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Biomedical subjects

M Hamon

Publications and source records attributed to M Hamon.

At least 253 records · Page 14Linked to original sources
PubMed1994

Mu and delta opioid receptors mediate opposite modulations by morphine of the spinal release of cholecystokinin-like material.

The possible modulations by morphine and various opioids of the spinal release of cholecystokinin-like material (CCKLM) evoked by 30 mM K+ was studied in vitro, using slices of the dorsal part of the rat lumbar enlargement superfused with an artificial cerebrospinal fluid. Addition of the mu agonist, DAGO (0.1-10 microM), to the perfusing fluid produced a concentration-dependent decrease in the peptide release, which could be prevented by the preferential mu antagonist, naloxone. Complex modulations were induced by the delta agonist, DTLET, as this drug inhibited CCKLM release when added at 10 nM-3 microM to the perfusing fluid, but enhanced it at 10 microM. Both effects were preventable by the delta antagonists naltrindole and ICI 154129, suggesting that delta receptors, possibly of different subtypes, mediated the inhibition and stimulation by DTLET. Morphine also exerted a biphasic effect, as the alkaloid decreased CCKLM release at 0.01-0.1 microM and enhanced it at 10 microM. Morphine-induced inhibition was preventable by naloxone, whereas its stimulatory effect could be blocked by naltrindole and ICI 154129. Although inactive on its own on CCKLM release, the selective kappa 1 agonist U 50488H (1 microM) prevented the inhibitory effects of both DAGO (10 microM) and morphine (0.1 microM), suggesting the existence of interactions between kappa 1 and mu receptors within the dorsal zone of the rat spinal cord. These data indicate that low concentrations of morphine exert an inhibitory influence on spinal CCKergic neurons that depends on the stimulation of mu opioid receptors. The excitatory influence of 10 microM morphine likely results from the simultaneous stimulation of mu, delta and kappa receptors, as the inhibitory effect of mu receptor stimulation can be masked by that of kappa 1 receptors, allowing only the expression of a delta-dependent excitatory effect similar to that induced by 10 microM DTLET.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Postnatal development and localization of 5-HT1A receptor mRNA in rat forebrain and cerebellum.

The localization of the rat brain 5-HT1A receptor mRNA was analyzed by RNAse mapping and in situ hybridization during postnatal development, particularly in the cerebellum. The regional distribution of 5-HT1A mRNA during the first 2 postnatal weeks was different from that found in adults. In some areas of the immature brain (hippocampus, cerebral cortex), 5-HT1A mRNA was found in lower density than in the adult brain. In contrast, high concentrations of the transcript were present in other brain structures only during the first days after birth. Thus, in the cerebellum, the density of 5-HT1A mRNA decreased markedly from day 2 to day 9 after birth and could hardly be detected in the adult animal. The localization of the mRNA in the molecular/Purkinje cell layer of the immature cerebellum agreed with that of the 5-HT1A receptor protein visualized by immunocytochemistry and was consistent with the hypothesis that Purkinje cells express this receptor.

Animals↗
PubMed1994

Neuronal localization of 5-HT1A receptor mRNA and protein in rat embryonic brain stem cultures.

The aim of the present work was to study the cellular localization of 5-HT1A receptor protein and mRNA in rat embryonic brain cultures. Primary cultures of the whole brain from rat fetuses at embryonic day (ED) 12 and of the brain stem at ED 14-ED 16 were stained with specific anti-5-HT1A receptor antibodies or a 40-mer biotin-labelled deoxyoligonucleotide complementary to the 5-HT1A receptor mRNA. The use of a biotinylated probe allowed the morphology of the cells to be preserved. 5-HT1A receptor mRNA was already detected in primary cultures from the brain of ED 12 embryos whereas the receptor protein first appeared two days later, at ED 14. Both 5-HT1A receptor mRNA and protein were found within neuron-like cells (labelled with antibodies against neuron specific enolase, microtubule-associated protein 2 or aromatic L-amino acid decarboxylase) but not in glial cells (specifically labelled with antibodies against glial fibrillary acidic protein, myelin basic protein or carbonic anhydrase II). Double staining with the 5-HT1A receptor mRNA probe and anti-5-HT antibodies suggests that 5-HT1A (auto)receptors are expressed by serotoninergic neurons during early ontogenesis.

