Experimental antiarteriosclerotic effects of calcium antagonists.
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Adult↗
Biomedical subjects
M Frey
Publications and source records attributed to M Frey.
Three-dimensional structures of complexes of Lathyrus ochrus isolectin I with glucose and mannose: fine specificity of the monosaccharide-binding site.
The structure of the methyl-alpha-D-mannopyranoside-LOL I complex has been solved by the molecular replacement method using the refined saccharide-free LOL I coordinates as starting model. The methyl-alpha-D-mannopyranoside-LOL I complex was refined by simulated annealing using the program X-PLOR. The final R-factor value is 0.182 [Fo greater than 1 sigma(Fo)]. The isostructural methyl-alpha-D-glucopyranoside-LOL I complex was refined by X-Ray coupled energy minimization using the methyl-alpha-D-mannopyranoside-LOL I structure as a starting model to an R factor of 0.179 (all data). In both crystal forms, each dimer binds two molecules of sugar in pockets found near the calcium ions. The two saccharide moieties, which are in the C1 chair conformation, establish the same hydrogen bond pattern with the lectin. However, the van der Waals contacts are different between the O2, C2, C6, and O6 atoms of the two molecules and the backbone atoms of residues 208-211. Mannose, due to its axial C2 conformation, encloses the backbone atoms of the protein in a clamplike way. Van der Waals energy calculations suggest that this better complementarity of the mannoside molecule with the lectin could explain its higher affinity for isolectin I.
Binding Sites↗
Excessive mural calcium overload--a predominant causal factor in the development of stenosing coronary plaques in humans.
Healthy human coronary artery walls contain, over their entire lifetime, more free and total cholesterol than calcium. However, as soon as arteriosclerotic alterations set in, the calcium content increases. Thus in coronary fatty streaks (arteriosclerotic plaques of WHO stage I), calcium was increased 13 times, in stage II plaques 25 times, and in fully developed stage III plaques 80 times above normal on average. The most dramatic calcium incrustation was found in coronary stage III plaques that had produced massive fatal coronary infarction. Here, the proportion of calcium salts (particularly hydroxyapatite) may amount to almost 50% of dry weight. Thus the most excessive accumulation of calcium seems to be correlated with the highest fatality. In contrast, there is no correlation between mural coronary free or total cholesterol content, and plaque severity. Accordingly, stenosing coronary stage III plaques contain less cholesterol than do fatty streaks. Moreover, in coronary stage III plaques the proportion of free cholesterol was 1.37%, and of total cholesterol only 2.34% of the whole mass, certainly not enough for directly causing coronary occlusion. Thus the calcium-rich plaques of human coronary arteries considerably differ from the well-known cholesterol-rich plaques (stage I and II) of human aortae. Our findings justify a new prophylactic approach with suitable calcium antagonists to interfere with deleterious calcium uptake in coronary plaque development.
Adult↗
Ipsilateral and cross-over elongation of the motor nerve by nerve grafting: an experimental study in sheep.
In difficult reconstructions, ipsilateral or cross-over nerve grafting is sometimes necessary to achieve reinnervation and motor function. This experimental study in sheep was to answer the question of limitation of elongation of a motor nerve by grafting, the question of the optimal time for suturing the nerve graft to the muscle nerve, and the question of the successful application of this surgical technique in extremities. In 18 sheep, the vastus nerve was elongated by a saphenous nerve graft as long as possible up to 30 cm (step 1). In 10 animals the nerve graft was applied ipsilaterally, and in 8 animals it was used as a cross-over nerve graft to the contralateral limb. The time between nerve grafting and connection of the distal end of the nerve graft to the freshly cut rectus nerve supplying the rectus femoris muscle (step 2) was variable: 0, 3, 6, 9, and 12 months. In all animals, the final experiments (step 3) were performed 6 months after the last operation (step 2). Muscle force measurements in the rectus femoris muscle and quantitative analysis of the number and diameter of myelinated nerve fibers in cross sections of the nerve biopsies at different levels showed that elongation of a motor nerve by nerve grafting is principally not limited. The functional results were rather inhomogeneous and therefore unpredictable (ipsilateral group: maximum tetanic tension = 27 to 172 N; cross-over group: 0 to 227.5 N). Nevertheless, crossover nerve grafting is recommended for selected cases even in extremities. There was no correlation between the time interval between the two operations and the functional or morphologic results, although better functional results were obtained when the distal nerve suture (step 2) was performed some months after nerve grafting (step 1). A clear correlation was found only between the number of regenerated axons in the rectus nerve behind the second suture line and the muscle function.
