摘要:

This study investigated the ability of 6 putative bombesin (BN) antagonists to inhibit BN-stimulated gastrin release from human antral G cells maintained in culture for 48 h. The analogs studied comprised different sequence changes based around a constant 6-amino-acid sequence from the C-terminal of the peptide. At concentrations of 1.0 μmol/l, analogs 1 and 2 stimulated gastrin release 3-fold above basal. The remaining 4 analogs showed no agonistic activity. After the addition of concentrations of 1.0 μmol/l against a BN concentration of 10.0 nmol/l the following levels of inhibition were obtained: analog 3, 90 ± 1.4%; analog 4, 95 ± 0.5%; analog 5, 99 ± 2.4%, and analog 6, 85 ± 3.8%. The 2 most effective analogs were analog 3, which was 9 amino acids in length with substitutions of two D-phenylalanine residues and a ψ-leucine bond [D-Phe6-ψ-Leu13-D-Cpa14-BN(6–14)NH2], and analog 5, which was 8 amino acids in length with a methyl ester at the C-terminus and a single D-phenylalanine substitution at the N-terminus [D-Phe6-BN(6–13)OMe]. These results suggest that the BN receptor present on the human antral G cells differs from that on guinea pig acinar cells and canine G cells, being less sensitive to C-terminal structural mo

ISSN:0031-7012    

DOI:10.1159/000138725

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Lacidipine is a new 1,4-dihydropyridine calcium entry blocker endowed with slow onset of action and potent and long-lasting antihypertensive activity. This study investigated the effect of lacidipine on some gastrointestinal functions, mainly gastrointestinal motility, in rats and dogs. In fasting conscious dogs chronically fitted with electrodes and strain gauges along the small bowel, lacidipine (12 μg/kg i.v. bolus or 10 μg/kg/h for 3 h) did not modify the migrating motor complex pattern or intestinal spike activity. In the rat, lacidipine proved less active (ED 50 > 100 mg/kg p.o.) than nitrendipine (ED 50 = 31 mg/kg p.o.) in inhibiting gastric emptying of a liquid meal, whereas the opposite was true after a solid meal (ED 50 = 10.9 and 35.0 mg/kg p.o., respectively). Lacidipine inhibited fecal pellet output at lower doses (ED 50 = 14.8 mg/kg p.o.) than nitrendipine (ED 50 = 40.1 mg/kg p.o.). On histamine-induced gastric acid secretion, the effect of 100 μg/kg i.v. lacidipine was moderate (maximum inhibition 45%). The gastrointestinal effects displayed by lacidipine appear at doses at least 5 and 50 times as high as those affecting blood pressure after intravenous and oral administration, respectively. Thus, lacidipine is unlikely to cause noteworthy unwanted effects on the gastrointestinal tra

ISSN:0031-7012    

DOI:10.1159/000138727

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The effect of 3-methylcholanthrene (MC) treatment on the cytochrome P-450c content of various rat tissues was examined by measuring the level of immunodetectable P-450c in conjunction with its aryl hydrocarbon hydroxylase (AHH) activity. Immunoblots revealed that P-450d was induced in the nasopharynx and pancreas in addition to its previously reported induction in the liver, lung and kidney. In contrast to P-450c, induction of the immunorelated P-450d was observed only in the liver. The specific content of immuno-detected P-450c in the tissue homogenates decreased in the order: liver, nasopharynx, pancreas, lung, kidney. The corresponding AHH activities decreased in the order: liver, kidney, lung, nasopharynx, pancreas. The ratio of AHH activity to P-450c content varied widely among tissues: ratios of 37.2:1.7:0.47:0.04:0.02 were obtained for the kidney, liver, lung, nasopharynx and pancreas, respectively. The absence of a direct relationship between the levels of AHH and P-450c indicates that the extrahepatic activity may partially derive from P-450 forms other than P-450c and/or the specific activity of P-450c varies among different tissues.

ISSN:0031-7012    

DOI:10.1159/000138729

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Desferrioxamine (DFO) metabolism and its pharmacokinetics were studied in a swine model using high-performance liquid chromatography. DFO and three iron-binding metabolites occurred in plasma. Interindividual differences in pharmacokinetics and metabolism were observed. Urine analysis in 4 pigs showed three iron-binding metabolites. The mean percent dose excreted in urine in the form of the parent drug was 45 ± 10% and 10 ± 2% (means ± SD) in the form of metabolites. Of the total amount of the parent drug infused, 3 h after initiation, 87% was in the form of DFO, whereas 13% was present as the DFO-iron III complex which represented 45 mg of urinary iron elimination. The described DFO infusion protocol provides for sufficient DFO to chelate significant amounts of ferric iron in excess of normal levels, thus allowing experimental studies of iron chelation in a variety of disease stat

