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C Wilm

Publications and source records attributed to C Wilm.

13 recordsLinked to original sources
PubMed1999

Benzofuro[3,2-b]pyridines as mixed ET(A)/ET(B) and selective ET(B) endothelin receptor antagonists.

The discovery, synthesis and structure-activity relationships of a series of novel benzofuro[3,2-b]pyridines as non-selective endothelin ET(A)/ET(B) as well as selective ET(B) receptor antagonists are described. The most potent non-selective inhibitor 7s displayed an IC50 of 21 nM and 41 nM for ET(A) and ET(B) receptors, respectively, whereas 7ee merely showed affinity for the ET(B) receptor (IC50 = 3.6 nM).

Animals↗
PubMed1998

Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist.

The discovery, in vitro and in vivo studies of the highly potent ETA antagonist EMD 122946 are presented. This compound displayed high binding affinity and functional antagonism [IC50 = 3.2 x 10(-11) M, pA2 = 9.5 (ETA)] and inhibited the ET-1 induced pressor response in pithed rats with an ED50 of 0.3 mg/kg. In conscious spontaneously hypertensive rats and in DOCA-salt hypertensive rats the compound lowered mean blood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bioavailability in rats and monkeys.

Animals↗
PubMed1998

Endothelin antagonists: evaluation of 2,1,3-benzothiadiazole as a methylendioxyphenyl bioisoster.

The methylendioxyphenyl group is present in a number of endothelin receptor antagonists thus far reported. By means of a Kohonen neural network we discovered with a benzothiadiazole a bioisosteric replacement instead. This group should be devoid of the negative metabolic interactions with cytochrome P450 ascribed to methylendioxyphenyl in vivo. The synthesis of a potent benzothiadiazole analogue EMD 122801 together with in vitro studies of different methylendioxyphenyl, benzothiadiazole and benzofurazan derivatives is described.

Dioxoles↗
PubMed1994

Augmented agonist-induced Ca(2+)-sensitization of coronary artery contraction in genetically hypertensive rats. Evidence for altered signal transduction in the coronary smooth muscle cells.

The Ca2+ responsiveness of vascular smooth muscle myofilaments is not unique: it is increased during neuro-humoral activation and decreased during beta-adrenergic stimulation. In this study we tested whether an augmented Ca2+ responsiveness of smooth muscle myofilaments may contribute to the increased coronary tone observed in hypertension using beta-escin-permeabilized coronary arteries from 3-mo-old stroke-prone spontaneously hypertensive rats (SHRSP) and their age matched normotensive reference strain (WKY rats). In intact coronary arteries, the response to 5-hydroxytryptamine (5-HT) but not to KCl was larger in SHRSP than in WKY rats. In beta-escin permeabilized coronary arteries in which the receptor effector coupling is still intact, 5-HT enhanced force at constant submaximal (Ca2+) (pCa 6.38) to a greater extent in SHRSP. The Ca2+ sensitizing effect of 5-HT was mimicked by GTP gamma S (0.01-10 microM); again this effect was larger in SHRSP. In the absence of 5-HT or GTP gamma S the Ca2+ force relation was similar in both groups. Forskolin induced relaxation at constant submaximal (Ca2+). This desensitizing effect was smaller in SHRSP than in WKY rats. In conclusion, this study shows that intracellular signalling pathways involved in modulating the Ca2+ responsiveness of coronary smooth muscle myofilaments are altered in the genetically hypertensive animals favoring a hypercontractile state in the coronary circulation.

Actin Cytoskeleton↗
PubMed1993

Ipsilateral retinopetal projection of the nucleus olfactoretinalis (NOR) during development and regeneration: a DiI study in a cichlid fish.

The development and regeneration of the ipsilateral retinopetal projection of the nucleus olfactoretinalis (NOR) in the cichlid fish Haplochromis burtoni was studied with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI) in fixed tissue. Throughout development most NOR cells projected to the contralateral retina. Only an insignificant, transient elevation of a projection to the ipsilateral retina was found in a few animals; however, after severing the contralateral processes of NOR cells by either enucleation or nerve crush, many animals had significantly more NOR cells with a regenerated process to the ipsilateral retina. Nevertheless, within a few weeks of surgery, the number of animals with ipsilaterally projecting cells were reduced to control values. The transiently enhanced ipsilateral projections to the retina imply changes in the guiding mechanism after these operations and the existence of control mechanisms against unusual connections to the retina in this bony fish.

