British journal of pharmacology
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Comparative Study
Assessment of the role of the renin-angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren.
1. The role of the renin-angiotensin system in the regulation of myocardial contractility is still debated. In order to investigate whether renin inhibition affects myocardial contractility and whether this action depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c.) infusions of the renin inhibitor remikiren, were compared and related to the effects on systemic haemodynamics and circulating angiotensin II in open-chest anaesthetized pigs (25-30 kg). ⋯ The blood levels of remikiren required for its vasodilator action are lower than the levels affecting cardiac contractile function. A decrease in circulating angiotensin II does not appear to be the sole explanation for these haemodynamic responses. Data support the contention that myocardial contractility is increased by renin-dependent angiotensin II formation in the heart.
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Comparative Study
Effect of dexfenfluramine on the transcriptional activation of CRF and its type 1 receptor within the paraventricular nucleus of the rat hypothalamus.
1. The present study investigated the effect of intraperitoneal (i.p.) administration of the indirect 5-hydroxytryptamine (5-HT) receptor agonist, dexfenfluramine, on the transcriptional activity of corticotropin-releasing factor (CRF) and its type 1 receptor in the brains of conscious male Sprague-Dawley rats via in situ hybridization histochemistry (ISHH) using both intronic and exonic probe technology. 2. The immediate early gene (IEG) c-fos mRNA was also used as index of cellular activity, whereas localization between CRF-immunoreactive (ir) perikarya and the IEG was accomplished to determine the site of CRF neuronal activation in the brain of dexfenfluramine-treated rats. 3. ⋯ Interestingly, CRF-ir neurones displayed a positive signal for the mRNA encoding the CRF1 receptor, 3 and 6 h after systemic treatment with dexfenfluramine. 8. These results indicate that although dexfenfluramine can generate a wide neuronal activation throughout the brain, this 5-HT agonist triggers the activity of CRF neurones selectively in the parvocellular division of the PVN, a mechanism possibly related to the activity of hypothalamic-pituitary-adrenal axis. Induction of CRF1 receptor mRNA in CRF cells of the PVN indicates that neuroendocrine CRF neurones can be targeted by CNS CRF under 5-HT stimulation.
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Comparative Study
Inhibition of cortical spreading depression by L-701,324, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complex.
1. Spreading depression (SD) is a propagating transient suppression of electrical activity, associated with cellular depolarization, which probably underlies the migraine aura and may contribute to neuronal damage in focal ischaemia. The purpose of this study was to examine whether L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1H)-quinolone), a high affinity antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, inhibits the initiation and propagation of K(+)-induced SD in the rat cerebral cortex in vivo. 2. ⋯ The higher potency of MK-801 against SD may reflect its use-dependency, i.e. binding of MK-801 and channel blockade are enhanced when the NMDA-receptor ionophore is open. 6. Taken together, these data demonstrate that L-701,324 has an inhibitory effect on both SD initiation and propagation. This action may be beneficial in focal ischaemia, and possibly also against migraine, especially as this drug was shown to be active when administered orally.
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1. In this study, the effects of a protein synthesis inhibitor, cycloheximide, and a soluble tumour necrosis factor (TNF) binding/IgG fusion protein, p55-sf2, on the priming and challenge stages of the local Shwartzman reaction (LSR) were assessed and compared with their effects on the acute inflammatory response induced by recombinant human tumour necrosis factor-alpha (rhTNF), lipopolysaccharide (LPS) and a reversed passive Arthus (RPA) reaction in rabbit skin. 2. The LSR was induced in skin by giving an intradermal (i.d.) priming injection of LPS followed by two i.v. challenge injections 20 h and 22 h later. ⋯ On the other hand, haemorrhage appears to be dependent on local protein synthesis during the priming phase but not during the challenge stage of the LSR. Importantly, haemorrhage and plasma leakage appear to be dependent on local TNF generation during the priming phase but not during the challenge stage of the LSR. Thus TNF appears to play a key role in the LSR in rabbit skin.
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1. Neuropeptide FF (NPFF) has been shown to produce antinociceptive effects and enhance morphine-induced antinociception after intrathecal (i.t.) injection. In this study, the spinal effects of two NPFF analogues, -D-Tyr1,(NMe)Phe3-NPFF (1DMe) and [D-Tyr1,D-Leu2,D-Phe3]NPFF (3D), which are resistant to degradation and exhibit a high affinity for NPFF binding sites, were examined in tests of thermal and mechanical nociception. 2. 1DMe and 3D produced potent dose-dependent spinal antinociception in the tail-flick test. ⋯ When administered in combination with antinociceptive doses of the mu-receptor agonist, morphine (13.2 nmol) or the delta-receptor agonist, [D-Ala2]deltorphin I (20 nmol), sub-effective dose of 1DMe or 3D (0.009 nmol) enhanced and prolonged the spinal effects of these opioid agonists. 5. The results of this study show that spinal mu- and delta-opioid receptors play a role in antinociception produced by NPFF analogues. These results also suggest a role for NPFF in modulation of nociceptive signals at the spinal level.