Animals↗
PubMed1994

Interactions of lesopitron (E-4424) with central 5-HT1A receptors: in vitro and in vivo studies in the rat.

Previous studies have shown that the 5-HT1A receptor ligand, lesopitron (E-4424, 2-[4-[4-(4-chloro-1-pyrazolyl)butyl]-1-piperazinyl]pyrimidine), exerts potent anxiolytic-like effects in rodents and monkeys (Costall et al., 1992, J. Pharmacol. Exp. Ther. 262, 90). In an attempt to determine whether these effects are really mediated through the interaction of lesopitron with central 5-HT1A receptors, we investigated the agonistic and/or antagonistic nature of this interaction under in vitro and in vivo conditions in the rat. In vitro binding and autoradiographic studies with [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and [3H]lesopitron as radioligands confirmed that lesopitron binds to 5-HT1A receptors in the rat brain with a relatively high affinity (pKi = 7.35). As expected of a full agonist at postsynaptic 5-HT1A receptors, lesopitron (IC50 = 125 nM) inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes to the same extent as 5-HT, and this effect was preventable by potent 5-HT1A receptor antagonists such as (-)-tertatolol, (-)-propranolol and N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl- propanamide ((+)-WAY 100135). As previously shown for agonists acting at the somato-dendritic 5-HT1A autoreceptors in the dorsal raphe nucleus, lesopitron inhibited the firing of serotoninergic neurons both in vitro (in brainstem slices, IC50 = 120 nM) and in vivo (in chloral hydrate-anaesthetized rats, ID50 = 35 micrograms/kg i.v.), and this effect was preventable by (-)-tertatolol. Interestingly, the inhibition of the discharge due to lesopitron lasted for only a few minutes both in vitro and in vivo whereas the anxiolytic-like properties of this drug lasted for hours after a single injection in mice (Costall et al., 1992). In addition, the doses required for the stimulation of pre- and postsynaptic 5-HT1A receptors were markedly higher than those producing significant anxiolytic-like effects in rodents (Costall et al., 1992). It is therefore unlikely that the anxiolytic-like properties of lesopitron involve its stimulatory action at central 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Effect of balloon inflation in angiographically normal coronary segments during coronary angioscopy: a quantitative angiographic study.

Visualization of coronary stenoses by coronary angioscopy is facilitated by inflating an occlusive cuff located near the distal end of the device to temporarily interrupt blood flow. In animal models, this procedure induces substantial endothelial denudation. Experimental studies show that endothelial denudation may lead to neointimal hyperplasia at the denuded site. This study was designed to determine whether angioscopy was associated with significant changes in lumen diameter at the site of cuff inflation. We studied 52 consecutive patients undergoing coronary angioscopy. We measured with use of quantitative edge-detection angiography [computer-assisted evaluation of stenosis and restenosis (CAESAR) system] the mean and minimal lumen diameters at the site of cuff inflation localized by filming the inflated cuff during angioscopy and at control non-instrumented segments on angiograms performed before angioscopy, after angioscopy, and at 6 months follow-up. Follow-up angiograms were performed in 80% of eligible patients. At follow-up, the mean (3.22 +/- 0.54 mm) and minimal (2.76 +/- 0.58 mm) diameters of the segment exposed to the inflated cuff were not significantly different from the equivalent values (3.22 +/- 0.58 and 2.75 +/- 0.61 mm) before angioscopy. No significant changes occurred in the mean or minimal diameters of the control segments over the same period. The late change (follow-up minus pre-angioscopy) in mean lumen diameter at the cuff inflation site (-0.005 +/- 0.18 mm) was not significantly different from that at the control site (0.004 +/- 0.20 mm).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Differential effects of the novel analgesic, S 12813-4, on the spinal release of substance P- and calcitonin gene-related peptide-like materials in the rat.

