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Biomedical subjects

M Borgers

Publications and source records attributed to M Borgers.

At least 163 records · Page 9Linked to original sources
PubMed1985

Intracellular Ca2+ shifts during the Ca2+ paradox.

The distribution of Ca2+ is assessed cytochemically in isolated rat hearts subjected to low Ca2+ environment with and without subsequent reexposure to normal external Ca2+. The same is done for isolated rat cardiac myocytes. The inclusion of 15 microM Ca2+ in the perfusate predisposes hearts to a partial paradox with increasing intensity towards the subepicardium. In affected areas, morphologically characterized by deviation of the lamina externa from the surface coat-sarcolemma and separation of some regions of the intercalated disk, the sarcolemma was devoid of Ca2+ deposits. Upon reperfusion, irreversible contracted cells with ruptured sarcolemma showed accumulation of Ca2+ precipitate in mitochondrial matrices. In non-affected cells (subendocardium) sarcolemmal Ca2+ was normal and mitochondria were virtually devoid of Ca2+ precipitate. Isolated myocytes were insensitive to Ca2+ deprivation and/or repletion and no Ca2+ shifts were demonstrated. These observations suggest a role for sarcolemma-bound Ca2+ in the integrity of this membrane.

Animals↗
PubMed1984

Localization of calcium in skeletal and cardiac muscle.

The requirement of calcium (Ca2+) in the excitation-contraction coupling of both skeletal and cardiac muscle is well established. However, the exact location of the intracellular storage sites of Ca2+ is not firmly established. We report here on the ultrastructural ultrastructural distribution of Ca2+ in white and red skeletal muscle and in cardiac muscle of the rat using combined phosphate-pyroantimonate (PPA) and oxalate-pyroantimonate (OPA) procedures. The methods are based on (a) stabilization and/or trapping of Ca2+ during the primary fixation step in glutaraldehyde by potassium phosphate or oxalate; (b) subsequent wash-out of all non-trapped cations such as Na+ and Mg2+ in potassium phosphate or oxalate; (c) conversion of the complexed or trapped Ca2+ into an electron-dense calcium pyroantimonate salt in 100 micron-thick tissue sections; and (d) wash-out of the excess potassium pyroantimonate at alkaline pH. With the OPA procedure, mitochondria of all muscle types showed little precipitate. The junctional sarcoplasmic reticulum was strongly reactive in relaxed white skeletal muscle, negative in contracted white fibres and negative in red skeletal and cardiac muscle, independent of the state of relaxation-contraction. Other organelles were essentially free of deposits. With the PPA method, the precipitate was almost exclusively confined to the sarcolemma and its T-tubular invaginations in cardiac and slow skeletal muscle, and was absent in fast skeletal muscle. Apart from occasional deposits in mitochondria, all other organelles were free of muscle. Apart from occasional deposits in mitochondria, all other organelles were free of precipitate. The sarcolemma-associated deposits were clearly confined to the inner leaflet of the lipid bilayer. The amount of precipitate varied within the contraction cycle, relaxed cells possessing the highest density. Exposure of the tissue to La3+ resulted in the complete absence of sarcolemma-bound precipitate suggesting that the Ca2+ is exchangeable. Furthermore, these cytological data suggest a basic difference in Ca2+ storage between white skeletal muscle on the one hand, and red skeletal and cardiac muscle on the other.

Animals↗
PubMed1984

Cardioprotective effects of mioflazine during 1 h normothermic global ischaemia in the canine heart.

The cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were investigated in 41 anaesthetised open chest Beagle dogs subjected to 1 h normothermic global myocardial ischaemia. The severity of the model is evidenced by the finding that only one out of 20 control dogs could be weaned from extracorporeal bypass. Oral pretreatment with mioflazine (2.5 mg X kg-1) resulted in complete functional recovery in 17 out of 20 animals. Biochemical analysis of left ventricular biopsies taken before, during and after aortic cross clamping showed a preservation of purines and a better recovery of ATP, ATP/ADP X Pi ratio and energy charge (p less than 0.05) in the pretreated animals. Morphological and cytochemical assessment of the myocardium demonstrated that the ultrastructure of the sarcolemma and its calcium binding capacity is remarkably well preserved in the drug treated animals. These results indicate a strong cardioprotective effect of mioflazine. The biochemical, cytochemical and ultrastructural findings suggest an interaction of the drug with the sarcolemma.

Animals↗
PubMed1984

Itraconazole, a new triazole that is orally active in aspergillosis.

Itraconazole is a new orally active triazole derivative with broad-spectrum antifungal activity. This drug is effective in experimental aspergillosis and possesses in vitro activity against various species and strains of Aspergillus. Morphological destruction of inoculated hyphae and complete inhibition of hyphal outgrowth in culture is obtained from 0.07 micrograms ml-1 (10(-7)M) onward. These properties make itraconazole a likely candidate for clinical evaluation in disseminated aspergillosis.

Administration, Oral↗
PubMed1984

Multivariate analysis of angiographic, histologic, and electrocardiographic data in patients with coronary heart disease.

In 61 consecutive patients undergoing aortocoronary bypass grafting, angiographic and electrocardiographic (ECG) changes were studied. Histologic delineation of myocardium was obtained by analysis of transmural biopsy specimens acquired at the time of surgery. The use of principal-component analysis revealed three definite groups of patients. Group I comprised patients with histologic findings associated with severe left anterior descending coronary artery (LAD) stenosis, without abnormal wall motion or ejection fraction. ECG abnormalities were limited to ST changes. Group II comprised patients with severe myocardial cell degeneration with only modest fibrosis associated with severe LAD stenosis and severely impaired wall motion. The incidence of infarction on the ECG was low. Group III patients had important myocardial cell degeneration with severe fibrosis associated with severe LAD stenosis, severely depressed wall motion, and significantly impaired ejection fraction. In this group there was a high incidence of infarction apparent on the ECG. Postoperative follow-up (24 months) showed a total survival of 94.4% in group I, 92.8% in group II, and only 72.7% in group III. This identification of subtypes of coronary artery disease seems to be helpful in estimating patient prognosis after coronary surgery.

Adult↗
PubMed1984

Identification of calcium in the retina by the combined use of ultrastructural cytochemistry and laser microprobe mass analysis.

The specificity of the combined oxalate-pyroantimonate (OPA) technique for subcellular localization of calcium was examined by laser microprobe mass analysis (LAMMA) of the same tissue sections. The recorded spectra strongly suggest that the cytochemically detected precipitates contained calcium. This could be confirmed by LAMMA analysis of ethylene glycol tetraacetic acid-treated sections. The detected calcium was localized mainly in the rod outer segments, more particularly in the middle part. The validity of the OPA and LAMMA methods is discussed. A combination of both techniques is found to be a valuable tool to elucidate the role of calcium in physiological mechanisms.

Animals↗
PubMed1984

Intermittent aortic cross-clamping versus St. Thomas' Hospital cardioplegia in extensive aorta-coronary bypass grafting. A randomized clinical study.