Animals↗
PubMed1993

Regenerating retinal fibers display error-free homing along undamaged normal fibers.

After crushing one optic nerve in a bony fish, retinal fibers regenerate to both tecta. Anterograde labelling indicates that the ipsilaterally regenerating fibers have a rather straight growth, apparently along the undamaged fibers of the contralateral retina. In contrast, the contralaterally regenerating fibers deviate widely from a straight course. Retrograde labelling shows a mirror-symmetric distribution of regenerated ipsilateral and resident contralateral ganglion cells in a comparable annulus. In contrast, ganglion cells in the regenerated contralateral retina show no topological order after comparable small Dil applications to the ventrolateral tectum. These data suggest that regenerating fibers can orient on the undisturbed, contralateral fibers.

Animals↗
PubMed1992

Evidence for a driving role of ingrowing axons for the shifting of older retinal terminals in the tectum of fish.

In amphibians and teleosts, retina and tectum grow incongruently. In order to maintain the retinotopy of the retinotectal projection, Gaze, Keating, and Chung (1974) postulated a shifting of terminals throughout growth. In order to test the possibility that ingrowing retinal fibers are the driving force for this shifting, we induced a permanent retinal projection into the ipsilateral tectum in juveniles of the cichlid fish Haplochromis burtoni. The surface of the tectum had increased (11-18 months later) 2.5-5.8 times, and the surface of the retina 8.6-14 times. Filling of ganglion cells with horseradish peroxidase (HRP) retrogradely from the tectum showed ipsilaterally regenerating ganglion cells only in the center of the retina. The position of ganglion cells indicated that the ipsilateral projection derived only from axotomized and regenerating retinal ganglion cells but not from those newly born. Ipsilaterally projecting retinal fibers showed terminals only in the rostral half of the tectum. Comparison of area of terminations of ipsilaterally projecting ganglion cells at various times after the crush provided no evidence for expansion or a shift into caudal tectal areas throughout the period of growth. These findings are compatible with the idea that newly ingrowing fibers induce older terminals to move caudally.

Animals↗
PubMed1992

Ipsilateral retinal projections into the tectum during regeneration of the optic nerve in the cichlid fish Haplochromis burtoni: a Dil study in fixed tissue.

Retinal projections were experimentally manipulated in a bony fish to reveal conditions under which considerably enlarged ipsilateral projections developed and persisted. Three experimental groups were studied: animals after unilateral enucleation, after unilateral nerve crush, and after enucleation and crush of the remaining optic nerve. At 29 days after unilateral enucleation alone, no enhanced ipsilateral projection had developed. After nerve crush, however, large numbers of retinal fibers regenerated into the ipsilateral tectum. Retrogradely filled, ipsilaterally projecting ganglion cells were distributed throughout the entire retina. After 15 days regenerating retinal fibers covered the entire ipsilateral tectum. At later stages the ipsilateral projection showed progressive reduction in coverage of the tectum. Combining enucleation with nerve crush led to an ipsilateral projection that covered the tectum at 28 days and later. In this experimental situation the development of an ipsilateral projection appears to be a two-step process: (1) Fibers are rerouted to the ipsilateral side at the diencephalon, and (2) ipsilateral fibers persist in the tectum only in the absence of a contralateral projection while they appear to be eliminated in the other cases.

Animals↗
PubMed1992

The development of ipsilateral retinal projections into the tectum in the cichlid fish Haplochromis burtoni: a Dil study in fixed tissue.

The normal development of the retinal projection was studied in a bony fish with Dil. Between 5.5 and 10 days postfertilization the contralateral retinal projection grows from the rostral pole of the tectum across its center. A maximum of 15 retinal fibers reaches the ipsilateral tectum. In 33-day-old juvenile animals, less than 15 ipsilateral fibers terminate in the entire tectum. Ipsilaterally projecting ganglion cells (maximal number = 20 cells) are scattered throughout the entire retina, and the location of ganglion cells in the retina and axonal terminations in the tectum display a large interindividual variability. This suggests that the small adult contingent of ipsilateral fibers in this bony fish develops without an initial exuberant ipsilateral retinal projection that is later pruned back.

