolated bladder strips of 1-day- and 1-week-old rabbits contracted in response to bethanechol to 98% of their maximal tension as opposed to 68% for their 8-week-old counterparts, (2) the ED50 (for calcium) for the 1-day and 1-week bladders was 0.4 mmol/l whereas the ED50 for the adult bladder strips was 2.2 mmol/l, and (3) the neonatal bladders demonstrated a much greater sensitivity to diltiazem than the adult bladders. The contractile response to calcium of the neonatal bladders was significantly inhibited by 1 µmol/l diltiazem whereas the 8-week-old bladders showed no inhibition at this concentration. In a second series of experiments, the effect of extracellular calcium on contraction was correlated with the intracellular concentration of free calcium using the calcium fluoride FURA-2 and surface spectrofluorometry. These studies confirmed that the increased contractile response of the neonatal bladder strips to calcium or cholinergic agonists was associated with an increase in the maximal intracellular free calcium concentratio

ISSN:0031-7012    

DOI:10.1159/000138829

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The contractile response of the rabbit urinary bladder to field stimulation consists of both cholinergic and purinergic components. In general, approximately 60% of the contractile response to field stimulation is cholinergic and 40% is purinergic. Although the purinergic response represents a significant proportion of the initial (phasic) pressure response to field stimulation of the isolated whole bladder, it contributes only 10–15 % of the ability of field stimulation to empty the bladder. The current study investigates the effects of pregnancy on the contractile responses of the isolated urinary bladder to cholinergic and purinergic stimulation. The results of these studies indicate that pregnancy induces substantial changes in the physiology and pharmacology of the urinary bladder. The following data are consistent with the theory that pregnancy substantially increases the relative purinergic component of the response to field stimulation (and presumably neuronal stimulation): (1) there was a significantly greater response of the bladders isolated from pregnant rabbits to low-frequency field stimulation; (2) atropine was more effective at inhibiting the pressure generation of bladders isolated from virgin female rabbits; (3) field stimulation was more effective at emptying bladders isolated from virgin female rabbits; (4) the response of the bladders from pregnant rabbits to bethanechol was significantly reduced, whereas the response to ATP was significantly increased. In addition to these effects of pregnancy on bladder physiology, pregnancy induced a 50% decrease in the muscarinic receptor density of the urinary bladder body, which correlated very well with the 50% decrease in the contractile response to bethanecho

ISSN:0031-7012    

DOI:10.1159/000138830

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Increased vascular permeability in the adult respiratory distress syndrome is due in part to toxic oxygen metabolites. In the present study, we produced lung injury in the isolated rabbit lung with hydrogen peroxide (H2O2) and examined its prevention with isoproterenol. Pulmonary arterial pressure (Ppa) and the fluid filtration coefficient (Kf) were measured as indices of lung injury. Rabbits were divided into two groups, and 7 mmol/l H2O2 was administered in both groups. In one group, isoproterenol (2 µg/ml) was administered 10 min before H2O2 injury. Ppa increased transiently after H2O2 administration in the control group but was unchanged in the isoproterenol group. Kf was significantly increased by H2O2 administration in the control group but not in the isoproterenol group. We conclude that H2O2 increases pulmonary vascular permeability and that isoproterenol may protect against H2O2-induced pulmonary injury

ISSN:0031-7012    

DOI:10.1159/000138831

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Endothelin-1 (ET-1) is a recently described potent vasoconstrictor peptide. Plasma and myocardial tissue levels of ET-1 are increased following myocardial ischemia, however, the factors which regulate ET-1 binding sites in vivo are not well understood. ET-1 binding sites were measured by Scatchard analysis of [125 septum (609 fmol/mg protein) = left ventricle (498 fmol/mg protein). Following coronary artery occlusion for 24 h, ET-1 binding sites of left atrium were decreased by 35 % (p < 0.01), without a change in the Kd (i.e., 98 pA/). Other regions of the myocardium did not exhibit any change in the number of ET-1 binding sites. Similarly, no change in ET-1 binding sites were observed following coronary artery occlusion for 0.5 h followed by 24 h reperfusion. These data indicate that there exists considerable regional differences in the density of ET-1 binding sites in the myocardium, and that ET-1 sites are selectively reduced in left atrial tissue following myocardial infarction.

ISSN:0031-7012    

DOI:10.1159/000138832

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The acute and chronic effects of a potent selective dopamine β-hydroxylase inhibitor, SK&F 102698, were assessed in chronically instrumented 1-kidney, 1-clip Gold-blatt hypertensive dogs. Blood pressure measured directly from either a carotid loop or from a vascular access port and cardiac output measured by impedence cardiography were monitored following acute (30 and 100 mg/kg, p.o.) and chronic (30 mg/kg/day for 4 days) administration of SK&F 102698. The data indicate that SK&F 102698 failed to alter blood pressure, cardiac output or total peripheral resistance after either acute or chronic administration. It is concluded that dopamine β-hydroxylase inhibition with SK&F 102698 is not an effective antihypertensive agent in the 1-kidney, 1-clip Goldblatt hypertensive dog mode

ISSN:0031-7012    

DOI:10.1159/000138833

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Adult male beagle dogs were treated with 10 weekly intramuscular injections of cobalt protoporphyrin (CoPP; 2 µmol/kg body weight). Treated dogs progressively lost weight to the extent of 20–30% at the end of the treatment period. Weight loss was accompanied by decreased food consumption. Following cessation of therapy with CoPP animal weights returned to pretreatment values within 5 weeks. These treatments were tolerated without detectable adverse side effects, and clinical, laboratory and histopathological analyses were normal. This study extends the spectrum of animals which decrease their body weight in response to CoPP administration from those which gain weight throughout life to those which maintain a stable body weight in adultho

ISSN:0031-7012    

DOI:10.1159/000138834

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The effects of 16 days of oral treatment with thyrotropin-releasing hormone (TRH, 1 mg/24 h) on serum levels of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) and the kinetics of TRH in the blood were studied in normal rats. A second group of animals served as controls. TRH was dissolved by sonification (10 mg/l) and was stable in tap water. TRH was measured by a radioimmunoassay procedure (normal range: 20–80 pmol/l, antiserum K2B9 1:120,000 final dilution). An increase in basal TSH (7,200 ± 440 ng/l, mean ± SD) was found after 2 days of treatment (11,420 ± 810 ng/l), but a significant increase was observed after 5 days of treatment (12,530 ± 640 ng/l, p < 0.001). T4 serum concentrations remained in the normal range during the entire period of study, whereas T3 serum concentrations (0.76 ± 0.1 µg/l) were increased to 1.22 ± 0.2 µg/l on day 5 (p < 0.001). A subsequent decline of TSH, T4 and T3 up to the end of the study was observed. TRHmax concentrations were registered on day 5 (790 ± 24 pmol/l). The mean value of TRHmax was 723 ± 34 pmol/l. To improve the stability of TRH in tap water, 1-ml samples of drinking water with dissolved TRH were measured. The mean TRH concentration in drinking water was 73 ± 1.5% (SD). No significant correlations were found between the area under the curve of TSH (184,340 ng·l–1·24 h) and that of TRH (14,954 pmol·l–1·24 h). These findings suggest that (1) chronic treatment with oral TRH cannot induce hyperthyroidism in rats, (2) oral TRH is absorbed when dissolved in tap water where it is stable and (3) the enzymatic process of TRH degradation is saturated at high doses of the peptide used in this study. Chronic treatment with oral TRH is a useful model to study the pituitary reserves in relation

ISSN:0031-7012    

DOI:10.1159/000138835

出版商:S. Karger AG    

年代:1991

数据来源: Karger