摘要:

Subchronic treatment of aged mice with piracetam (500 mg/kg p.o. for 14 days) elevates N-methyl-D-aspartate (NMDA) receptor density by about 20% and normalizes the enhanced affinity of L-glutamate for the NMDA receptor. Since deficits at the level of the NMDA receptor might be one of the mechanisms underlying age-associated cognitive impairment, the effects reported for piracetam may be relevant for the cognition-enhancing properties of this drug.

ISSN:0031-7012    

DOI:10.1159/000139100

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Tacrine (THA) selectively modulates binding of M1 ligands in an allosteric fashion causing positive cooperativity. The binding affinity of THA to M1 and M2 cholinoceptors is similar. It is therefore proposed that the allosteric selectivity of THA is a function of the binding site and not of THA itself. Its interaction of M1 and M2 cholinoceptors was examined in guinea pig brain homogenates using the selective M1 and M2 antagonists [3H]-pirenzepine ([3H]PZ) and [3H]AF-DX 384. The dissociation constants were 0.36 nmol/l for the M1 receptor and 0.23 nmol/l for the M2 receptor. We also compared the binding of THA and methoctramine (MTA) at M2 receptors. Tacrine displayed similar binding affinity for both M1 and M2 receptor subtypes. MTA was 100 times more potent an inhibitor of [3H]AF-DX 384 binding at M2 receptors than THA. In addition, THA was found to slow the dissociation of [3H]PZ from the M1 receptor. In contrast, the dissociation of [3H]AF-DX 384 from M2 receptor subtypes was unaffected. We conclude that THA acts as an agonist at M1 cholinoceptors because it slowed the dissociation of [3H]PZ. At M2 cholinoceptors its nature is that of an antagonist because it had no effect on [3H]AF-DX 384 dissociation.

ISSN:0031-7012    

DOI:10.1159/000139101

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Studies investigated the effect of the opiate antagonist naloxone (10 mg/kg) on stomach to caecum transit (SCTT) during ileal infusion of saline or Intralipid. SCTT of the head of the meal was measured by hydrogen analysis and meal distribution by the radiolabelled meal technique. Intralipid delayed SCTT by delaying both gastric emptying (p < 0.01) and small bowel transit. Naloxone did not affect SCTT during ileal saline infusion, but produced a distal shift (p < 0.05) in the geometric centre of the meal and increased radioactivity in the caecum (p < 0.001) 100 min after gavage. Naloxone abolished the delayed SCTT of the meal induced by ileal lipid infusion, with an associated increase in radioactivity in the caecum at 200 min (p < 0.01), although the geometric centre was shifted proximally within the intestine (p < 0.01). The results suggest that the ileal brake is mediated in part by endogenous opiate pathways.

ISSN:0031-7012    

DOI:10.1159/000139102

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Chronic exposure of rats to cold (5°C, 3-4 weeks) results in the development of hypertension. To assess potential mechanisms by which this may occur, the vascular responsiveness to administration of phenylephrine (an α-adrenergic agonist) and angiotensin II (AII) was studied in unanesthetized rats at 1, 3 and 5 weeks of exposure to cold (5°C). Vascular responsiveness to intravenous administration of graded doses of phenylephrine was reduced in cold-treated rats, the earliest effect being observed within 1 week of exposure. With respect to AII, vascular responsiveness to graded intravenous doses increased maximally within 1 week of exposure to cold and returned toward the level of the control group at 3 weeks. After 5 weeks of exposure to cold, it had returned to the level of the control group. These results suggest that vascular responsiveness to α-adrenergic stimulation appears to be directed toward prevention of an elevation of blood pressure in cold-treated rats. In contrast, vascular responsiveness to administration of AII is increased during the first 3 weeks of exposure to cold, at a time when plasma renin activity is also increased, and may thus play an important role in the initiation of cold-induced elevation of blood press

