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Biomedical subjects

R Boucher

Publications and source records attributed to R Boucher.

At least 55 records · Page 3Linked to original sources
PubMed1984

Bioelectric properties and ion flow across excised human bronchi.

Bioelectric properties and ion transport of excised human segmental/subsegmental bronchi were measured in specimens from 40 patients. Transepithelial electric potential difference (PD), short-circuit current (Isc), and conductance (G), averaged 5.8 mV (lumen negative), 51 microA X cm-2, and 9 mS X cm-2, respectively. Na+ was absorbed from lumen to interstitium under open- and short-circuit conditions. Cl- flows were symmetrical under short-circuit conditions. Isc was abolished by 10(-4) M ouabain. Amiloride inhibited Isc (the concentration necessary to achieve 50% of the maximal effect = 7 X 10(-7) M) and abolished net Na+ transport. PD and Isc were not reduced to zero by amiloride because a net Cl- secretion was induced that reflected a reduction in Cl- flow in the absorptive direction (Jm----sCl-). Acetylcholine (10(-4) M) induced an electrically silent, matched flow of Na+ (1.7 mueq X cm-1 X h-1) and Cl- (1.9 mueq X cm-12 X h-1) toward the lumen. This response was blocked by atropine. Phenylephrine (10(-5) M) did not affect bioelectric properties or unidirectional ion flows, whereas isoproterenol (10(-5) M) induced a small increase in Isc (10%) without changing net ion flows significantly. We conclude that 1) Na+ absorption is the major active ion transport across excised human bronchi, 2) Na+ absorption is both amiloride and ouabain sensitive, 3) Cl- secretion can be induced by inhibition of the entry of luminal Na+ into the epithelia, and 4) cholinergic more than adrenergic agents modulate basal ion flow, probably by affecting gland output.

Acetylcholine↗
PubMed1984

Effects of cigarette smoking and short-term smoking cessation on airway responsiveness to inhaled methacholine.

Threshold of airway responsiveness to methacholine aerosol was determined in 53 apparently healthy persons. In 18 nonallergic nonsmokers matched according to sex and age to 18 nonallergic smokers, the mean methacholine threshold of airway response (T), as measured using partial flow-volume curves, had a tendency to be greater in nonsmokers, but the difference was not significant for the group as a whole; it was, however, significant for a subset of 9 matched pairs with a cigarette consumption greater than 10 pack-years (mean T nonsmokers, 2.8 mg/ml; smokers, 0.3; p = 0.036). In 17 smokers who stopped smoking for 99 days in average, T was not significantly different for the group as a whole, although the majority of the smokers reported improvement of respiratory symptoms after cessation of smoking. The results of this study indicate that cigarette smoking is associated with increased airways responsiveness to inhaled methacholine and that this effect is dose related.

Adult↗
PubMed1983

Biphasic effect of estradiol and domperidone on lingual dyskinesia in monkeys.

In previous work, we demonstrated in animals and humans an antidopaminergic effect of estradiol at the level of the striatum. In the present study, we tested the effect of a large dose of estradiol (0.5 mg s.c.) administered either acutely or during several days in four female ovariectomized monkeys, displaying a persistent buccolingual dyskinesia due primarily to a midbrain lesion, but which is markedly enhanced by dopaminergic agonists. One of the monkeys also displayed a lesion-induced parkinsonian-like tremor of the opposite limbs. Chronic administration of estradiol markedly reduced the apomorphine-induced potentiation of the dyskinesia but did not affect the tremor. A single dose of estradiol was followed after 24 h by a 75% reduction of the effect of apomorphine on the dyskinesia but a 50% increase in the response to apomorphine was seen after 2 weeks. The response was at the control level after 30 days. Domperidone, a peripheral dopamine agonist that does not cross the blood-brain barrier and which causes an elevation of prolactin similar to that seen after estradiol, is followed by a similar biphasic modification of the response to apomorphine. Our results suggest that estradiol may have opposite effects on the sensitivity of the striatal dopamine receptors and therefore on dyskinesia, depending on the time of observation. An elevation of prolactin appears to have similar effects. Moreover, some effects of these hormones may be delayed by several days to weeks in primates.

Animals↗
PubMed1983

The output organization of the substantia nigra in primate as revealed by a retrograde double labeling method.

The cellular origin and degree of collateralization of the efferent projections of the substantia nigra pars reticulata (SNr) in the squirrel monkey (Saimiri sciureus) were studied using the following combinations of fluorescent retrograde tracers: Evans blue and DAPI-Primuline, Fast blue and Nuclear yellow, True blue and Nuclear yellow. In a first series of experiments one tracer was injected in the ventral anterior (VA) and ventral lateral (VL) thalamic nuclei, and the complementary tracer was delivered in the peribrachial area of midbrain tegmentum. After thalamo-tegmental injections numerous nigrothalamic neurons occur in clusters, particularly in rostrolateral part of SNr, whereas the nigrotegmental neurons prevail in caudomedial segment of SNr. However, a significant overlap exists between these two populations. The nigrothalamic and nigrotegmental neurons are present in about equal number in SNr with as much as 60% of these neurons being double-labeled. In a second series of experiments injections were made concomitantly in VA/VL nuclei and in superior colliculus. After thalamo-collicular injections the nigrothalamic neurons are found in larger number than the nigrocollicular neurons which are mostly confined to the middle third of SNr. About 15-20% of all SNr positive neurons are double-labeled, although this proportion climbs to 30-40% in certain sections taken through the middle third of SNr. Finally, injections were made concomittantly in superior colliculus and in midbrain tegmentum. In contrast to the findings obtained after thalamo-tegmental and thalamo-collicular injections, only about 10% of SNr neurons appear to be double-labeled after colliculo-tegmental injections. All injections made in present study have produced retrograde cell labeling in contralateral SNr. However, by far the largest number of contralateral labeled neurons is found after superior colliculus injection. These findings reveal that the SNr neurons in primate, as those in rat and cat, display a high degree of axonal branching. As such, the output organization of SNr appears to differ markedly from that of the substantia nigra pars compacta, but is remarkably similar to that of the internal pallidum which is the other major output structure of the basal ganglia.

Animals↗
PubMed1983

Relative ion permeability of normal and cystic fibrosis nasal epithelium.

The raised transepithelial electric potential difference (PD) across respiratory epithelia in cystic fibrosis (CF) has suggested an abnormality in ion permeation. We characterized this abnormality further by measuring in the nasal epithelia of CF and normal subjects the concentration-PD relationship for amiloride, an inhibitor of cell Na+ permeability, and PD responses to superfusion with solutions of different composition. Amiloride was more efficacious in the CF subjects but the ED50 was not different from that of normals (approximately 2 X 10(-6) M). Na+ replacement by choline induced effects similar to those of amiloride, i.e. a greater depolarization in CF subjects. A 10-fold increase in the K+ concentration of the perfusate induced a small (less than 10 mV) depolarization in both subject populations. When Cl- in the perfusate was replaced by gluconate or SO2-(4) the nasal PD of normal subjects hyperpolarized (lumen became more negative) by approximately 35 mV. A significantly smaller response (less than 17 mV) was induced in CF homozygotes but not in heterozygotes (38 mV). The smaller response of CF subjects appears to reflect an absolute decrease in luminal surface Cl- permeability because pretreatment with amiloride did not increase the response to Cl- free solution (7 mV). Accordingly, three abnormalities (decreased Cl- permeability, raised PD, greater amiloride efficacy) have been identified in CF respiratory epithelia. Whereas "excessive" active Na+ transport can account for these abnormalities and the dessication of airway surface liquid, it is possible that a lower lumenal cell membrane Cl- permeability and inhibition of a potential path of Cl- secretion can also explain the observations.

Adult↗
PubMed1982

Metabolism of prostaglandin endoperoxide by microsomes from human lung parenchyma and comparison with metabolites produced by pig, bovine, rat, mouse and guinea-pig.

The metabolism of PGH2 by human lung parenchymal microsomes was characterized by radiometric high performance liquid chromatography and compared with metabolism by pig, bovine, rat, mouse, and guinea pig lung microsomes. Microsomes from human lung synthesized 0.74 nmoles/mg protein and 0.72 nmoles/mg protein, PGI2 (6-Keto-PGF1 alpha) and TxA2 (TxB2) respectively, upon incubation with 4.0 nmoles of PGH2. Pig, bovine, rat, mouse, and guinea pig microsomes respectively synthesized 1.0, 1.0, 0.9, 0.4, and 0.1 nmoles of PGI2/mg protein, and 0.9, 1.0, 0.7, 0.3, 1.8 nmoles of TxA2/mg protein, and preparations formed some PGE2, PGF2 alpha, and PGD2. Mouse lung microsomes were unique in synthesizing PGE2 as the major prostaglandin. The thromboxane synthetase inhibitor 1-benzylimidazole was a specific inhibitor in these six species.

Animals↗
PubMed1982

Experimental tardive dyskinesia.

In this work, we have attempted to reproduce dyskinesia similar to tardive dyskinesia by two methods. In the first experiment, we have administered to 6 macaca mulatta, haloperidol 0.25 mg/kg daily for six months. During that period we observed in all monkeys, after each dose: restlessness, akinesia and tremor. One monkey developed choreoathetoid movements, which were seen each day after the first month. They disappeared however upon cessation of the drug administration. Only one animal developed a bucco lingual dyskinesia after two months which was still present when they were sacrificed six month after the drug administration was discontinued. At that time, harmaline 3 mg/kg induced a postural tremor in all monkeys suggesting a lesion of the rubro-olivo-cerebello rubral loop. Histological analysis of the brains revealed no gross abnormality. In a second experiment, a left midbrain electrolytic lesion was performed in twelve monkeys. One monkey, developed a contralateral tremor but five including the trembling one developed a buccolingual dyskinesia which has now lasted more than a year. This dyskinesia is present at rest but increased by dopaminergic agents and blocked by haloperidol. Histological analysis of the brain of one of the monkeys revealed a dorsal lesion involving the region of the nucleus parafascicularis thalami. The substantia nigra was spared.

Animals↗
PubMed1981

Acetylcholinesterase-containing neurons in cat pallidal complex; morphological characteristics and projection towards the neocortex.

The cat globus pallidus (GP) was found to contain both small and large cells that stain lightly and intensely for acetylcholinesterase (AChE), respectively. The small GP cells are similar to entopeduncular (EN) cells and it is proposed that both should be considered as 'typical' pallidal neurons. In contrast, large GP cells are similar to intensely stained AChE cells present in the substantia innominata (SI) and the putamen (PUT). Furthermore, HRP injection into the neocortex was found to label numerous large AChE cells in GP and a lesser number of similar neurons in PUT and SI. No HRP labeling was observed in the smaller cells of EN, GP and PUT. These findings suggest that the magnocellular AChE neurons in feline basal ganglia may be part of a single population of 'limbic' elements.

Acetylcholinesterase↗
PubMed1981

Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis.

To investigate respiratory epithelial function in cystic fibrosis, we measured the transepithelial electrical potential difference across the upper and lower respiratory mucosa in patients with cystic fibrosis and control subjects. The nasal potential difference in the 24 patients with cystic fibrosis exceeded by more than 3 standard deviations the mean voltage in healthy controls, subjects with other diseases, and subjects heterozygous for cystic fibrosis. Potential differences in lower airways were measured in four patients and were significantly greater than in controls (P less than 0.05). Superfusion of the luminal surface with amiloride, an inhibitor of active sodium absorption, induced greater reductions in both nasal and airway potential difference in patients than in controls. We conclude that the increased respiratory-epithelial potential differences appear to be a specific abnormality in homozygotes for cystic fibrosis. The greater reduction in potential difference in response to amiloride suggests that absorption of excess salt and perhaps liquid from respiratory epithelial surfaces contributes to the pathogenesis of lung disease in cystic fibrosis.

Adolescent↗
PubMed1981

The origin of forebrain afferents to the habenula in rat, cat and monkey.

Injections of horseradish peroxidase (HRP) involving the entire habenular complex in rat, cat and squirrel monkey (Saimiri sciureus) label (1) numerous cells in anterior lateral hypothalamic area, (2) a moderate number of cells in lateral preoptic area, substantia innominata, nucleus of diagonal band and postcommissural septum, and (3) a few cells in medial hypothalamus, ipsilaterally, in all three species. Some labeled cells also occur in corresponding regions contralaterally. The contribution of these limbic structures to the innervation of habenula is thus strikingly similar in the three groups. In contrast, significant species variations are found in respect to pallidal afferents. Whereas the entopeduncular nucleus in rat stands out as the main source of forebrain habenular afferents, the same structure in cat appears to contribute less substantially than adjoining lateral hypothalamus to the innervation of habenula. In monkey habenular afferents also arise principally from lateral hypothalamic neurons. At pallidal levels, labeled cells are nevertheless abundant in the rostral pole of primate internal pallidum. More caudally, they are found in significant number along internal and accessory medullary laminae where they intermingle with acetylcholinesterase-containing neurons which do not themselves project significantly upon habenula. This heterogeneous distribution of labeled pallidal cells indicates that the pallidohabenular projections in primate may arise, at least in part, from specific neuronal subpopulations within internal pallidum.

Afferent Pathways↗
PubMed1981

Formation of angiotensin II by tonin from partially purified human angiotensinogen.

The renin substrate (angiotensinogen) has been purified from outdated human blood bank plasma. A 100-fold purification was achieved by ammonium sulphate protein fractionation and four successive chromatographic procedures. We show that tonin, a serine protease enzyme found in submaxillary glands of the rat, cleaves the human plasma angiotensinogen, devoid of tonin inhibiting factor(s), at a pH optimum of 5--5.5. It generates a pressor substance that was identified as angiotensin (A) II. The rate of cleavage of the human angiotensinogen preparation by 1 nmol of renin or tonin was calculated to be 1320 nmol AI/h for renin and 26 nmol AII/h for tonin.

Angiotensin II↗
PubMed1981

Purification and partial characterization of a plasma inhibitor of tonin.

A plasma inhibitor of tonin activity in the rat, was purified by ammonium sulfate precipitation, ion-exchange of chromatography, and gel filtration. Its purity was investigated by analytical electrophoresis on polyacrylamide gel and by ultracentrifugation sedimentation velocity. The molecular weight (360 000) of the purified inhibitor was determined by sodium dodecyl sulfate electrophoresis and its isoelectric point (4.5) by gel isoelectrofocusing. The Stokes radius (640 nm) was evaluated by gel filtration studies and a frictional ratio (f/fo) of 1.95 was calculated from the molecular weight and Stokes radius. Kinetic studies using angiotensin I as substrate showed that the inhibition of tonin by the purified inhibitor was noncompetitive and does not exceed 70%. Electrophoresis showed the same mobility for [125I]tonin bound to plasma proteins and for [125I]tonin bound to the purified inhibitor. The inhibitor may be a protein resembling half of the dimeric protease inhibitor rat alpha 1-macroglobulin or human alpha 2-macroglobulin.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1981

Effects of tonin on the response to norepinephrine by the aortic strip of the hypertensive rat.

The response to norepinephrine (NE) of arterial smooth muscle from two types of experimental hypertensive rats was investigated. Aortic strips from one-kidney, one-clip hypertensive animals were less responsive to NE than those from their normotensive controls but strips from one-kidney, one-clip hypertensive animals showed no difference from their corresponding controls. The contractility in response to NE was the same in all groups. These results suggest that the mechanisms responsible for lesser reactivity in the one-kidney hypertensive group are not a consequence of elevated blood pressure itself but may be related to changes in the intrinsic sensitivity of aortic smooth muscle. Tonin potentiated the contraction induced by NE in aortic strips from hypertensive and normotensive rats. This effect was more pronounced in the one-kidney, one-clip hypertensive animals, so that although the aortic smooth muscle from these animals is less reactive to NE, the decreased reactivity can be more than compensated by the presence of tonin. The mechanism of potentiation is not yet clear but the fact that Saralasin did not inhibit it suggests that angiotensin II is not generated in situ.

Animals↗
PubMed1981

Detection from rat pituitary of beta-lipotropin and materials containing opiatelike activity by combined enzymatic radioreceptor assay.

Tonin, a proteolytic enzyme isolated from rat submaxillary gland, was allowed to react upon ovine beta-lipotropin (beta-LPH) at 37 degrees C at a variety of pH values and for different lengths of time. Opiatelike activity generated by the reaction was assessed using a radioreceptor assay for beta-endorphin with rat brain homogenate. [3H]naloxone, and beta-endorphin as receptors, tracer, and hormone standard, respectively. Cleavage of beta-LPH with tonin produced a 10-fold increase in opiatelike activity as compared with beta-LPH alone. Digestion of beta-LPH with other enzymes such as renin, cathepsin D, trypsin, and chymotrypsin produced much less opiatelike activity. beta-Endorphin and methionine-enkephalin were not cleaved by tonin. Using this new assay, we were able to detect beta-LPH and materials containing opiatelike activity from rat pituitary extracts after gel chromatography. It is more specific and more sensitive than trypsin digest.

Animals↗
PubMed1981

Pressor effect of tonin in anephric animals.

Tonin was injected intravenously to normal rats without effect on blood pressure. Twenty-four hours after bilateral nephrectomy, tonin produced a dose-dependent pressor effect in rats which was abolished by the angiotensin antagonist [Sar1-Ala8]-angiotensin II. Vascular response to angiotensin II was slightly increased after nephrectomy. Plasma angiotensin II increased significantly after injection of tonin and disappeared biexponentially with a half-life of less than 1 min for the fast component and 9 min for the slow component. The change in plasma angiotensin II correlated with the elevation in mean blood pressure. No difference in inhibitory power of plasma on tonin activity could be shown between intact and nephrectomized rats. In vitro, the initial velocity of generation of angiotensin II by tonin acting on plasma increased after addition of semipurified rat renin substrate and was significantly greater in plasma of nephrectomized rats. In nephrectomized rabbits, but not in intact ones, a dose-dependent pressor effect was produced by tonin. These data demonstrate the in vivo production of angiotensin II by tonin in an animal model with elevated substrate levels. Together with the in vitro data, these results suggest a role for substrate concentration in the expression of tonin enzymatic activity in vivo.

Angiotensin II↗
PubMed1981

Brain receptor binding and central actions of angiotensin analogs in rats.

The possible physiological importance of brain receptors for angiotensin was investigated. Structure-activity relationships were established for 12 fragments and analogs of angiotensin II (ANG II). 1) Affinities of the peptides were determined in an in vitro assay of rat brain angiotensin receptors. 2) Blood pressure (BP) and water intake following intracerebroventricular administration of the peptides to conscious rats were monitored. In vitro, ANG II and [des-Asp1]ANG II displayed the highest affinities. [Trp1]ANG II and [Trp8]ANG II had one-eighth and one-ninth the affinity of ANG II, respectively. Multiple substitutions in positions 1, 4, and 8 produced a 1,000-fold fall in binding affinity. Excellent correlation was found between the in vitro binding affinities and the in vivo central activities of the peptides on BP (r = 0.975) and on water intake (r = 0.900). The results suggest that the biochemically characterized brain angiotensin receptors may be physiologically relevant to BP and body fluid homeostasis. The brain angiotensin receptors mediating BP and thirst have very similar structural requirements.

Angiotensin II↗