Animals↗
Amlodipine, a new 1,4-dihydropyridine calcium antagonist with a particularly strong antihypertensive profile.
The effects of a new 1,4-dihydropyridine derivative amlodipine have been compared with results from our previous work. Application of amlodipine at a concentration of 1.6 X 10(-6) M to isolated guinea-pig papillary muscle for 120 minutes produced a 50% reduction in tension development compared with a concentration of 3.7 X 10(-7) M nifedipine needed to produce the same result under identical conditions. This suggests that amlodipine has even weaker negative inotropic effects than nifedipine. In isolated porcine coronary strips, the K+-induced contractions were approximately 10,000 times more sensitive to the relaxing effects of nisoldipine, nitrendipine and nicardipine than to those of papaverine, whereas nifedipine and amlodipine were 3,000 times more potent than papaverine. However, in comparison with these in vitro actions, the efficacy of amlodipine appears to be greater in vivo: Simultaneous subcutaneous injection of nifedipine (20 mg/kg) and of equimolar doses of nisoldipine and felodipine attenuated the myocardial calcium uptake by rat hearts in situ (stimulated with a single subcutaneous dose of 30 mg/kg isoproterenol) with the same efficacy, whereas the actions of nitrendipine and nimodipine were considerably weaker. In contrast, amlodipine antagonized isoproterenol-stimulated myocardial calcium accumulation more effectively. Furthermore, amlodipine exhibited a high antihypertensive potency combined with rapid onset and long duration of action: Amlodipine (10 mg/kg orally [p.o.]) reduced the blood pressure of spontaneously hypertensive rats almost to the same extent as nifedipine, nitrendipine, verapamil and felodipine administered at the much higher doses of 100 mg/kg p.o. Amlodipine (20 mg/kg/day p.o.) maintained normal blood pressure during the whole life span of Dahl-S rats (5 months), but this dose is considerably lower than that reported for other 1,4-dihydropyridines. The survival of NaCl-loaded Dahl-S rats increased from 20 to 100% after administration of amlodipine (20 mg/kg/day p.o.) over 10 weeks: The effective dose of other calcium antagonists is approximately 5 times higher, but well tolerated as, e.g., demonstrated in long-term studies on Dahl-S rats with nitrendipine over 12 months. Increases in systemic arteriolar tone can be visualized in the ocular fundus of spontaneously hypertensive rats. After amlodipine (10 mg/kg p.o.) arteriolar spasm declines. Prophylaxis with 2 doses of 20 mg/kg amlodipine daily in NaCl-loaded Dahl-S rats abolished the macroscopic and histologic changes that are normally seen in branches of the mesenteric artery. With use of electron microscopy, calcium accumulation in the lamina elastica interna was demonstrated by the potassium-pyr-oantimonate technique.(ABSTRACT TRUNCATED AT 400 WORDS)
Amlodipine↗
Pyrrolo[2,3-d]pyrimidines as inhibitors of cAMP-phosphodiesterase. Structure-activity relationship.
The effects of pyrrolo[2,3-d]pyrimidine compounds (7-desazapurines) on cAMP hydrolyzing, calmodulin dependent and calmodulin independent phosphodiesterase were studied. Phosphodiesterase inhibition depended on the chemical nature of substituents attached to the pyrrolo-pyrimidine-nucleus at positions 2, 4, 5, 6 and 7. Among a total of 28 compounds tested, the 4-amino-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dicarbaldehyde (9) was the most potent inhibitor of phosphodiesterase activity (IC50 = 16 microM). In addition to the 5,6-disubstitution, position 2 of the pyrrolo-pyrimidine derivatives had to be unsubstituted and position 4 had to bear an amino-group for an optimal inhibitory effect. Calmodulin dependent and calmodulin independent isozymes were affected to the same extent. Inhibition of PDE activity was reversible upon removal of the pyrrolo-pyrimidine derivative 9 and non-competitive with respect to cAMP (Ki = 27 microM).
3',5'-Cyclic-AMP Phosphodiesterases↗
[Free functional muscle transplantation with microneurovascular anastomosis: development of a standardized surgical procedure].
Although investigated experimentally almost at the same time, free muscle transplantation without microvascular anastomoses was accepted as a clinical method earlier than muscle transplantation with microneurovascular anastomoses, which finally proved to be the method with better functional results in the late seventies. Our experimental investigations of different factors such as anoxemia, reinnervation, initial muscle tension, and of the functional capacity of this kind of muscle graft and of the time course of the alterations in the microsurgically vascularized muscle transplants influenced the operative concept for clinical application to a great extent. Besides general details of the operative technique, specific considerations with respect to the two main regions of clinical application namely the face and the extremities are presented.