ISSN:0031-7012    

DOI:10.1159/000138730

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The metabolism of 5-hydroxytryptophan (5-HTP) and tryptophan (TRP) in a single pass across the pulmonary circulation was studied in the isolated ventilated perfused rat lung and by high pressure liquid chromatography. The metabolism of 5-HTP was dependent on the rate of lung perfusion and the duration of infusion of 5-HTP, and was a saturable process with an apparent Km of 1.8 mM and Vmax of 0.14 μmol/g/3 min. The indoles found in the lung were 5-HTP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA); only 5-HIAA was detected in the lung effluent. The efflux of 5-HTP from the lung had two exponential components with half-lives of 0.15 and 3.65 min. After an infusion of 3H-5-HTP, the radiolabel that accumulated in lung was located mainly in the soluble fraction. An infusion of TRP resulted in the synthesis of 5-HTP, 5-HT and 5-HIAA in the lung, and 5-HTP was detected in the lung effluent. The results suggest that 5-HT can be synthesized in the intact lung from circulating TRP and 5-HTP. Since the rate of lung metabolism is low and no 5-HT is released into the lung effluent, the contribution of the lung to circulating levels of 5-HT is likely to be insignificant. Synthesis of 5-HT in intact lung suggests an intrapulmonary role for 5-HT

ISSN:0031-7012    

DOI:10.1159/000138732

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

To investigate the mechanism of lidocaine’s effect to cause vasorelaxation, swine epicardial mid-right coronary arterial rings were placed under constant (5 g) tension in a muscle bath, precontracted with 35 mmol/l KCl and exposed to increasing concentrations of lidocaine (3–2,000 μg/ml). At a concentration of 10μg/ml, mild vasoconstriction occurred, increasing tension 1.9 ± 0.1 % above baseline. Vasodilation began to occur at 30 μg/ml and was maximal at 2,000 μg/ml, reducing tension 97.5 ± 0.2% below baseline. Vasodilation was not altered significantly by removal of endothelium or by pretreatment with propranolol or in

ISSN:0031-7012    

DOI:10.1159/000138734

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

In rats anesthetized with urethane, intraperitoneal administration of a water-soluble organogermanium compound 2-carboxyethyl germanium sesquioxide (Ge-132) produced a dose-related reduction in either the mean arterial pressure or the heart rate. Both hypotension and bradycardia responses induced by Ge-132 injection were significantly inhibited by pretreatment of the animals with either spinal transection or bilateral vagotomy. The data indicate that Ge-132 induces both hypotension and bradycardia by promoting an activation of the parasympathetic efferent mechanisms and an inhibition of the sympathetic efferent mechanisms. On the other hand, following intraperitoneal injection of Ge-132, increased grooming and head swaying (as shown by an enhancement in fine movements monitored by an electronic activity counter) were provoked. Furthermore, the amphetamine-induced enhancement in fine movements was potentiated by pretreatment of the animals with Ge-132. Thus, it appears that Ge-132 acts through the catecholaminergic mechanisms in the brain to induce locomotor stimulation in rats.

ISSN:0031-7012    

DOI:10.1159/000138736

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

Profound obesity is conferred on the Zucker rat by homozygosity for a recessive gene (fa/fa); the heterozygous animal is lean. Subcutaneous administration of the heme analogue cobalt-protoporphyrin produces a long-sustained reduction in body weight of the homozygous Zucker rat. Intracerebroventricular injection of the compound, in a single small dose, results in an extremely prolonged (≈300 days) lowering of the ‘set point’ for body weight regulation, confirming a central nervous system action of the metalloporphyrin. The effect of cobalt-protoporphyrin is so pronounced that the phenotype of the homozygous, obese Zucker rat is changed to that of its lean litte

ISSN:0031-7012    

DOI:10.1159/000138738

出版商:S. Karger AG    

年代:1990

数据来源: Karger

摘要:

The pharmacology of SK&F R-105058 and SK&F R-106114, N-ethyl carbamate ester prodrugs of fenoldopam, was evaluated in pentobarbital-anesthetized dogs. The selective dopamine 1 (DA1) antagonist, SCH 23390, significantly attenuated the renal vasodilator effects of SK&F R-82526, the active enantiomer of fenoldopam. This dose of SCH 23390 also significantly attenuated the increase in renal blood flow and decrease in renal vascular resistance induced by the administration of either SK&F R-106114 or SK&F R-105058. The cholinesterase inhibitor, physostigmine, at a dose that significantly enhanced the renal effects of acetylcholine, did not alter the in vivo renal vasodilator effects of SK&F R-105058 or prevent conversion of SK&F R-105058 to fenoldopam. Thus, these data indicate that the renal vasodilator activity of fenoldopam prodrugs involves activation of DA1 receptors and that, unlike other carbamate ester prodrugs, conversion to the parent compound is unlikely to involve cholinesterase.

ISSN:0031-7012    

DOI:10.1159/000138739

出版商:S. Karger AG    

年代:1990

数据来源: Karger