ISSN:0031-7012    

DOI:10.1159/000139103

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Bladder contraction, similar to most smooth muscle contraction, is dependent on both the translocation of extracellular calcium across the cell membrane, and the calcium-stimulated release of intracellular bound calcium. Partial outlet obstruction of the urinary bladder induces a marked increase in bladder mass which results in part from a substantial hypertrophy of the smooth muscle elements. In addition, the increase in bladder mass is associated with specific contractile dysfunctions. It is not known if the contractile dysfunction induced by partial outlet obstruction is related to alterations in calcium metabolism. Ryanodine is a pharmacological tool which can be utilized to study the role of intracellular calcium in mediating contractile events. Ryanodine stimulates the loss of intracellular calcium (bound in the sarcoplasmic reticulum) and reduces the participation of intracellular calcium in the contractile response to specific forms of stimulation. The current study investigates the effect of partial outlet obstruction on the ryanodine inhibition of the contractile response of rabbit urinary bladder to field stimulation. New Zealand White rabbits were anesthetized and catheterized with an 8-french Foley catheter. A 00 silk suture was surgically placed around the catheterized urethra, the incision closed, and the catheter removed. After 1, 3, 5 and 7 days of partial outlet obstruction, the bladder was rapidly removed and utilized immediately for contractile studies. The effect of ryanodine (0-80 µM) on the peak response to 2-, 8- and 16-Hz field stimulation at 0.6, 1.8 and 5.4 mM calcium was determined. Ryanodine induced a dose-dependent inhibition of the contractile response of control bladder strips to 2-Hz stimulation (all calcium concentrations), whereas it had no statistically significant inhibitory effect at 8- and 16-Hz stimulation on control tissue. Bladder hypertrophy resulted in a significant and substantial increase in the inhibitory effect of ryanodine at 2, 8 and 16 Hz. In general, the inhibitory effect of ryanodine was most effective at 0.6 mM calcium, and equally effective at 1.8 and 5.4 mM Thus, bladder hypertrophy secondary to partial outlet obstruction induced a marked and significant increase in the inhibitory effect of ryanodine. This indicates that bladder hypertrophy induces a significant alteration in intracellular calcium storage and utilization

ISSN:0031-7012    

DOI:10.1159/000139104

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Enzymatic scavenging of O2 radicals by injections of superoxide dismutase has been described to inhibit the free radical reactions resulting in tissue damage. Using a biochemically induced model of osteoarthritis (OA) in the knee joints of hens, we investigated the histomorphological alterations under therapy with recombinant human superoxide dismutase (rH-SOD) in various doses by histological-histochemical grading. Treatment of experimental OA with rH-SOD (0.1 mg/ 0.1 ml intra-articularly) led to a significant reduction in the intensity of cartilage degradation. The pathomorphological alterations in the osteoarthritic cartilage of hens treated with rH-SOD were quantitatively but not qualitatively different from the placebo-treated group. Our results indicate that rH-SOD exerts an inhibitory effect on the deleterious processes on articular cartilage tissue during the course of OA and may counteract cartilage degradations induced or accelerated by oxygen radicals.

ISSN:0031-7012    

DOI:10.1159/000139105

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The pharmacokinetics of tobramycin as a single intravenous dose (3 mg/kg) were determined in young (2–3 months) and aged (22–24 months) rats and in similar groups 24 h after a single intraperitoneal injection of endotoxin (5 mg/kg). In aged rats the systemic clearance of tobramycin was significantly lower than in young rats. Endotoxin significantly decreased tobramycin clearances in both age groups, the effect being more pronounced in aged rats. The endogenous creatinine clearance followed a similar pattern as the tobramycin clearance. The volume of distribution at steady state (Vdss) was significantly lower in aged rats than in young rats. Endotoxin tended to increase Vdss in both age groups. In aged rats, however, Vdss was still significantly lower than values from young rats. The mean residence time (MRT) and terminal half-life (t½β) of tobramycin were similar in young and aged rats. Endotoxin had no effect on these parameters in young rats when compared with their controls. In aged rats, however, endotoxin significantly prolonged both MRT and t½β when compared with normal aged rats and with young endotoxin-treat

ISSN:0031-7012    

DOI:10.1159/000139106

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Biotransformation of the triazolobenzodiazepine alprazolam (ALP) was studied in vitro using hepatic microsomal preparations from human, monkey, mouse, and rat liver tissue. Two principal hydroxylated metabolites were identified: 4-hydroxy- and α-hydroxy-alprazolam (4-OH-ALP and α-OH-ALP). In all species, rates of 4-OH-ALP formation exceeded those of α-OH-ALP. In human liver microsomes, ratios of 4-OH-ALP/α-OH-ALP reaction velocities calculated at clinically relevant plasma concentrations of ALP ranged from 7 to 17, qualitatively consistent with, but numerically larger than, the ratio of the plasma levels of the two metabolites during clinical use of ALP in humans. Km values for both 4-OH-ALP (170–305 µM) and α-OH-ALP (63–441 µM) considerably exceeded the usual maximum plasma concentration observed in humans (200 ng/ml, 0.65 µM), consistent with the linear (dose-independent) pharmacokinetic characteristics of ALP observed in humans. Thus formation of 4-OH-ALP via hydroxylation is the major route of ALP metabolism. This pathway is probably mediated by the cytochrome P-450-3A subfamily. Factors that impair the activity of this cytochrome subtype are likely to impair clearance of

ISSN:0031-7012    

DOI:10.1159/000139107

出版商:S. Karger AG    

年代:1993

数据来源: Karger