Biomedical subjects
Publications and source records attributed to J Traber.
Acute mesenteric ischemia (AMI) is an acute life-threatening vascular emergency. Clinical presentation is often unspecific. Rapid diagnosis and therapy are essential in survival. Contrast-enhanced spiral computed tomography is sensitive and highly specific in the diagnosis of AMI.
OBJECTIVE: To assess the influence of myocardial structure and pericardial constraint during exercise ischemia on regional left ventricular passive elastic properties. METHODS: Left ventricular regional function was assessed at rest and during exercise using biplane angiography and high-fidelity pressure measurements. Twenty patients with either normal (n = 7) or stenotic coronary arteries (n = 13) were studied before and after successful bypass surgery. At the time of surgery, left ventricular transmural biopsies were taken from a normally perfused and a hypoperfused left ventricular region. RESULTS: Regional stiffness increased in the ischemic zone during exercise, but remained unchanged after revascularization. Regional fibrosis was significantly enhanced in the ischemic region compared with that in the normally perfused zone. No correlation was found between structural data and regional passive elastic properties, but there was a significant correlation between right atrial pressure and the asymptote of the diastolic pressure--volume relationship. CONCLUSIONS: Acute regional diastolic dysfunction can be observed during exercise in patients with coronary artery disease. Structural changes seem to have a minor role in the occurrence of diastolic dysfunction in the absence of myocardial infarction. The observed upward shift of the pressure-volume relationship during ischemia can be attributed to pericardial constraint that is manifested by an increase in right arterial pressure.
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The early postnatal development of immunoreactive calbindin-D28k (CaB-ir) containing neuronal systems in hippocampus and parietal cortex was studied in offspring of Wistar rats chronically treated with either the Ca(2+)-channel antagonist nimodipine or placebo food. The drug was applied to the mother animals during the last week of gestation and continued until the end of the experiment. The CaB-ir was investigated in the period of the highest rate of hippocampal and cortical fiber growth at postnatal days (PD), 5, 7, 10 and 20. In the dorsal hippocampus from PD5 to 20, the dentate granule cells and their mossy fiber connection expressed increasing CaB-ir in a topographically organized manner. In the parietal cortex at PD5, 7 and 10 interneurons and a few pyramidal cells gradually appeared immunoreactive for CaB with progressively increasing intensity and approached their adult-like pattern at PD20. Chronic nimodipine treatment resulted in a transient and markedly enhanced ir-CaB expression up to the age of PD10, which was quantified by cell counts and image analysis. Nimodipine induced a more than twofold increase in the number of CaB-ir neurons in the cortex at PD5-PD10. The developmental enhancement in the hippocampus appeared slightly earlier mainly at PD5 and 7. The findings indicate that the antihypoxic effect of nimodipine, previously found in the perinatal age, may be associated with an increased Ca2+ buffering capacity of neurons due to an enhanced expression of ir-CaB during the early postnatal period.
Postnatal development of ingrowing cholinergic and serotonergic fiber patterns were studied in the rat hippocampus and parietal cortex employing a histochemical procedure for acetylcholinesterase as a cholinergic fiber marker, and immunocytochemistry of serotonin for serotonergic fiber staining. The rat pups were killed at postnatal days 1, 3, 5, 7, 10, and 20. The development of cholinergic and serotonergic innervation was described and the fiber density quantified under normal conditions and after long-term prenatal anemic hypoxia induced by chronic exposure to sodium nitrite. Furthermore, a third group was studied in which the nitrite hypoxia was combined with a simultaneous treatment with the Ca(2+)-entry blocker nimodipine to test the neuroprotective potential of this drug. Quantitative measurement of fiber density from postnatal day 1 to day 20 yielded the following results: (i) both neurotransmitter systems revealed an age-dependent and an anatomically-organized developmental pattern; (ii) the serotonergic innervation of the dorsal hippocampus preceded that of cholinergic afferentation in postnatal days 1-3; (iii) prenatal hypoxia induced a transient delay in the innervation of parietal neocortex and dentate gyrus for both neurotransmitter systems, but left the innervation of the cornu ammonis unaffected; and (iv) the hypoxia-induced retardation of cholinergic and serotonergic fiber development was prevented by concomitant application of the Ca(2+)-antagonist nimodipine during the hypoxia. The results indicate that prenatal hypoxia evokes a temporary delay in the cholinergic and serotonergic fiber outgrowth in cortical target areas in a region-specific manner. The hypoxia-induced growth inhibition is prevented by the calcium antagonist nimodipine, which supports the importance of the intracellular Ca2+ homeostasis of cells and growth cones in regulating axonal proliferation.