The possible inhibitory control by the novel analgesic S 12813-4 (3-(2-(4-phenylpiperazine-1-yl)-ethyl)-2-oxo-2,3- dihydrooxazolo(b)pyridine) of spinal neurones containing substance P (SP) and/or calcitonin gene-related peptide (CGRP) was assessed in vitro and in vivo in the rat. S 12813-4 (10 nM-0.1 mM) did not affect the spinal release of CGRP-like material (CGRPLM) but inhibited in a concentration dependent manner the K(+)-evoked overflow of SP-like material (SPLM) from slices of the dorsal half of the rat lumbar enlargement. The inhibitory effect of 10 microM S 12813-4 on SPLM release was not additive with that of Na (0.1 mM), and could be prevented by the alpha 2-adrenoceptor antagonist idazoxan (10 microM). Similarly, idazoxan (10 microM) suppressed the inhibition by intrathecally administered S 12813-4 (10 microM) of the spinal outflow of SPLM in halothane anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid. These data suggest that the analgesic effect of S 12813-4 might involve some alpha 2-adrenoreceptor-mediated control of SPLM release within the spinal cord. Whether this control concerns SP-containing primary afferent fibres (presynaptic inhibition) or SP-containing interneurones and/or bulbo-spinal SP-ergic pathways (postsynaptic inhibition) deserves further investigations.

Adrenergic alpha-Antagonists↗
PubMed1994

Effects of acute and chronic treatment with amoxapine and cericlamine on the sleep-wakefulness cycle in the rat.

Antidepressant drugs, such as the tricyclics and the serotonin reuptake inhibitors, are well known to decrease paradoxical sleep and occasionally increase slow wave sleep in human and in animals. In order to examine whether amoxapine (a mixed NA reuptake blocker and 5-HT2/5-HT3 antagonist) and cericlamine (a selective 5-HT reuptake inhibitor) exert the same effect in rats, and to investigate the possible relationships between sleep, the action of antidepressants and the serotoninergic system, the effects of these two different drugs were examined under acute and chronic conditions. Acutely, amoxapine (1, 5 and 10 mg/kg; i.p.) and cericlamine (1, 8, 16 and 32 mg/kg; i.p.) decreased paradoxical sleep and increased deep slow wave sleep especially when they were given at a low dose. When administered for 14 days, amoxapine induced a sustained decrease of paradoxical sleep during the whole treatment, while some tolerance was observed with regard to the inhibitory effect of cericlamine on this state of sleep. In addition, a rebound of paradoxical sleep occurred on the first day of cericlamine withdrawal. Thus, amoxapine and cericlamine exerted the same effects on the states of vigilance in the rat as do other antidepressants. The effects of cericlamine on sleep probably reflect its blocking action on 5-HT uptake, whereas the more complex effects of amoxapine might involve its 5-HT2/5-HT3 antagonist properties.

Amoxapine↗
PubMed1994

Effects of 5-HT1A receptor ligands on a safety signal withdrawal procedure of conflict in the rat.

