British journal of pharmacology
-
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.
-
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.
-
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.
-
1. Human GABAA receptors containing different alpha and beta subunits with a gamma 2s subunit were expressed in Xenopus oocytes and the effects of pentobarbitone on these subunit combinations were examined by electrophysiological recording of GABA currents with the two-electrode voltage-clamp method. 2. Pentobarbitone has previously been shown to have three actions on GABAA receptors: a potentiation of GABA responses, a direct activation of GABAA receptors and, at high concentrations, a block of the GABA chloride channel. ⋯ The direct effect of pentobarbitone was blocked by picrotoxin but not by competitive antagonists, such as bicuculline or SR95531, indicating that the direct agonist activity of pentobarbitone was not mediated via the GABA binding site. 7. For the first time the influence of the various alpha and beta subunits on the effects of pentobarbitone were demonstrated. The results indicate that GABAA receptors containing alpha 6 subunits have both a higher affinity and efficacy for direct activation by pentobarbitone, and reveal that pentobarbitone binds to more than one site on the GABAA receptor, and these are dependent on receptor subunit composition.
-
1. The purpose of this study was to investigate the topical and systemic anti-hyperalgesic effect of the newly-developed pseudopeptide B2 receptor antagonist, NPC 18688, in different models of nociception in mice. 2. Given systemically 30 min beforehand, NPC 18688 (10-300 nmol kg-1, i.p.) caused no agonist effect, but produced a dose-related and significant inhibition of abdominal constrictions caused by intraperitoneal injection of acetic acid (0.6%), acetylcholine (ACh, 4.5 mg kg-1) or kaolin (50 mg kg-1). ⋯ Finally, NPC 18688 (1 microM) did not affect ACh-mediated contraction in the guinea-pig ileum or toad rectus abdominii in vitro. 7. These results demonstrate that the newly-developed and selective pseudopeptide B2 receptor antagonist, NPC 18688, although less potent than the available second generation of B2 peptide BK receptor antagonists, exhibits topical and long-lasting systemic anti-hyperalgesic properties when analysed in several models of nociception in mice, making it a useful tool for investigating the participation of BK and related kinins in physiological and pathological processes. Finally, this new class of selective pseudopeptide B2 receptor antagonist may constitute a new strategy for developing the third generation of potent and long-lasting orally-active non-peptide BK antagonists, which may be useful for the management of clinical disorders involving BK and relate