摘要:

Abstract:The use ofin vitromodels for the study of cardiovascular effects of drugs may not be representative for thein vivotherapeutic effects. However, drug effectsin vivoare often difficult to assess because of counteracting reflexes and auto‐regulatory rearrangements. To solve this dilemma, the present study presents a two‐step method using bothin vivoandin vitrotechniques to investigate vascular versus myocardial selectivity of three dihydropyridine calcium antagonists: amlodipine, felodipine and nifedipine. The ratio between intravenous drug doses causing 25% reduction in mean arterial blood pressure (vascular potency) and in heart rate (cardiac chronotropic potency) was determined in anaesthetised spontaneously hypertensive rats during autonomic cardiac blockade. In isolated hearts from spontaneously hypertensive rats, the inotropic versus chronotropic potency ratio was determined between the two drug concentrations producing a 25% reduction in cardiac contractility (dP/dt max) and in heart rate, respectively. The vascular versus chronotropic selectivityin vivowas higher for felodipine (121) than for nifedipine (47) and amlodipine (15). The inotropic versus chronotropic potency ratios obtained from thein vitrostudies were: felodipine (1), amlodipine (2) and nifedipine (20). Thein vitroresults were used to extrapolate the vascular versus cardiac chronotropic selectivity obtainedin vivoto a vascular versus myocardial selectivity drug ratio, being 20 and 60 times higher for felodipine than for amlodipine and nifedipine, respectiv

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00103.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:We have investigated the effects of the novel phospholipid′ yceryl‐phosphoryl‐O‐serine (GPS) on pituitary ACTH and hypothalamic corticotropin releasing hormone secreti ro in cultures from both 2‐ and 24 month‐old Sprague‐Dawley rats. Basal levels of ACTH in primary cultures o′ cells from 24 month‐old rats were lower than (100±12 pg/105cells) in 2 month‐old rats (207±18 pg/105cells). medium corticotropin releasing hormone levels in hypothalamic cultures were higher in 24 month‐old rats (45±7 pg/well/20 min.), than in 2 month‐old rats (29±5.5 pg/well/20 min.). Treatment of both pituitary cells with corticotropin releasing hormone and hypothalami with serotonin resulted respectively in a significant, concentration‐dependent, increase of medium ACTH and corticotropin releasing hormone. However, concentration‐response curves for ACTH and corticotropin releasing hormone were shifted to the right in cultures from 24 month‐old rats. Incubation with graded concentrations of GPS produced significant increase in medium ACTH and corticotropin releasing hormone in cultures from 24 month‐old rats, whereas the drug was ineffective in stimulating secretion of both hormones from 2 month‐old rat cells. In addition, the adenylate cyclase stimulator forskolin and the protein kinase C activator oleyl‐acyl‐glycerol stimulated ACTH secretion in pituicytes from rats of both ages. However, response to oleyl‐acyl‐glycerol was blunted in pituicytes from 24 month‐old rats. Combination of either forskolin or oleyl‐acyl‐glycerol with GPS resulted in a potentiation of the effect. Our data confirm an impairment of both pituitary ACTH and hypothalamic corticotropin releasing hormone secretion in the aging rat. Results suggest that defi‐citary signal transduction is possibly among causes of such impairment. Phospholipid drugs, such as GPS, appear to possess modulating effects on both pituitary

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00104.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The present study was undertaken to develop an improved and stabilized method for isolating cardiomyocytes from perfused rat heart. Different lots of the commercial collagenases used for isolating cardiomyocytes give variable results both with respect to the total cell yield and the percentage of elongated cells obtained. When trypsin was present both before and during collagenase treatment of the tissue, the performance of the collagenases was improved and stabilized, and a high and stable cell yield (7.5X106cells per heart), and a high percentage of elongated cells (about 70%) was regularly obtained. The cells posessed aradrenergic binding sites with binding properties (Bmax=43.5 fmol/mg protein and Kd=125.5 pmol/1) in agreement with values previously reported. The cells were able to respond functionally, as the cellular uptake of86Rb+increased by 18% after α1‐adrenoceptor stimulation with phenylephrine. These criteria indicate that the cells were well preserved during the isolation procedu