Animals↗
PubMed1990

Ipsilateral retinofugal projections in a percomorph bony fish: their experimental induction, specificity and maintenance.

Adult bony fish possess only a small ipsilateral retinofugal projection, if any. Experimental manipulation, such as unilateral enucleation, can lead to an enhancement of this projection. We examined the patterns of, as well as the conditions for the development and maintenance of an enhanced ipsilateral retinofugal projection (EIRP) after nerve crush, after enucleation, and after various combinations of both types of surgery in juvenile and adult Haplochromis burtoni (Cichlidae). Retinal projections were labeled either unilaterally with horseradish perixodase, or with the lipophilic fluorescent dye DiI in aldehyde-fixed animals, or bilaterally with differently colored fluorescent dextran amines. Unilateral nerve crush always leads to the regeneration of retinofugal fibers to the contralateral tectum but spares some contralateral diencephalic nuclei. In addition, unilateral or bilateral nerve crush in many cases, and unilateral enucleation in some cases, leads to the development of an EIRP to the ipsilateral diencephalon and tectum. This EIRP persists (4 months and longer postoperatively) in only 10% of the unilaterally enucleated animals, in none of the animals subjected to unilateral nerve crush and in 79% of the animals subjected to bilateral nerve crush. All unilaterally enucleated animals in which the remaining, contralateral optic nerve was crushed develop and maintain an EIRP. These data suggest that nerve crush alone is sufficient to cause regenerating fibers to project, at least transiently, to the ipsilateral side of the brain. When the normal contralateral projection is either absent or in the process of regeneration, an EIRP can be maintained. In the latter case, alternate bands or patches of ipsi- and contralateral fibers in the tectum may result. Ipsilateral fibers follow unusual pathways by recrossing at the rostral diencephalon. Likewise, regenerating contralateral retinal fibers grow differently in this area; here, where the optic-nerve projection is reorganized into the optic tract, many regenerating fibers are deflected to the ipsilateral side of the brain. Despite atypical routes taken by some fibers, the EIRP nevertheless ends only in specific retinorecipient areas. An EIRP develops independently of the age of the animal, independently of the time lapse between enucleation and nerve lesion, and independently of persisting debris. However, in animals receiving an optic nerve lesion a long time after unilateral enucleation, the size of the EIRP and its tectal extent are reduced compared to that in animals enucleated around the same time as receiving the crush of the contralateral optic nerve.

Animals↗
PubMed1989

Development of tectal neurons in the perciform teleost Haplochromis burtoni. A Golgi study.

The differentiation of the tectum mesencephali of Haplochromis burtoni (Teleostei, Cichlidae) was studied using a modified Golgi rapid impregnation. The analysis concentrated on the gradient of differentiation of four neuronal types, type I, IIIu, VI and XII, in 15-day-old larvae. The following developmental steps taken by these neuronal types are identified: (1) morphogenesis and growth are largely independent developmental events. Tectal neurons first develop their typical dendritic morphology. The tectal lamination, as indicated by the spatial relationships of the dendrites of tectal neurons, is acquired already in 15-day-old larvae. Subsequently the neurons grow to their adult size. Intersegments of dendrites elongate considerably. Dendritic and axonal reorganization and/or intersegmental growth may take place. (2) The teleost cell types I and VI show variable positions of their perikaryon in 15-day-old larvae, but not in adults. It is suggested that they translocate their perikaryon inside their stem dendrite, while their dendrites are already well developed.

Animals↗
PubMed1987

Ipsilateral retinofugal and retinopetal projections in normal and monocular cichlid fish.

A previously unknown ipsilateral retinotectal projection in juvenile and adult cichlid fishes is revealed by anterograde labelling with horseradish peroxidase (HRP). Enucleation results in an enlarged ipsilateral projection from the intact eye; after 4 months this projection may cover the tectum almost completely. These data are interpreted as an increase in the normally occurring ipsilateral projection of newly differentiated ganglion cells due to the absence of interocular competition. Conversely, after enucleation cells of the homolateral thalamoretinal nucleus seem, on the basis of retrograde HRP staining to develop a new connection with the remaining eye.

Animals↗