Sensitivity of (1)H NMR analysis of rat urine in relation to toxicometabonomics. Part I: dose-dependent toxic effects of bromobenzene and paracetamol.

(1)H nuclear magnetic resonance (NMR) spectroscopy of rat urine in combination with pattern recognition analysis was evaluated for early noninvasive detection of toxicity of investigational chemical entities. Bromobenzene (B) and paracetamol (P) were administered at five single oral dosages between 2 and 500 mg/kg and between 6 and 1800 mg/kg, respectively. The sensitivity of the proposed method to detect changes in the NMR spectra 24 and 48 h after single dosing was compared with histopathology and biochemical parameters in plasma and urine.

Uniform procedure of (1)H NMR analysis of rat urine and toxicometabonomics Part II: comparison of NMR profiles for classification of hepatotoxicity.

A procedure of nuclear magnetic resonance (NMR) urinalysis using pattern recognition is proposed for early detection of toxicity of investigational compounds in rats. The method is applied to detect toxicity upon administration of 13 toxic reference compounds and one nontoxic control compound (mianserine) in rats. The toxic compounds are expected to induce necrosis (bromobenzene, paracetamol, carbon tetrachloride, iproniazid, isoniazid, thioacetamide), cholestasis (alpha-naphthylisothiocyanate (ANIT), chlorpromazine, ethinylestradiol, methyltestosterone, ibuprofen), or steatosis (phenobarbital, tetracycline).

Oestrogen modulates cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms.

Aim: Observational and clinical studies suggest different responses upon sex hormone replacement therapy in ischaemic heart disease. Few studies, however, have examined the impact of oestrogen receptor-dependent mechanisms on the extent of injury after myocardial infarction (MI). Therefore, we set out to evaluate the effect of oestrogen (E2) replacement on infarct size and remodelling, and the respective role of the oestrogen receptors (ER)alpha and -beta in this process, using ERalpha- and ERbeta-deficient mice.

Estrogen receptor beta protects the murine heart against left ventricular hypertrophy.

Background: Left ventricular hypertrophy (LVH) displays significant gender-based differences. 17beta-estradiol (E2) plays an important role in this process because it can attenuate pressure overload hypertrophy via 2 distinct estrogen receptors (ERs): ERalpha and ERbeta. However, which ER is critically involved in the modulation of LVH is poorly understood.

Lack of difference among progestins on the anti-atherogenic effect of ethinyl estradiol: a rabbit study.

Background: Progestins in combination with estrogen are believed to have different effects on the cardiovascular system. The aim of this study was to investigate the influence of different oral contraceptive formulations on the development of experimental atherosclerosis and vascular reactivity.

Methods: A total of 160 sexually mature rabbits were ovariectomized and randomly assigned to equally large groups: (i) a cholesterol-rich diet (320 mg/day), either given alone (placebo), or together with (ii) ethinyl estradiol (EE 70 micro g/day, oral), (iii) desogestrel (DSG 525 micro g/day, oral), (iv) gestodene (GSD 262.

Comparison of the antiatherosclerotic effect of tibolone with that of estradiol and ethinyl estradiol in cholesterol-fed, ovariectomized rabbits.

Objective: Tibolone is a synthetic steroid with tissue-specific estrogenic, progestogenic, and androgenic properties. The drug relieves climacteric symptoms and prevents osteoporosis but does not stimulate the endometrium. We have previously shown that in laboratory animals tibolone inhibits the atherogenesis induced by a high-cholesterol diet.

Tibolone prevents atherosclerotic lesion formation in cholesterol-fed, ovariectomized rabbits.

Tibolone (Org OD14), a synthetic steroid with estrogenic and progestogenic/androgenic properties, is clinically effective for the treatment of climacteric symptoms and the prevention and treatment of osteoporosis in postmenopausal women. The effect on atherogenesis, however, is not known. In the current study, we investigated the effect of tibolone in comparison with that of estradiol and norethisterone acetate on atherogenesis in 140 ovariectomized New Zealand White rabbits that had been induced by an atherogenic diet (0.

In vitro and in vivo characterization of a calcium modulator of the diphenylalkylamine type with selective coronary dilatory properties.

Unlabelled: VUF 8929 (N-¿2-[bis(p-fluorophenyl)methoxy]ethyl¿-(2-phenyl)ethylamine maleate, CAS 140890-71-7) is a diphenylalkylamine derivative structurally related to prenylamine. The calcium antagonistic properties of this compound have been studied in in vitro and in vivo systems. VUF 8929 has affinity for the voltage-operated calcium channel.

Two new closely related rat models with relevance to arterial thrombosis--efficacies of different antithrombotic drugs.

Two thrombosis models in rats are described in which mixed type thrombi are formed at arterial and venous flow rates. The models, containing a silk thread in the aorta and vena cava, respectively, were characterised for the activity of three platelet inhibitors, three thrombin active site inhibitors and five glycosaminoglycans (GAGs). In the two models a similar highly platelet-dependent thrombus developed both in size and composition during the first 10 min after insertion of the silk thread.

Hemodynamic profiles of methoxamine and B-HT 933 in spinalized ganglion-blocked dogs.