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00105.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The influence of lactation on hepatic and intestinal glutathione S‐transferase activities in mother rats was studied. Cytosolic and microsomal activities were assessed 7, 14 and 21 days after delivery, using 1‐chloro‐2, 4‐dinitroben‐zene as substrate. Cytosolic and microsomal activities from liver and small intestine determined 7 dayspost partumdid not differ from those of virgin female rats. The hepatic cytosolic activity was significantly increased with respect to that of virgin females 14 days after delivery and tended to revert to the control value on day 21 of lactation, whereas the intestinal activity was increased on day 14 and remained augmented even 21 dayspost partum. Although the respective microsomal activities showed percent increases higher than those of the cytosolic enzymes, they both exhibited a similar pattern of stimulation in response to

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00106.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:In mice given a single intraperitoneal injection of the antithyroid drug methimazole (0.44 mmol/kg; 50 mg/kg) detachment of the olfactory neuroepithelium and necrosis of the Bowman’glands in the lamina propria was observed 24 hr after administration. Three days after administration there was an atypical epithelium throughout the olfactory region and the Bowman's glands had disappeared. Pretreatment with the olfactory cytochrome P450 inhibitor metyrapone protected against the methimazole‐induced changes at this site. In mice injected with the methimazole analogues 1‐methylimi‐dazole or 4‐methylimidazole (0.44 mmol/kg; 36 mg/kg) or the antithyroid drug propylthiuracil (0.22 mmol/kg; 38 mg/kg) no morphological changes were observed in the olfactory mucosa. The results suggest that methimazole‐induced toxicity in the olfactory mucosa is related to metabolism‐dependent changes of th

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00107.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:Golden Syrian hamster pups were administered a single subcutaneous dose of203Hg‐labeled methyl mercury (MeHg), 0.4 nmol/g body weight, seven days after birth, and were sacrified 2, 7, 14, 21 or 28 days later. The excretion of203Hg followed a biphasic elimination pattern with an average half‐time of 8.7 days for the rapid component. The slow component had a much longer half‐time and probably reflects binding of203Hg to growing hair. The concentration of203Hg in the liver, kidneys and brain two days after administration was 0.44, 0.38 and 0.19 nmol/g, respectively. The retention of203Hg was higher in the kidney than in the liver and the brain. The content of inorganic203Hg in the liver and kidneys increased the first weeks after administration, demonstrating that hamsters are able to demethylate MeHg before two weeks o

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00108.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:The dopamine D2receptor antagonist remoxipride (30 μM) stimulated prolactin release from the prolactin‐producing rat pituitary tumour cell strains GH3and GH4C1as well as from transfected GH4C1cells expressing the short isoform of the rat D2receptor (GH4ZR7). The effect of remoxipride on prolactin release is probably not due to an interaction with D2receptors since GH4C1cells, in contrast to GH3and GH4ZR7cells, are completely devoid of D2receptors; in contrast, we have previously shown that the D2antagonist haloperidol causes prolactin release from D2receptor‐expressing cells, only. Exposure of GH3cells to the inhibitor of intracellular Ca2+mobilization, 8‐(diethylamino)‐octyl 3, 4, 5‐trimethoxybenzoate hydrochloride (TMB‐8) prevented the prolactin‐releasing effect of remoxipride whereas pretreatment with the membrane Ca2+channel antagonist nimodipine did not influence the response. The D2receptor antagonist raclopride counteracted the reduction of VIP‐stimulated prolactin release induced by the D2agonist quinpirole but caused no prolact

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00109.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Abstract:Trophoblast from term and first trimester placenta, maintained in culture, were exposed to 20 μmoles/1 zidovudine or 2′3'dideoxyinosine. Several indices of function were measured and compared to control trophoblast in parallel culture. The results from individual placentas were examined by Student's t‐test and cumulative results by ANOVA. Neither zidovudine or 2′3'‐dideoxyinosine had statistically significant effects on the function of term trophoblast, following a 48 hr exposure to the drug as indicated by hCG secretion, protein synthesis and glucose consumption. In one of five placentas exposed to zidovudine, progesterone secretion was reduced as compared to its control but remained in the high range. Zidovudine had no significant effect on cultured trophoblast isolated from first trimester placenta even after prolonged exposure to the drug for eleven days. Both term and first trimester trophoblast in culture tolerate prolonged exposure to high concentrations of zidovudine or 2′3'‐dideoxyinosine. Human trophoblast in culture provides a safein vitromodel for the screening of drugs intended for use duri

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1995.tb00110.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY