Le profil ECORS-Nord de la France, implanté sur la bordure nord-ouest du bassin Parisien, ne traverse pas celui-ci dans sa région de subsidence maximale. Il apporte néanmoins une vision générale d'un transect et permet de préciser l'histoire du Bassin. Nous retiendrons, parmi les éléments les plus intéressants : - la présence possible de petits bassins stéphaniens ou permiens dans la région de Banthelu et Marville; - la structuration jurassique à éocène le long des grands accidents que sont les failles de la Seine, du Bray et de la Somme; - l'histoire de la subsidence de la bordure nord-ouest du Bassin. The Nord de la Francedeep seismic profile has been shot on the northwestern edge of the Paris Basin, about 100 km away from its main subsiding center. It is, however, the first regional line crossing the basin and some details of its geological history have been emphasized: (a) Stephanian or Permian basins with restricted sizes have been encountered below the Mesozoic cover along some parts of the line. Their location has been made possible by the simultaneous use of seismic refraction and reflection data. (b) 3 major faults have been crossed: the Seine, Bray and Somme faults. All of them had normal displacements in Jurassic and Lower Cretaceous times. This is clearly observed today through differences in sedimentary thicknesses on both sides of the faults. The Seine and Bray faults were reactivated as transcurrent and/or reverse faults in Eocene time during the north-south oriented Pyreneanshortening. This tectonic event has led to slight inversions of the basin between these 2 faults. (c) The subsidence history of the basin has been computed along the seismic line. The total tectonic subsidence was very small in Mesozoic times (500-400 m). A slight increase in subsidence in the Upper Jurassic is correlated with the Cimmerian rifting which is well known in the North Sea.

The present studies were designed to measure the affinity of UP 269‐6, a newly developed angiotensin AT 1 receptor antagonist, for vascular AT 1 receptors from normotensive and hypertensive rats and to investigate in vitro , its effects on angiotensin II (AII)‐induced hyperplasia and hypertrophy of vascular smooth muscle cells (VSMC). In addition the in vivo effects of UP 269‐6 on neointimal proliferation in a carotid artery balloon injury in normotensive rats were also investigated. UP 269‐6 selectively inhibited [ 125 I]‐Sar 1 ‐Ile 8 ‐AII binding to vascular AT 1 receptors present on VSMC derived from normotensive Wistar rat and from SHR (K i = 16.6 ± 3.6 nM and 7.5 ± 2.0 nM, respectively). In comparison, losartan and its metabolite, EXP 3174, inhibited [ 125 I‐Sar 1 ‐Ile 8 ‐AII binding to vascular AT 1 receptors derived from both cell models with K i values slightly lower (losartan) and higher (EXP 3174), respectively, than that of UP 269‐6. AII (1 μM) induced a weak and variable hyperplastic response (4 to 32% increase in cell number) in Wistar rat VSMC after 96 h. AII (1 μM) induced a time‐dependent increase in cell number in VSMC from SHR. UP 269‐6 inhibited concentration‐dependently this effect with an IC 50 value of 159 ± 58 nM. Losartan was clearly less potent and EXP 3174 showed nearly the same inhibitory potency, compared to UP 269‐6. UP 269‐6 (1 μm) inhibited nearly completely the action of AII. AII (500 nM) caused maximal stimulation of protein synthesis in Wistar rat VSMC (117 ± 36%). UP 269‐6, losartan and EXP 3174 totally inhibited this stimulation with IC 50 values of 28 ± 6 nM, 3504 ± 892 nM and 21±3 nM, respectively. AII (50 nM) induced maximal stimulation of protein synthesis in SHR VSMC (237 ± 67%). UP 269‐6, losartan and EXP 3174 totally inhibited this stimulation with IC 50 values of 16 ± 3 nM, 282± 122 nM and 3.3 ± 1.0 nM, respectively. UP 269‐6 (75 mg kg −1 day −1 ) administered orally in the diet for 20 days induced a 38% reduction in neointimal area and a 36% reduction in neointima/media ratio associated with the intimal thickening induced by carotid artery balloon injury. In conclusion, UP 269‐6 was shown to be a potent antiproliferative agent both in vitro on AII‐induced hyperplasia and hypertrophy of VSMC derived from normotensive and hypertensive rats, and in vivo upon intimal thickening induced by carotid artery balloon injury in the rat.

To estimate the effects of UP269-6, a nonpeptide angiotensin II receptor antagonist, and captopril, a converting enzyme inhibitor, on the progression of nephropathy, 77 uninephrectomized diabetic rats were maintained for 8 months with plasma glucose levels from 300 to 500 mg/dL. Systemic and renal parameters were periodically measured, and, at the time of death, a histological evaluation of renal damage was performed. Control rats (no additional treatment but insulin) showed increased blood pressure and urinary albumin levels, together with prominent alterations in the kidney (renal and glomerular hypertrophies, tubular atrophy, and 19% of sclerotic glomeruli). Captopril (50 mg/kg/day) and UP269-6 (10 mg/kg/day) reduced blood pressure and albumin excretion levels, and improved histological renal preservation (lower renal and glomerular hypertrophies, tubular atrophy, and percentage of sclerotic glomeruli: 5% and 7%, respectively). Finally, a low dose of UP269-6 (1 mg/kg/day), which induced an intermediate level of blood pressure between control and the other treated groups, produced an equivalent degree of nephroprotection. Our data demonstrate the efficacy of this new angiotensin II receptor antagonist on the progression of diabetic renal damage. These results also reinforce the role attributed to angiotensin II in the development of renal derangement in this model, as UP269-6 is devoid of agonistic effect on the kinin system.

Summary— The in vitro pharmacology of UP 269‐6, a novel nonpeptide angiotensin II antagonist, was examined in radioligand binding and functional isolated tissue assays. UP 269‐6 bound selectively to AT 1 receptors as evidenced by the inhibition of specific [ 125 I] Sar 1 , Ile 8 ‐AII binding in rat adrenal membranes (IC 50 = 35.8 nM) and in cultured vascular smooth muscle cells (IC 50 = 23.8 nM). UP 269‐6 displayed a very high selectivity for the AT 1 compared to the AT 2 receptor subtype (IC 50 > 10,000 nM). UP 269‐6 inhibited the AII‐induced contraction of isolated rabbit aortic strips. The pattern of AII antagonism suggested competitive antagonism at low concentrations (10 −10 , 3 × 10 −10 , 10 −9 M) of UP 269‐6 and insurmountable antagonism at higher concentrations (3 × 10 −9 , 10 −8 , 3 × 10 −8 M). Based on the calculated p A 2 values, UP 269‐6 (9.86 ± 0.25) was an angiotensin II receptor antagonist as potent as L‐158,809 (9.82 ± 0.37) and much more potent than losartan (7.96 ± 0.38). UP 269‐6 was devoid of affinity (IC 50 > 10,000 nM) for many other receptors, ion channels and uptake sites, demonstrating its high specificity for AII receptors. Furthermore, this compound did not affect the contractile response to KCl or phenylephrine in rabbit aorta and exhibited no effect on angiotensin converting enzyme activity. These data demonstrate that UP 269‐6 is a highly potent, selective and specific AT 1 receptor antagonist.

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to to the discovery of compounds with potent oral antihypertensive activity in a renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors. In vivo structure-activity relationship study has shown the importance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for oral activity and the critical role of alkyl substituents at the 1- or 2-position. In the case of oral administration, 5-C derivatives were found to be, on the whole, more potent than 5-O derivatives. UP 221-78, 5-hydroxymethyl-3-n-propyl-1-(2,2,2-trifluoroethyl)-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equivalent antihypertensive activity to the well known antagonist Losartan at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-78, respectively.

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These [1,2,4]-triazolo[1,5-c]pyrimidine and 1,2,4-triazolo[4,3-c]-pyrimidine derivatives represent a new class of bicyclic antagonists that produced a potent, oral antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors and were found to be specific for the AT(1) receptor subtype. A SAR study has shown the importance of the 8-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl for oral activity and the critical role of alkyl substituents at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c] series. UP 269-6 (5-methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-[1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compound. It was shown to be a highly potent antihypertensive derivative (decrease in mean arterial pressure of 39.6 +/- 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which displayed a high affinity for adrenal AII receptors with a marked selectivity for the AT(1) receptor subtype (K-i AT(1) = 24 nM; K-i AT(2) = 79 200 nM). This compound is currently undergoing extensive pharmacological and clinical development.

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Novel 2-arylbenzimidazoles and azabenzimidazoles were synthesized, and their inotropic action was evaluated. Changes in left ventricular pressure, dP/dt max, were measured as an index of cardiac contractility. The structural features that impart optimal inotropic activity are presented. The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers. To investigate the mechanism of action, the most potent compounds were tested for their calcium-sensitizing properties and their potential for the inhibition of phosphodiesterase. Two compounds, 1 and 41, showed interesting in vitro and oral activity without side effects. They have a more potent calcium-sensitizing effect than MCI-154 and are under further investigation.

Other| March 01, 1990 Major Hercynian thrusts along the ECORS Pyrenees and Biscay lines P. Choukroune; P. Choukroune Author Univ. Rennes I, CAESS, Rennes 35042, France Search for other works by this author on: GSW Google Scholar B. Pinet; B. Pinet Author Search for other works by this author on: GSW Google Scholar F. Roure; F. Roure Author Search for other works by this author on: GSW Google Scholar M. Cazes M. Cazes Author Search for other works by this author on: GSW Google Scholar Author and Article Information P. Choukroune Author Univ. Rennes I, CAESS, Rennes 35042, France B. Pinet Author F. Roure Author M. Cazes Author Publisher: Société Géologique de France First Online: 03 Mar 2017 Online ISSN: 1777-5817 Print ISSN: 0037-9409 GeoRef, Copyright 2012, American Geosciences Institute. Reference includes data from PASCAL, Institute de l'Information Scientifique et Technique, Vandoeuvre-les-Nancy, France Bulletin de la Société Géologique de France (1990) VI (2): 313–320. https://doi.org/10.2113/gssgfbull.VI.2.313 Article history First Online: 03 Mar 2017 Cite View This Citation Add to Citation Manager Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Search Site Citation P. Choukroune, B. Pinet, F. Roure, M. Cazes; Major Hercynian thrusts along the ECORS Pyrenees and Biscay lines. Bulletin de la Société Géologique de France 1990;; VI (2): 313–320. doi: https://doi.org/10.2113/gssgfbull.VI.2.313 Download citation file: Ris (Zotero) Refmanager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentBy SocietyBulletin de la Société Géologique de France Search Advanced Search This content is PDF only. Please click on the PDF icon to access. First Page Preview Close Modal You do not have access to this content, please speak to your institutional administrator if you feel you should have access.

The anticholinergic effects of cibenzoline, disopyramide, and atropine were compared on experimental models. Using inhibition of specific binding of 3H-quinuclidinyl benzylate (3H-QNB) in rat heart and cerebral cortex, K1 values were 15.8 ± 1.6, 12 ± 3.5, and 0.013 ± 0.001 μM, respectively, for heart membranes and 31.6 ± 1.5, 7.8 ± 1.3, and 0.006 ± 0.001 μM, respectively, for cerebral cortex membranes. In isolated guinea pig ileum, disopyramide was about 15 times more anticholinergic than cibenzoline but about 900 times less so than atropine. In anesthetized dogs, the three drugs administered by intravenous bolus reduced bradycardia caused by vagal stimulation. The effect of cibenzoline at 7 mg/kg i.v. (double the antiarrhythmic dose) was approximately the same as that of disopyramide at 2.5 mg/kg (half the anti-arrhythmic dose). The drugs were infused for 1 h at 0.17 mg/kg/h for atropine, 11.6 mg/kg/h for disopyramide, and 5.5 mg/kg/h for cibenzoline. The maximal inhibition of the vagal stimulation was 98, 95, and 52%, respectively, for the three drugs. In nonanesthetized dogs, inhibition of the vagal-tone-induced tachycardia reached 33 ± 4, 134 ± 20, and 206 ± 19% for cibenzoline, disopyramide and atropine, respectively. These results show cibenzoline to exert less potent anticholinergic effects than disopyramide.