The present study evaluated in the rat the ability of various 5-HT1A receptor agonists to exert an "anxiolytic-like" release of the suppression of lever pressing for food induced by the withdrawal of a conditioned signal for safety without presentation of a conditioned signal for punishment. During the period associated with the safety signal withdrawal (Saf.CS-/Pun.CS-), control rats exhibited a typical pattern of responding with an initial strong blockade of responding that lessened over the period as presses were rewarded and shocks omitted. The 5-HT1A receptor partial agonists buspirone (0.125-0.5 mg/kg) and 8-(2-[2,3-dihydro-1,4-benzodioxin-2-yl- methylamino]ethyl)-8-azaspiro[4,5]decane-7,9-dione methyl sulfonate (MDL 73005EF; 0.5-2 mg/kg) and the full agonist (+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]-butyl-8- azaspiro[4,5]decane-7,9-dione (S 20499; 0.125-1 mg/kg) produced a robust and dose-related release of pressing during the Saf.CS-/Pun.CS- period. This effect was less marked with ipsapirone (0.125-1 mg/kg). Conversely, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.06-0.25 mg/kg), a full agonist, was completely inactive and did not prevent MDL 73005EF (1-2 mg/kg) or diazepam (0.125 mg/kg) from releasing the suppressed behavior. The specific 5-HT1A antagonist (+)-N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenylpr opa namide [(+)-WAY 100135; 0.25-8 mg/kg] and the beta-adrenoceptor/5-HT1A antagonist (-)-tertatolol (2-8 mg/kg) did not modify the behavioral blockade, nor did (+)-WAY 100135 (2-4 mg/kg) reduce the ability of buspirone (0.25 mg/kg) to enhance responding during the Saf.CS-/Pun.CS- period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Morphine reduces the release of met-enkephalin-like material from the rat spinal cord in vivo by acting at delta opioid receptors.

The modulation by morphine of the spinal release of met-enkephalin-like material (MELM) was investigated in anaesthetized rats whose intrathecal space was perfused with an artificial CSF (ACSF). Morphine (10 microM in the ACSF), as well as a mu- (DAGO, 10 microM) or delta opioid receptor agonist (DTLET, 10 microM), significantly decreased the outflow of MELM. The effects of morphine and DTLET were prevented by the delta antagonist, naltrindole (10 microM), but not by naloxone (10 microM). Conversely, naloxone, but not naltrindole, prevented the inhibitory effect of DAGO. Although neither the kappa 1 agonist, U 50488H (10 microM), nor the kappa 1 antagonist, norbinaltorphimine (10 microM), exerted on their own any significant effect, norbinaltorphimine enhanced the inhibitory action of morphine. In contrast to the inhibition induced by morphine (with or without naloxone) which was preventable by 10 microM naltrindole, the inhibition of MELM release by morphine plus norbinaltorphimine was only partly reduced by naltrindole. Thus, concomitant stimulation of mu, delta and kappa 1 receptors might account for the apparent delta opioid receptor-dependent inhibition of MELM release by morphine. Indeed, its potential inhibitory effect through the stimulation of mu receptors (normally prevented by the concomitant stimulation of kappa 1 receptors) becomes efficient only when kappa 1 receptors are blocked.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Production and characterization of polyclonal antibodies recognizing the intracytoplasmic third loop of the 5-hydroxytryptamine1A receptor.

The portion of the complementary DNA encoding the third intracellular loop of the rat 5-hydroxytryptamine1A (serotonin) receptor was subcloned into the vector pGEX-KG and expressed in Escherichia coli as a fusion protein coupled with the glutathione S-transferase of Schistosoma japonicum. The fusion protein was purified on a glutathione-agarose affinity column and used to immunize rabbits for the production of polyclonal anti-5-hydroxytryptamine1A receptor antibodies. Enzyme-linked immunosorbent assay revealed that antibodies were produced as early as one month after the first injection of the fusion protein, and immune response plateaued at a maximum after the third (monthly) booster injection. These antibodies only marginally affected the specific binding of [3H]8-hydroxy-2-(di-n-propyl-amino) tetralin to solubilized and membrane bound 5-hydroxytryptamine1A receptors, and did not interfere with serotonin-induced inhibition of forskolin-stimulated adenylate cyclase negatively coupled to 5-hydroxytryptamine1A receptors in rat hippocampal membranes. However, antibodies were able to immunoprecipitate 5-hydroxytryptamine1A receptor binding sites solubilized from rat hippocampal membranes. The distribution of immunoautoradiographic labelling and immunohistochemical staining of rat brain sections exposed to the antibodies raised against the fusion protein superimposed to that of 5-hydroxytryptamine1A receptor binding sites labelled by specific radioligands, with marked enrichment in the limbic areas (dentate gyrus and CA1 area in the hippocampus, lateral septum, entorhinal cortex) and the anterior raphe nuclei. The differential cellular location of immunoreactivity within the hippocampus (where dendritic fields but not pyramidal cell somas were immunostained) and the median raphe nucleus (where the plasmic membrane of somas was strongly immunoreactive) suggests that the addressing of 5-hydroxytryptamine1A receptors might differ from one neuronal cell type to another.

Adenylyl Cyclases↗
PubMed1994

Characterization of an atypical member of the Na+/Cl(-)-dependent transporter family: chromosomal localization and distribution in GABAergic and glutamatergic neurons in the rat brain.

A 3.7-kb cDNA fragment, designated rat-XT1, was isolated from a rat whole-brain cDNA library. The nucleotide sequence of XT1 codes for a 727 amino acid protein with a calculated molecular mass of 81,139 Da and 12 putative transmembrane domains. This protein shares significant homology (28-32%) with the monoamine- (dopamine, norepinephrine, serotonin), amino acid- (taurine, proline, GABA, glycine), choline-, and betaine-, Na+/Cl(-)-dependent transporters. The homology is especially high within the first, second, sixth, and eighth transmembrane domains (45-75%). Thus, XT1 clearly belongs to the Na+/Cl(-)-dependent neurotransmitter transporter superfamily. However, XT1 may define a new subfamily of transporter because it differs structurally from other members of this family in that the extracellular loop linking transmembrane domains 7 and 8 and the C-terminal tail are significantly larger in size. Transient or stable expression of rat-XT1 failed to confer to the transfected cells the ability to transport actively any of the > 60 established or putative neurotransmitter substances assessed. Northern blot analyses of peripheral and neural tissues demonstrated that expression of the 8-kb XT1 mRNA is essentially restricted to the nervous system. In situ hybridization demonstrated a broad but discrete localization of XT1 message in the CNS, particularly in the cerebellum (Purkinje and granular cell layers), the hippocampus (pyramidal and granular cell layers), and the thalamus and throughout the cerebral cortex. This distribution parallels that of the neurotransmitters glutamate and aspartate; however, neither of these excitatory amino acids is a substrate for transport. One noticeable exception to the codistribution of the mRNA for rat-XT1 and these excitatory neurotransmitters is the cerebellar Purkinje cell layer, in which GABAergic neurons are localized. The gene encoding for XT1 is localized to the mouse chromosome 3 in the vicinity of the locus for the mouse neurological disorder spastic (spa).

Amino Acid Sequence↗
PubMed1994

Pharmacological evidence for the involvement of calcium/calmodulin in serotonin 5-HT3 receptor-mediated cation permeability in NG 108-15 cells.

In NG 108-15 clonal cells, extracellular application of micromolar concentrations of serotonin [5-hydroxytryptamine (5-HT)] and substance P induces the opening of a cation permeability monitored by the influx of [14C]-guanidinium. The serotoninergic component of this cation permeability is linked to 5-HT3 receptor activation, whereas the substance P component probably involves an "N-terminal-dependent substance P receptor." In this study, [14C]guanidinium influx triggered by 1 microM 5-HT plus 10 microM substance P was shown to be insensitive to tetrodotoxin, verapamil, diltiazem, nimodipine, and omega-conotoxin, as expected from a process independent of voltage-sensitive sodium and calcium channels. In contrast, [14C]guanidinium influx was inhibited by millimolar concentrations of extracellular calcium and by the chelation of intracellular calcium by bis-O-aminophenoxyethanetetraacetic acid. The inhibition by extracellular calcium apparently involved a competition between the divalent cation and [14C]guanidinium for the same channel. When NG 108-15 cells were exposed to X537A, an ionophore that specifically induces release of calcium from intracellular stores, [14C]guanidinium uptake was markedly increased even in the absence of 5-HT and/or substance P. Conversely, [14C]guanidinium influx due to the latter substances could be reversibly and dose-dependently blocked by various drugs that possess calmodulin-antagonizing properties. These results strongly suggest that the cation permeability opened by 5-HT and substance P in NG 108-15 cells involves a calcium/calmodulin-dependent process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Expression of preproenkephalin A gene and presence of Met-enkephalin in dorsal root ganglia of the adult rat.

