摘要:

The effect of Y-24180, a potent antagonist to platelet-activating factor (PAF), was evaluated on the antigen-induced immediate asthmatic response (IAR) in actively sensitized guinea pigs that were pretreated with an antihistaminic agent, pyri-lamine. Then, the effect was compared with that of other antiasthmatic agents. In a dose-dependent manner, Y-24180 (0.01–1 mg/kg, p.o.) suppressed the IAR, and WEB 2086 (0.1–10 mg/kg, p.o.), another PAF antagonist, also suppressed IAR in the same fashion as Y-24180. In contrast, AA-2414 (1–100 mg/kg, p.o.), a thromboxane A2 (TXA2) antagonist, was effective only at the beginning of the IAR and ONO-1078 (1–100 mg/kg, p.o.), a peptide leukotriene (pLT) antagonist, was effective only in the latter period, OKY-046, a TXA2 synthetase inhibitor, showed no significant suppression of the IAR at doses up to 100 mg/kg. Thus, PAF antagonists were more effective than the other agents tested in the present model for IAR. In a subsequent test, Y-24180 (1 mg/kg, p.o.) was confirmed to enhance the suppressive effects of theophylline (10 and 30 mg/kg, p.o.), procaterol (0.1 and 1 µg/kg, i.v.), OKY-046 (100 mg/kg, p.o.) and ONO-1078 (100 mg/kg, p.o.) on the IAR. A combination of three agents, namely Y-24180 with OKY-046 and ONO-1078, completely suppressed the IAR. The results demonstrate that Y-24180 not only suppresses the IAR, but also enhances the suppressive effect of other antiasthmatic agents. Therefore, Y-24180 would be a clinically promising drug for the treatment of bronchia

ISSN:0031-7012    

DOI:10.1159/000139463

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Sch 37224 is an experimental antiallergy coumpound that inhibits hyperventilation-induced bronchoconstriction (HIB) in guinea pigs and cold air bronchospasm in human asthmatics. HIB in guinea pigs may involve the release of tachykinins, such as neurokinin A (NKA) and substance P (SP), and the action of Sch 37224 in this model may relate to inhibition of these neuropeptides. We studied the effect of Sch 37224 on the neuropeptide component of HIB that was enhanced in guinea pigs treated with the neutral endopeptidase inhibitors, thiorphan and phosphoramidon. Pulmonary resistance (RL) and dynamic lung compliance (Coyn) were measured in anesthetized, mechanically ventilated guinea pigs. RL and CDyn were measured at baseline (1 ml/l00 g tidal volume and 50 breaths/min) and after a 10-min period of hyperventilation (1 ml/l00 g, 150 breaths/min). Hyperventilation produced modest changes in RL (+41 ± 12%) and Coyn (–12 ± 3%) which were markedly enhanced by treatment with 3 mg/kg of either thiorphan or phosphoramidon (Rl + 269 ± 43% for thiorphan, + 292 ± 63% for phosphoramidon and Coyn70%) with 5 mg/kg, p.o., of Sch 37224. In other studies, the peptidergic (conducted in the presence of ipratropium bromide and phosphoramidon) bronchoconstrictor response to intravenous nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p.o.). However, Sch 37224 (5 mg/kg, p.o.) had no effect on the bronchoconstrictor response to intravenous NKA. These results indicate that Sch 37224 inhibits the neuropeptide component of HIB and nicotine in guinea pigs and this effect appears to be mediated by the inhibition of the release of tachykinins from airway

ISSN:0031-7012    

DOI:10.1159/000139464

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

A serotonin mechanism has been reported to contribute to the hyperdynamic circulation of portal hypertension. Different studies have demonstrated that serotonin antagonists decrease portal pressure in portal hypertensive patients and animals. The present study was undertaken to investigate the effect of AT-112, an analog of ketanserin, on portal hypertension induced by partial portal vein ligation in rats. Since ketanserin is known to possess α1-adrenergic antagonistic activity, the effect of AT-112 was compared to that of prazosin. A single dose (prazosin 4.2 µg/kg, AT-112 1 mg/kg) was chosen to produce a similar hypotensive effect (–20 ± 4% for prazosin and -24 ± 4% for AT-112). At this dose, prazosin significantly decreased total peripheral resistance whereas AT-112 significantly decreased cardiac index and heart rate. Both agents significantly decreased the portal tributary blood flow and portal pressure. In rats receiving AT-112, a significant correlation was found between the magnitudes of decrease in cardiac index and the decrease in portal tributary blood flow. We also found that the magnitude of reduction in portal pressure was greater following AT-112 administration. This study suggested that AT-112 may have more beneficial hemodynamic effects than prazosin in portal hypertensive rats. Our results provide further support for the serotonergic mechanism in the pathogenesis of hyperdynamic circulation in portal hyperte