From southern Ireland to the northern Bay of Biscay, subduction was active from the Proterozoic to the late Palaeozoic. They led to the Cadomian, Caledonian and Variscan collisions. Features characterizing these three orogenies have been crossed by the WINCH, SWAT, WAM and Bay of Biscay deep seismic profiles recorded by the BIRPS and ECORS groups. In the Celtic Sea, the Variscan front is characterized by a S-dipping ramp rising directly from the middle crust with much less northward flattening than shown by the front in the northern France and West Germany profiles. South of the Variscan front, other S-dipping reflections occur above a possible deep detachment. The Lizard ophiolitic suture marks S-dipping events traversing the entire crust and the present Moho in the English Channel. Several sets of prominent N-dipping reflections occurring in the Celtic Sea and south Irish Sea are interpreted as Caledonian features running parallel to the Caledonian Iapetus suture and the pattern of folds and faults recognized in Wales and southeastern Ireland. Proterozoic S-dipping subduction is recorded by geological data in northern Wales and the English Channel. Related crustal structures correspond to deep seismic events cutting across the lower crust and the Moho and show the same apparent dip as the Variscan features. Parallelism between dips and/or strikes of structural features with different ages suggests a tectonic heritage. The crust thus appears to be characterized by N and S-dipping features which cut across large parts of it and may be assigned to Variscan, Caledonian or Candomian thrusts or shear zones. The lower part of the crust shows a band of high-amplitude subhorizontal reflections and a flat Moho reflection, which seem to have overprinted the above-mentioned dipping features in a later period. The lack of evidence of any shallow detachment in the Caledonian and Variscan belts together with the presence of dipping crustal thrust-like features suggest that the region may have reached the very latest collisional stage, the end of both of these orogenies.

The area between France and the British Isles has undergone three major orogenies since Proterozoic times, the Cadomian-Monian (late Proterozoic), Caledonian (late Silurian-early Devonian) and Variscan (Devonian-Carboniferous). This paper shows that crustal structures related to the first two orogenies can be recognized in deep seismic profiles in the English Channel, the Celtic Sea and the Irish Sea. In the northernmost area. remarkable north-dipping reflections in the deep crust of the Celtic and Irish Seas may be correlated with surface structures and interpreted as Caledonian south-verging thrusts parallel to the lapetus suture. These features occur as far south as the Cornubian ridge (Cornwall), within the northern segment of the Variscan north-verging thrust belt. The latter is characterized by south-dipping reflections interpreted as Variscan thrusts. Caledonian thrusts were probably re-activated by the Variscan compression. Evidence of Caledonian thin-skinned detachment cannot be recognized in the seismic profiles. It is possible that either detachment structures were strongly deformed and obliterated by late Caledonian thrusting, or that detachment may never existed. Caledonian shortening was probably dominated by deep-rooted crustal thrusts as a result of the overall obliquity of the collision. Caledonian thrusts are regarded as very late features formed when the crust between the colliding continents was already relatively thick. They are distributed throughout the southern Caledonides including the lapetus suture area. Deep south-dipping reflections in the lower crust in the southern Irish Sea and the English Channel may be related to the Cadomian-Monian orogenic event. The Cadomian, Caledonian and Variscan features have probably been re-activated a number of times.