The expression of the preproenkephalin A gene was investigated in adult rat dorsal root ganglia (DRG). A radioimmunoassayable Met-enkephalin (ME)-like material was detected in 0.1 M HCl extracts of rat DRG, representing approximately 60 pg of ME equivalents/mg of protein. Chromatographic analyses indicated that the major component of the ME-like material coeluted with authentic ME. In northern blot experiments on total RNA extracted from DRG, a cDNA probe corresponding to the entire coding region of rat preproenkephalin A mRNA yielded a single band of the expected size for this mRNA, i.e., 1.5 kb. Polymerase chain reaction (PCR) experiments were carried out with DRG, striatum, and liver cDNAs using two primers flanking the 1,371-1,771 base region of the preproenkephalin A gene. Thirty PCR cycles performed on both striatum and DRG cDNAs generated a single band of 400 bp, as expected, whereas only trace amounts of this product were detectable using liver cDNAs. Nucleotide sequencing of the PCR product obtained with DRG cDNAs revealed a 100% homology with the 1,371-1,771 sequence of the preproenkephalin A gene. In situ hybridization with a cRNA probe showed that about 3.5% of DRG cells expressed the preproenkephalin A transcript. However, most of these cells probably did not process proenkephalin to enkephalins, as thorough immunohistochemical investigations with anti-ME antibodies allowed the detection of only one in approximately 6,000 cells (in 30 sections of DRG) that exhibited ME-like immunoreactivity. Cells expressing preproenkephalin A mRNA were intermediate-sized neurons, suggesting that primary afferent ME-containing fibers belong to the A category and may participate in a local (spinal) inhibitory control of nociception.

Amino Acid Sequence↗
PubMed1994

Efficient phosphate binding using a combination of gluconolactate and carbonate calcium salts.

Although renal-failure-related hyperphosphataemia can be corrected by various phosphate binders, there remains a need for safer and more efficient formulations to precipitate phosphate. This work describes both a theoretical approach and a phosphate precipitation test in order to design efficient binding calcium salts formulations. The results show that the combination of a soluble calcium salt (the gluconolactate) and a proton-consuming calcium salt (the carbonate) can precipitate phosphate effectively. Furthermore, the theoretical computations correlate well with the ability of the salt to bind phosphate in vitro.

Acetates↗
PubMed1994

Opioidergic control of the spinal release of neuropeptides. Possible significance for the analgesic effects of opioids.

Several neuropeptides play a key role in the transfer (substance P, calcitonin gene-related peptide, etc) and control (enkephalins, cholecystokinin, etc) of nociceptive messages from primary afferent fibres to spino-thalamic neurones in the dorsal horn of the spinal cord. This first relay in nociceptive pathways has been shown to be a major target for opioids such as analgesic drugs, and the effects of exogenous (mainly morphine) and endogenous opioids on the release of neuropeptides within the dorsal horn are reviewed here for a better understanding of the cellular mechanisms responsible for their antinociceptive action. Complex modulations of the in vitro (from tissue slices) and in vivo (in halothane-anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid) release of substance P and calcitonin gene-related peptide by opioids have been reported, depending on the opioid receptor (mu, delta, kappa, and their subtypes) stimulated by these compounds. In particular, the inhibition by delta agonists of substance P release from primary afferent fibres, and that by the concomitant stimulation of mu and kappa receptors of the release of calcitonin gene-related peptide are very probably involved in the analgesic action of specific opioids and morphine at the level of the spinal cord. Furthermore, the negative modulation (through presynaptic opioid autoreceptors) by delta and mu agonists of the spinal release of met-enkephalin, and the complex inhibitory/excitatory influence of delta, mu and kappa receptor ligands on the release of cholecystokinin within the dorsal horn very likely also contribute to the antinociceptive action of these drugs and morphine. The reviewed data strongly support the existence of functional interactions between mu and kappa receptors within the spinal cord, and their key role in the analgesic action of non specific opiates (acting on mu, delta and kappa receptors) such as morphine.

Analgesics, Opioid↗
PubMed1994

Long-term oral administration of L-arginine reduces intimal thickening and enhances neoendothelium-dependent acetylcholine-induced relaxation after arterial injury.

BACKGROUND: Nitric oxide (NO), in addition to its potent vasorelaxant properties, may participate in growth regulation of cultured smooth muscle cells. It was recently demonstrated that in vivo endothelial injury induces the production of NO from L-arginine in the arterial wall. METHODS AND RESULTS: We studied the effects of long-term administration of L-arginine, the precursor of NO, on neointimal thickening and on neoendothelium-dependent vasorelaxation 4 weeks after balloon denudation of normocholesterolemic rabbit iliac arteries. Rabbits were fed with either a standard diet or a diet supplemented with L-arginine (2.25%) in their drinking water 3 days before and during 4 weeks after balloon denudation. The effectiveness of L-arginine supplementation was confirmed by measurement of plasma arginine levels. L-Arginine had no effect on hemodynamic parameters. All animals were killed 4 weeks after balloon denudation, and a digital histomorphometric analysis of three serial nonconsecutive histological cross sections per iliac artery was performed. Intimal thickening was reduced (P < .05) from 0.43 +/- 0.08 (SE) mm2 in controls (n = 8) to 0.24 +/- 0.02 mm2 in treated animals (n = 8). Ten animals (n = 5 in each group) were used for in vitro vasoreactivity assessment 4 weeks after balloon denudation. Neoendothelium-dependent acetylcholine-induced relaxation (10(-8) mol/L to 3.10(-5) mol/L) in treated animals (Emax = -24.1 +/- 5.5%) was significantly greater than in controls (Emax = -8.9 +/- 2.2%). Endothelium-independent relaxation did not differ between groups (Emax = -58.1 +/- 6.5% in L-arginine-supplemented animals versus -52.9 +/- 6.8% in controls). CONCLUSIONS: Our results demonstrate that L-arginine, a precursor of NO, reduces neointimal thickening after balloon denudation and improves neoendothelial-dependent acetylcholine-induced relaxation.

Acetylcholine↗
PubMed1994

Unilateral control of ovarian oxytocin release and the facilitatory effects of insulin-like growth factor-I in sheep.

Prostaglandin F2 alpha (PGF2 alpha)-induced release of ovarian oxytocin was investigated to determine whether the effect in vivo was local. [3H]PGF2 alpha infused downstream into a single ovarian lymphatic was transferred into the adjacent ovarian vasculature (estimated transfer 1.1 and 1.7%, two experiments). When unlabelled PGF2 alpha was infused in a similar manner (76 pmol min-1), there was a prompt eightfold increase in ovarian oxytocin release from the adjacent ovary containing a corpus luteum, but no effect on the opposite corpus luteum, showing that the effect was local. Instillation of 2% lignocaine into the ovarian vascular pedicle did not affect PGF2 alpha-induced oxytocin release, supporting the idea that neural mechanisms are not involved. Repeated doses of PGF2 alpha given close-arterially produced a successive reduction in oxytocin release. This effect was prevented by a prior infusion of insulin-like growth factor-I (IGF-I), which itself gave a small, but significant, increase in oxytocin release. The results show that PGF2 alpha in ovarian lymphatics acts locally and directly to stimulate ovarian oxytocin secretion, that repeated exposure of the corpus luteum to pulses of PGF2 alpha can result in tachyphylaxis, and that this latter effect can be ameliorated by IGF-I infused in vivo.

Animals↗