1. Neuropathy is a frequently diagnosed complication of diabetes mellitus. Effective pharmacotherapy is not available. 2. The spontaneously diabetic BB/Wor rats develop secondary complications like neuropathy as do human diabetic patients. 3. BB/Wor rats treated with insulin via a subcutaneous implant show a significant impairment of sensory and motor nerve conduction velocity 6 weeks after the onset of diabetes mellitus. 4. Intraperitoneal treatment of diabetic BB/Wor rats with the Ca2+ antagonist, nimodipine (20 mg kg-1), from week 6 onwards every 48 h for a period of 6 weeks resulted in a significant increase of sensory and motor nerve conduction velocity. 5. Twelve weeks after the onset of diabetes mellitus BB/Wor rats show a 40% impairment of sciatic nerve blood flow as compared to the non-diabetic age-matched controls. Treatment with nimodipine (20 mg kg-1) from week 6 onwards significantly increased the sciatic nerve blood flow as compared to placebo-treated diabetic BB/Wor rats. 6. The adrenergic responsiveness of the vasa nervorum of the sciatic nerve to tyramine and phenylephrine was investigated as a parameter for autonomic neuropathy. 7. The fact that nimodipine treatment restored the reduced response to tyramine independently of the reduced postsynaptic phenylephrine responsiveness indicates that nimodipine improves adrenergic responsiveness mainly at the presynaptic level.
A putative animal model of anxiety based on shock-induced ultrasonic vocalization was pharmacologically validated in young adult rats. Suppression of shock-induced ultrasonic vocalization was obtained with diazepam, chlordiazepoxide, meprobamate and pentobarbital; the serotonin (5-HT)1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], buspirone, ipsapirone, gepirone and tandospirone; the nonselective 5-HT receptor agonists TFMPP [1-(3-trifluoromethylphenyl)piperazin], mCPP [1-(3-chlorophenyl)piperazin] and DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane); the NMDA antagonists PCP (phencyclidine) and MK-801; the alpha 2-adrenoceptor antagonists idazoxane, yohimbine and 1-PP (1-pyrimidinylpiperazine); and the atypical neuroleptic clozapine. The alpha 2-adrenoceptor agonist clonidine, the 5-HT2/5-HT1C antagonist ritanserin, the 5-HT3 antagonists ondansetron and ICS-205,930, and the 5-HT reuptake inhibitor fluoxetine did not, or only partially, reduce ultrasonic vocalization. Tricyclic and tetracyclic, as well as some atypical antidepressants and a monoamineoxidase (MAO) inhibitor, showed no ultrasonic vocalization reducing effects, or reduced ultrasonic vocalization only at high doses. An opiate, an antimuscarinic, (pro)convulsants and typical neuroleptics did not reduce ultrasonic vocalization. The present findings suggest that the ultrasonic vocalization model specifically measures anxiolytic effects. Because ultrasonic vocalization responding develops within five days, remains stable for at least three months and gives highly reproducible results, the test appears suitable for rapid and repeated testing of new anxiolytics in the same animals.
Over the years, it has become apparent that many cytotoxic events employ a common pathway in destroying cells, namely the disruption of calcium homeostasis. Further studies show that the aging process is also accompanied, perhaps even partly caused, by changes in cellular calcium regulation. Finally, initial evidence has appeared in the literature showing that the Alzheimer beta-amyloid protein also interferes with calcium homeostasis. In these situations, the use of calcium antagonists, such as nimodipine, is expected to prevent part of the damage resulting from disrupted calcium regulation. Indeed, studies with nimodipine show that the compound reduces neuronal degeneration in a variety of toxic conditions. In addition, the compound has a functional effect in that it increases spontaneous neuronal firing of aged neurons, presumably by reducing the age-dependently increased afterhyperpolarization. Nimodipine also reduces age-related perivascular anomalies and increases cerebral blood flow. A combination of these effects is probably why the substance is found to improve cognition in aged animals and in aged humans with impaired brain function.
1. Neuropathy is a frequently diagnosed complication in diabetic patients but an effective treatment does not exist. 2. The development of neuropathy in streptozotocin-induced diabetic rats was monitored by measuring the motor and sensory nerve conduction velocity in the sciatic nerve. 3. A significant decrease in sensory and motor nerve conduction velocity was apparent in young, 14-week-old diabetic rats as compared to non-diabetic, age-matched controls 4 weeks after the induction of diabetes with streptozotocin. 4. Intraperitoneal treatment with the Ca2+ channel blocker, nimodipine, from week 4 onwards, in a dosage of 10 mg kg-1 or 20 mg kg-1 intraperitoneally per 48 h, resulted in a significant increase in sensory and motor nerve conduction velocity whereas treatment with 5 mg kg-1 intraperitoneally per 48 h was not effective. 5. One-year-old, adult, diabetic rats treated with nimodipine 20 mg kg-1 (treatment started again 4 weeks after induction of diabetes mellitus) also showed an increase of both sensory and motor nerve conduction velocity as compared to diabetic rats treated with placebo. 6. It is concluded that nimodipine ameliorates existing experimental diabetic neuropathy in streptozotocin-induced diabetic rats in both young and adult animals.