The hemodynamic profiles of methoxamine and B-HT 933 during a stepwise-increased infusion in spinalized ganglion-blocked dogs show that both compounds induce a dose-dependent increase in arterial blood pressure due to an increase in total peripheral resistance. Methoxamine initially also increases cardiac output, which contributes to the increase in blood pressure. The increased cardiac output is the result of an increased stroke volume, because heart rate is unchanged.

Protective effects of prostaglandins against ulcerogenic activity of indomethacin during different stages of erosion development in rat stomach. Role of acid and bicarbonate secretion.

Prostaglandin E2 (PGE2) and PGF2 beta decreased the gastric erosive activity of orally administered indomethacin in a dose-dependent manner, when given as a continuous intravenous infusion in the conscious rat. PGE2 protected both during the initial stage of erosion induction and during the later outgrowth to larger erosions. Moreover PGE2 was able to stop the eroding process at any stage as long as the infusion continued.

Protection by paracetamol against various gastric irritants in the rat.

Four nonsteroid anti-inflammatory drugs (NSAID), indomethacin, phenylbutazone, ibuprofen, and glafenine, caused erosions in the rat stomach in a dose-dependent manner. Paracetamol, which has been shown to protect against the gastric erosive activity of aspirin, reduced the gastric toxicity of indomethacin but was ineffective against the erosive activity of phenylbutazone and glafenine. Only the high erosion score of a large dose of ibuprofen was partly decreased by paracetamol.

The influence of orphenadrine or imipramine on the hypertensive response of physostigmine in the rat.

Unlabelled: An intravenous infusion of orphenadrine or imipramine to artificially ventilated, urethane anaesthetized rats, completely blocked the physostigmine induced increase in blood pressure and the blood pressure increase induced by electrical stimulation of the posterior hypothalamus; effects mediated via the sympathetic nerve. The noradrenaline induced blood pressure increase was not changed during an infusion with orphenadrine but was markedly depressed during an infusion with imipramine. During an infusion with both orphenadrine or imipramine the pressor response induced by stimulation of the spinal cord were completely blocked in pithed rats.

The influence of paracetamol on the erosive activity of indomethacin in the rat stomach.

Indomethacin induced erosions in the glandular part of the rat stomach in a dose-dependent manner. Gastric erosions became apparent about 15 min after administration of indomethacin and the damage was maximal at about 4 h. The erosive activity of indomethacin administered subcutaneously was similar to that after oral administration, confirming the data of other authors.

The influence of physostigmine on respiratory and circulatory changes caused by overdoses of orphenadrine or imipramine in the rat.

Orphenadrine or imipramine were given intravenously as an infusion to spontaneously breathing, anaesthetized rats until respiratory arrest, the primary cause of death for both drugs. Intravenous injections of physostigmine did not prolong survival. Artificial ventilation prolonged survival for orphenadrine and imipramine by about a factor 3 and the rats died from cardiogenic shock.

The anti-inflammatory, analgesic and antipyretic activities of non-narcotic analgesic drug mixtures in rats.

The effects of non-narcotic analgesics have been examined, separately and in admixture, on carrageenan-induced hind paw oedema and on yeast-induced hyperalgesia and hyperthermia in adult rats. The efficacy of the drugs was evaluated using the kinetics of drug-receptor interaction. In addition, the hypothesis was tested that the anti-inflammatory, analgesic and antipyretic activities of the drug mixtures used equal the addition of the activities of the individual drugs and could be predicted from their intrinsic activities and affinities.

Hypotensive response in spontaneously hypertensive rats following microinjection of alpha-methylnoradrenaline in the caudal brain-stem.

Local microinjection of 1.25 nmol (-)-alpha-methylnoradrenaline in the A2-region of the nucleus tractus solitarii (NTS) caused a decrease of blood pressure and heart rate in both spontaneous hypertensive rats (SHR) and Wistar-Kyoto (W/K) rats. Although the maximal responses in both strains did not differ, the decrease in blood pressure lasted longer in the SHR.

Effect of catecholamine-receptor stimulating agents on blood pressure after local application in the nucleus tractus solitarii of the medulla oblongata.

The effect of various catecholamines and alpha-mimetics, given by microinjection in the A2-region of the nucleus tractus solitarii (NTS), on blood pressure was investigated in anesthetized male rats. A dose-dependent decrease of blood pressure and heart rate was induced by adrenaline as the most effective drug, followed by noradrenaline, dopamine, alpha-methylnoradrenaline and octopamine. Ablation of the rostral or caudal part of the NTS, or removal of the area postrema did not diminish the effect of alpha-methylnoradrenaline.

The area postrema and control of arterial blood pressure; absence of hypertension after excision of the area postrema in rats.

Acute surgical excision of the area postrema (AP) in the rat failed to affect arterial blood pressure or heart rate. The was no effect on cardiovascular reflex responses during diving or on the heart rate responses to acute decreases or increases of blood pressure caused by bradykinin or angiotensin, respectively. Electrolytic lesions of the AP in acute experiments caused variable damage to the nucleus tractus solitarii (NTS).