ISSN:0031-7012    

DOI:10.1159/000139465

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The effects of carvedilol, a vasodilating β-blocker with antioxidant activity, and nifedipine, a calcium channel blocker, were investigated on aortic lipid deposition and the accumulation of monocytes and foam cells at the sites of atherosclerotic lesions in rats subjected to a hypercholesterolemic diet. Fifty rats were randomly assigned to the following experimental groups: (1) regular rat chow (n = 5); (2) regular rat chow supplemented with a high-cholesterol diet (1 % cholesterol and 1 % cholic acid; n = 15); (3) a high-cholesterol diet plus nifedipine (n = 15), and (4) a high-cholesterol diet plus carvedilol (n = 15). Animals were maintained on these diets for 12 weeks. None of the treatment groups had blood pressures that were outside the normotensive range, and no significant differences in plasma lipid levels were observed among the high-cholesterol diet and drug-treated groups. There was a significantly lower lipid content (p < 0.001) in the thoracic aortas of the nifedipine-treated (211 ± 23 nmol/mm2) and carvedilol-treated (182 ± 23 nmol/mm2) groups compared to cholesterol-fed controls (242 ± 27 nmol/mm2). Furthermore, carvedilol-treated animals showed significantly less (p < 0.001) lipid accumulation than did the nifedipine-treated animals. The number of monocytes and foam cells were decreased in both drug-treated groups compared to animals receiving high-cholesterol diets without drug treatment. The results demonstrate that treatment with carvedilol or nifedipine can significantly inhibit lipid deposition in the aorta and reduce monocyte and foam cell accumulation, and that carvedilol is significantly more effective than nifedipine in inhibiting lipid deposit

ISSN:0031-7012    

DOI:10.1159/000139466

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The role of tubular accumulation in renal disposition and diuretic efficacy of hydrochlorothiazide was studied in the isolated perfused rat kidney. Hydrochlorothiazide resulted in a dose-dependent increase in the fractional excretion of sodium, chloride and potassium, and in urinary flow and pH. Renal clearance of the drug was low as a result of a low extraction ratio and extensive nonionic back-diffusion. Hydrochlorothiazide was subject to saturable tubular secretion, following Michaelis-Menten kinetics. Parameters obtained after nonlinear regression analysis were a maximum tubular transport velocity of 42 ± 6 µg/min, a Michaelis-Menten constant of secretion of 38 ± 11 µg/ml and a fraction of excreted drug reabsorbed passively of 0.49 ± 0.03. The thiazide diuretic accumulated extensively in kidney tissue due to active cellular uptake (maximum capacity of renal accumulation of 500 ± 270 µg/g; affinity constant of renal accumulation of 28 ± 16 µg/ml) and passive diffusion. Plots were constructed of the sodium excretion rate versus hydrochlorothiazide perfusate concentration or the renal excretion rate. The perfusate plot could be described by the sigmoid Emax model, while a simplification of the model had to be used for the response curve in urine because a maximum effect was not observed. The apparent maximum effect resulting from the perfusate concentration-response curve and the discrepancy with the renal excretion rate-response curve indicates that the diuretic effect of hydrochlorothiazide is restricted by saturable accumulation and s

ISSN:0031-7012    

DOI:10.1159/000139467

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Fructose-1,6-diphosphate (FDP) was found to cause significant stimulation of nitric oxide synthase (NOS) in rat liver homogenates in vitro. This effect was more pronounced for the inducible isoform than its constitutive counterpart. Furthermore, FDP restored rat liver inducible NOS levels following their depletion by carbon tetrachloride (CCl4). This finding may have further practical implications in hepatoprotection from various noxious chemical and biological agents.

ISSN:0031-7012    

DOI:10.1159/000139468

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid, which has displayed potent anti-inflammatory properties in animal studies combined with low gastrointestinal toxicity. Other NSAIDs have been shown, in vitro, to have a variety of effects on cartilage repair processes in diseased articular cartilage. The aim of this study was to ascertain the effects of meloxicam on some of these processes using in vitro models. Acetylsalicylic acid, a NSAID whose characteristics have been previously elucidated in the models, was used as an active comparator. The effects of meloxicam were different from those of acetylsalicylic acid on chondrocyte clusters. At pharmacologically active concentrations, meloxicam was a potent inhibitor of prostaglandin-E2 production. However, all chondroformative processes were unaffected by meloxicam as indicated by a lack of effect on DNA synthesis and on type-II collagen and proteoglycan levels in chondrocyte culture medium and clusters, while acetylsalicylic acid decreased proteoglycan production and cell proliferation. Consequently, these in vitro findings suggest that meloxicam does not adversely affect the reparative processes active within the cartilage matrix of a diseased joint. This study represents a sound basis for future studies to establish the effects of meloxicam on osteoarthritis disease progression.

ISSN:0031-7012    

DOI:10.1159/000139469

出版商:S. Karger AG    

年代:1997

数据来源: Karger