In view of the calcium hypothesis the effect of nimodipine (Bay e 9736, CAS 66085-59-4) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletions in dopamine and serotonin were investigated in C57-BL/6 mice. Oral treatment with nimodipine (5 mg/kg and 20 mg/kg b.i.d., respectively, for 9 days) prior to, during and following administration of MPTP appeared to attenuate MPTP-induced neurochemical changes in a dose-related manner. The results suggest that nimodipine reduces MPTP-induced damages, especially in the serotoninergic system, through its calcium antagonistic effects.
At the ultrastructural level two main categories of microvascular anomalies can be distinguished in the aged rat brain. These categories comprise [1] membranous inclusions within the basement membrane and [2] microvascular deposits, which include microvascular fibrosis and thickening of the basement membrane (BMT). In this study we examined the percentage of microvessels displaying ageing-related malformations in the frontoparietal motor cortex of rats aged 16, 24, 30 and 32 months. The percentage microvessels with membranous inclusions and microvascular deposits both gradually increased until the age of 30 months, after which no further increase was observed. The percentage fibrotic microvessels, however, increased until the age of 30 months, but was decreased at 32 months. This decrease of fibrotic microvessels at 32 months coincided with a proportional increase of cerebral microvessels provided with a thickened basement membrane. Combined with qualitative observations these data suggest that in a very late stage of the ageing process collagen fibrils in microvascular fibrotic plaques are depolymerized and degradated. By this mechanism it appears that microvascular fibrosis is transformed into basement membrane thickening. Long-term application of the calcium entry blocker nimodipine did not influence the amount of microvessels with membranous inclusions within the basement membrane, but in contrast resulted in a prominent reduction of ageing-related microvascular deposits when administered from 24 to 30 months. The effect of a prolonged nimodipine treatment from 24 to 32 months on the amount of microvascular deposits was still significant, however, much less conspicuous. We now conclude that chronic administration of nimodipine delays the formation of microvascular deposits up to the age of 30 months. Furthermore, the beneficial effect of nimodipine treatment from 24 to 30 months on microvascular integrity is not accompanied by a reduced systolic blood pressure.
The aim of the present work was to modulate in vivo the level of hepatic mitochondrial glutathione (GSH). Rats were given phorone (diisopropylidene acetone), which in vivo becomes enzymatically conjugated to GSH, and were subsequently treated with N-acetylcysteine (NAC) to rescue GSH. In liver homogenate, a rapid and biphasic (T1/2 less than or equal to 15 min and 1.5 hr) drop of GSH was observed upon phorone administration. NAC treatment led to a restoration (T1/2 about 1 hr) of GSH in the homogenate above control values within 3 hr. The mitochondrial GSH level decreased with T1/2 of about 1.5 hr upon phorone treatment, and was 75% restored by NAC treatment within 3 hr. Hydroperoxide-induced mitochondrial pyridine nucleotide oxidation and Ca2+ release were impeded in GSH-depleted organelles, and NAC treatment restored these processes. The GSH status had no influence on mitochondrial pyridine nucleotide oxidation and Ca2+ released induced by alloxan, which reacts directly and non-enzymatically with pyridine nucleotides. It is concluded that NAC is able to rescue mitochondrial GSH in vivo and restore important mitochondrial functions. The data suggest that NAC may be a useful antidote in oxidative stress-related diseases.
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Polymyxin B, a cyclic peptide antibiotic, is considered to be a rather selective antagonist of protein kinase C. This drug is therefore widely used to evaluate the involvement of protein kinase C in cellular processes. In the present study, we investigated the effects of polymyxin B on the activity of calmodulin-dependent cyclic 3':5'-nucleotide phosphodiesterase in vitro. The drug potently inhibited this enzyme (IC50 80 nM in the presence of 500 microM Ca2+), while about 200-fold higher concentrations were required to inhibit protein kinase C to the same extent. Phosphodiesterase inhibition was competitive with respect to Ca2+ and calmodulin. Evidence for the formation of a complex between polymyxin B and calmodulin was obtained by polyacrylamide gel electrophoresis under non-denaturing conditions, and by affinity chromatography of calmodulin on polymyxin B-agarose. We therefore suggest that, at least in vitro, polymyxin B is a potent and selective inhibitor of calmodulin.
Various studies have suggested that calmodulin (CaM) is involved in the pathophysiology of psoriasis. Protein kinase C (PKC) is also accepted as playing a regulatory role in cell proliferation as well as in inflammatory processes. Therefore, we investigated the effects of the known CaM antagonist tiflucarbine (BAY/TVX P 4495) on two cellular systems related to the major clinical symptoms of psoriasis: proliferation of cultured human keratinocytes (HaCa T cell line) and release of reactive oxygen species (ROS) from human polymorphonuclear leukocytes (PMNL). Tiflucarbine inhibited both cellular responses in a dose dependent manner. Furthermore, tiflucarbine directly affected PKC, and may thus be considered to be a dual PKC/CaM antagonist with putative antipsoriatic activity. The effects of tiflucarbine on the different parameters were compared with those of the structurally unrelated dual PKC/CaM inhibitor W-7 and those of the potent PKC inhibitor staurosporine. The potencies of all three compounds were found to be in the same range as their PKC-inhibiting potency. Our data indicate that PKC, rather than CaM, may play a regulatory role in the release of ROS as well as in keratinocyte proliferation. Therefore, inhibition of PKC in general might have a therapeutic benefit in psoriasis.
The first part of this article deals with several aspects of efferents and afferents of the rat basal forebrain cholinergic system (BFChS) studied with anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). PHA-L tracing of the BFChS efferents revealed topographically differentiated axonal trajectories and patterns of presynaptic endings to the neocortex, mesocortex, olfactory nuclei and hippocampus. Combining this method with second immunolabeling, we identified the muscarinic cholinoceptive neurons in the neocortex and the somatostatinergic neurons in the hippocampus as being directly innervated by the magnocellular basal nucleus and the medial septum, respectively. The prefrontal cortex was identified as a source of afferent input to the basal forebrain cholinergic neurons. This projection also exhibits a topographic organization, which shows a reciprocal relationship with the BFChS efferents to the cortex. The second part of this article describes the anatomical changes of cortical cholinergic and some other neurotransmitter systems after long-term cholinergic denervation in the aged rat cortex. The spared cholinergic projection in the largely denervated areas shows abundant malformations, which are similar in appearance to the anatomical alterations of the surviving cholinergic fibers in dementia of the Alzheimer type (AD). Hypertrophic changes also occur in the serotonergic system. The neuropeptide-Y- and somatostatin-containing cortical systems respond with an increment of their axonal densities, in contrast to the decline of these peptides in AD. Although transsynaptic effects are mediated by long-term cholinergic lesions, they do not support the hypothesis that the cholinergic deficiency is a primary event in the pathophysiology of AD.
The putative antidepressant drug tiflucarbine (BAY P 4495) has previously been shown to inhibit calmodulin-dependent cyclic nucleotide phosphodiesterase competitively with respect to calmodulin. In order to determine whether this effect is mediated by a direct interaction with calmodulin, we measured the effects of radiolabelled triflucarbine in a direct ligand binding assay, using agarose-immobilized calmodulin. [3H]Tiflucarbine associated with low micromolar affinity with an apparently homogeneous class of recognition sites on calmodulin-agarose. No binding could be observed on calmodulin-deficient agarose. The effect was specific, saturable and reversible. Triflucarbine was the most potent calmodulin antagonist from a variety of structural analogues examined. The potencies of these derivatives to inhibit calmodulin-stimulated phosphodiesterase significantly correlated with their affinities towards the tiflucarbine binding site on calmodulin. No such correlation was evident when structurally unrelated reference compounds were tested. The association of tiflucarbine with calmodulin thus appears pharmacologically specific and selective and possibly contributes to the potent antidepressant activity of the drug.
The present study has been designed to investigate the effects of the 5-HT1A receptor agonist, ipsapirone (TVX Q 7821), a representative of a novel class of anxiolytics, and the classical benzodiazepine anxiolytic, diazepam, on cardiac and behavioural responses in an emotional stress situation. The emotional stress of fear of punishment, induced by training male Wistar rats in an inhibitory avoidance situation, was followed by a bradycardiac response relative to similarly trained, but non-punished, freely moving rats. The behavioural response of stressed rats was immobility in the dark compartment in which an electric footshock (0.6 mA a.c. for 3 s) had been administered as punishment a day earlier. Diazepam administered i.p. in doses of 2.5 mg/kg and 7.5 mg/kg caused a decrease in the interbeat interval (IBI) in shocked and non-shocked rats whereas ipsapirone administered i.p. in doses of 2.5 and 12.5 mg/kg decreased the IBI in shocked rats only. Ipsapirone diminished the duration of immobility in both shocked and non-shocked animals whereas diazepam decreased immobility in shocked rats only. These results suggest a differential effect of the two anxiolytics on the behavioural and cardiac responses to an emotional stress situation. It is suggested that ipsapirone has an anxiolytic-like effect and 'anti-stress' action that is clearly reflected in the cardiac physiology in an anxiety-inducing situation.