Anastomosis, Surgical↗
[Reconstruction of deformities of the external ear].
Microtia is a rare malformation. Reconstruction of microtia is not a routine operation because of its rarity of occurrence and the complex deformity. In this paper the indication for surgical treatment, technique, results and complications are discussed. Two different operation methods were used in our patients. A multiple-stage and a single-stage reconstruction procedure. We used autogenous rib cartilage. Five of the seven treated patients came to the follow-up examination. Reconstruction was performed 2 years ago in two cases and between 4 and 12 years ago in three cases. Our patients were content with the result in so far as they would be prepared to undergo treatment again. Carefully built rib framework is an essential prerequisite for a successful postoperative result. Microtia represents a greater psychological problem than a cosmetically imperfect result after reconstruction.
Adolescent↗
The maize En-1/Spm element transposes in potato.
The maize transposable element En-1 has been introduced into a diploid potato line via transformation with Agrobacterium tumefaciens. The element is transcriptionally active in potato. Numerous En specific RNAs are observed, including a 6 kb transcript characteristic of an active En-1 element in maize. In contrast to maize, where the 6.0 kb transcript is hardly detectable, this transcript is very abundant in the transgenic potato. Transposition of En-1 in the potato clone was analysed by Southern blot hybridization and confirmed by molecular isolation of En-1 excision and integration events. Sequence data of excision and integration sites revealed footprints and target site duplications similar to the ones described for En-1 in maize.
Blotting, Southern↗
Advantages of magnetoencephalography (AC and DC) in focal and generalized brain activity.
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Brain Ischemia↗
[Late results following surgical correction of syndactyly and symbrachydactyly].
Growth and the type of surgical treatment of the hand play an important role in the results of surgery in children. 29 patients have been operated on because of syndactyly and symbrachydactyly and were controlled. The following parameters were assessed: kind of incision and skin graft, functional results, x-ray to examine the skeleton and the depth of the commissure, colour of the skin graft and use of the hand. After operation of syndactyly all patients were able to use their hands normally, although full extend of flexion and extension was achieved only in 20 of 22 hands. In 5 divided pairs of fingers there was recurrence of syndactyly. In all cases except one, a split thickness skin graft has been used. After operative treatment of symbrachydactyly and complex syndactyly, full extent of flexion was achieved in 13 of 19 hands, in 6 hands the range of flexion was incomplete because of skeleton abnormalities. Recurrence occurred in 9 divided pairs of fingers; in 7 cases, a split thickness skin graft had been used. Despite this, all patients were able to use their hands normally. The use of split thickness skin grafts resulted in a 60% recurrence rate, whereas the use of full thickness skin graft led merely to 7.5% recurrence rate. Our results show the advantage of the full thickness skin graft. As a consequence, full thickness skin graft should be used in all cases. Furthermore, the operation should be performed at an early age, if fingers of unequal length have to be separated. Zig-zag incision should be used in all cases.
Child↗
[Iodine-accumulating, hormone-producing liver metastasis of a follicular thyroid carcinoma].
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Adenocarcinoma↗
Antihypertensive, anticalcinotic, and antiarteriosclerotic properties of anipamil, a long-acting new derivative of verapamil.
The classical indication for calcium antagonists has for a long time been coronary heart disease. However, more recent experimental data as well as a host of clinical observations now encourage a broader use of these drugs also for antihypertensive purposes and for prevention of concomitant sclerotic vascular injury. Needless to say, for the treatment of hypertensive crises rapidly acting calcium antagonists are required, whereas for chronic therapy of hypertension calcium antagonists with a long duration of action on blood pressure are advantageous. In this context anipamil seems to be particularly suited for long-term control of elevated blood pressure. Thus, anipamil justifies good therapeutic expectations regarding the clinical management of essential or renal hypertension.
Animals↗
Free calcium in rat papillary muscle at contraction assessed with Ca-selective microelectrodes.
Direct measurements of free intracellular calcium (Ca)i are needed for an understanding of the regulation of contractility. An on-line measurement of (Ca)i with Ca-selective microelectrodes in intact muscle strips provides a suitable means of investigating this problem, although considerable methodologic difficulties exist. Measurements of (Ca)i concentrations during muscle contraction have been carried out by different methods such as Ca-binding techniques and aequorin luminescence, but remain unsatisfying, since they were not performed on intact muscle strips. The authors' measurements were carried out with Ca-selective microelectrodes on rat papillary muscles (stretched to optimal length in a perfusion bath of 1.54 mL at 30 degrees C). The impalement of electrodes was considered adequate when the heights of Ca-electrode potential and membrane potential remained constant for more than twenty minutes. For provoking contractile responses, the authors replaced the normal Tyrode solution by a caffeine-containing contracture solution (content in mM: 0 NaCl [choline], 4 CaCl2, 30 KCl, 25 caffeine, 1.05 MgCl2). Ca-selective microelectrodes were calibrated before and after each measurement and only those impalements were taken as adequate that showed identical calibration curves before and after the experiment. They measured the (Ca)i at 20%, 50%, and 80% of maximal contractile force and obtained (Ca)i concentrations of 1.1 +/- 0.3 microM (at 20%), 3.6 +/- 1.2 microM (at 50%), and 11.8 +/- 0.27 microM (at 80%) (n = 6, +/- SEM). These results represent the fist on-line measurements of the myocardial (Ca)i concentrations with Ca++-selective microelectrodes in intact muscle strips during various degrees of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Calcium antagonism and ACE inhibition. Two outstandingly effective means of interference with cardiovascular calcium overload, high blood pressure, and arteriosclerosis in spontaneously hypertensive rats.
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Angiotensin-Converting Enzyme Inhibitors↗
[Biochemical changes in skeletal muscles after chronic indirect stimulation].
The skeletal muscle has the capacity to respond adaptively to increased use. This observation could open up the feasibility of constructing pumping chambers to support or even replace cardiac work. We investigated the changes in enzyme activity due to chronic stimulation in an animal skeletal muscle. In 5 adult sheep the psoas muscle of one side was electrically stimulated through the muscle nerves, with an implantable stimulation unit for 5 weeks. The activity of the hexokinase (E.C.2.7.1.1.), lactate dehydrogenase (E.C.1.1.1.27), malate dehydrogenase (E.C.1.1.1.37), creatine kinase (E.C.2.7.3.2.) choline acetyltransferase and the contents of adenosine triphosphate and adenosine diphosphate were determined in bioptic specimen. The use of only 15 Hertz as a stimulation frequency led to a transformation of an originally fast-twitch muscle into a slow-twitch muscle with reduced susceptibility to fatigue. These results indicate a potential role of the skeletal muscle as an ideal myocardial substitute with the ability to perform hemodynamic work.
Adenosine Diphosphate↗
A double-blind placebo controlled trial of diltiazem in Duchenne dystrophy.
The role of calcium accumulation in the pathogenesis of Duchenne muscular dystrophy (DMD) has already been discussed. Several trials with different calcium-blocking drugs have revealed no clinical benefit. In addition, the present study includes histological investigations and computer tomography to verify therapeutic effects. In a randomized placebo-controlled double-blind study, 13 DMD patients aged from 3-10 years (mean, 7 years) were treated with 5 mg/kg diltiazem daily for 1 year. Compared with before therapy, the number of calcium-positive muscular fibres was remarkably reduced in the treated DMD patients, but not in the placebo group. The evaluation of all other biochemical and clinical parameters revealed no significant effects of the diltiazem therapy. The muscular X-ray density measured by computer tomography decreased under treatment. After the evaluation of the double-blind study, the code was broken. Therapy, however, was continued in the treated group and started in the placebo group. After 3 years of diltiazem therapy the clinical status of all 26 patients of the study and 20 additional DMD patients who were treated with diltiazem was compared with 46 untreated DMD patients of the same age and stage in our department. No obvious clinical benefit of diltiazem therapy could be observed.
Calcium↗
Model of a complex between the tetrahemic cytochrome c3 and the ferredoxin I from Desulfovibrio desulfuricans (Norway strain).
A three-dimensional model of an electron-transfer complex between the tetrahemic cytochrome c3 and the ferredoxin I from the sulfate-reducing bacterium Desulfovibrio desulfuricans (Norway strain) has been generated through computer graphics methods. The model is based on the known X-ray structure of the cytochrome and on a model of the ferredoxin that has been derived through computer graphics modeling and energy minimization methods, from the X-ray structure of the homologous ferredoxin from Peptococcus aerogenes. Four possible models of interaction between the two molecules were examined by bringing in close proximity each of the four hemes and the redox center (4Fe-4S) of the ferredoxin and by optimizing the ion pairs interactions. One of these models shows by far the "best" structure in terms of charges, interactions, and complementarity of the topology of the contact surfaces. In this complex, the distance between the iron atoms of the ferredoxin redox center and the hemic iron atom is 11.8 A, which compares well with those found between redox centers in other complexes. The contact surface area between the two molecules is 170 A2.
Amino Acid Sequence↗