Myocardial preservation was assessed in 72 patients undergoing extensive myocardial revascularization. The patients were allocated at random to three surgical techniques: Group 1, intermittent aortic cross-clamping at 32 degrees C; Group 2, intermittent aortic cross-clamping at 25 degrees C; and Group 3, St. Thomas' Hospital cardioplegia. As intraoperative markers of ischemic damage, adenosine triphosphate, creatine phosphate, and glycogen contents were determined in transmural left ventricular biopsy specimens taken at the beginning and at the end of cardiopulmonary bypass. Ultrastructure was studied in a similar pair of biopsy specimens. Release of myocardium-specific creatine kinase isoenzyme was determined intraoperatively and postoperatively. Functional recovery was assessed before and after weaning from cardiopulmonary bypass. The incidence of low cardiac output, myocardial infarction, and rhythm disturbances was compared between groups. Finally, actuarial survival and event-free curves were studied after 18 months' follow-up. The results show a better preservation of high-energy phosphates, glycogen, and ultrastructure in the cardioplegia group as compared to the two cross-clamp groups. However, severe myocardial damage was never observed. Release of MB creatine kinase isoenzyme was the same in all three groups. Functional recovery of the hearts immediately after cessation of cardiopulmonary bypass was better in the cardioplegia group, but the incidence of rhythm disturbances (atrioventricular conduction problems) was higher in the cardioplegia group than in the other two groups (p less than 0.05). Clinical outcome in terms of incidence of perioperative infarction, survival, and event-free follow-up was not different between groups. It is concluded that both techniques (aortic cross-clamping at 32 degrees C or 25 degrees C and St. Thomas' Hospital cardioplegia) offer good myocardial protection in extensive aorta-coronary bypass operations. St. Thomas' cardioplegia, however, in contrast to intermittent aortic cross-clamping, prevents the onset of ischemia-induced deterioration of cardiac metabolism, i.e., destruction of the adenine nucleotide pool.

Adenosine Triphosphate↗
PubMed1984

Histologic changes in the hypoxic brain.

Two animal models were used for the morphologic study of hypoxic or ischemic cerebral injury. In the first model ("Levine preparation") rats were subjected to a unilateral carotid artery ligation, followed by intermittent exposure to pure nitrogen. Damage, which was examined 24 h after this bypoxic insult, was largely restricted to the ipsilateral cerebral cortex. In the second model ("Pulsinelli preparation") severe bilateral transient ischemia was induced by permanent occlusion of both vertebral arteries, followed by temporary ligation of both carotid arteries. Damage was examined after short recirculation times and after a 3-day survival period. Injury was largely confined to the CA1 layer of the hippocampus. In both experimental models two types of cell change were prominent: coagulative cell change which was restricted to neurons, and edematous cell change which was largely confined to astrocytes. Studies on cerebral microcirculation revealed a close relationship between areas of reduced flow and areas with structural damage. Cytochemical demonstration of subcellular calcium indicated an early and important redistribution of this cation, indicative for toxic calcium overload in the cytosol. Data on therapeutic intervention with Ca2+-overload blocker flunarizine are included.

Animals↗
PubMed1984

Beneficial effect of mioflazine in limiting myocardial infarct size in the anesthetized dog.

The effect of mioflazine (R 51 469) on infarct size was studied in anesthetized dogs subjected to 24 h of LAD (left anterior descending) coronary artery occlusion. The myocardium normally supplied by the occluded coronary artery (perfusion area, PA) was delineated by perfusion of the arterial bed distal to the occlusion with colorless fluid while the remainder of the heart was simultaneously perfused with an Evans blue solution. After sectioning the heart, infarct areas (IA) could be visualized by incubation of the slices in triphenyl-tetrazolium-chloride (TTC). Quantification of the areas was performed using a Quantimet 900 image analysis system. The animals either received mioflazine (2.5 mg X kg-1 orally) or a same volume of 20% polypropylene glycol, the solvent of mioflazine 2.5 h before the start of the surgical procedure. For perfusion areas greater than 20% of the left ventricle infarct size was significantly reduced in mioflazine pretreated animals compared with the control group, both expressed as per cent of the left ventricle (10.6 +/- 2.3 vs 19.2 +/- 1.5, p less than 0.005) and as per cent of the perfusion area (35.1 +/- 7 vs 64.4 +/- 5, p less than 0.005).

Anesthesia↗
PubMed1983

The mechanism of action of the new antimycotic ketoconazole.

Ketoconazole is one of the new members of the imidazole series with a broad-spectrum antifungal profile. Although sharing its basic active principles with the other imidazoles, ketoconazole obtains its superior in vivo activity mainly from its good oral absorption and its lower degree of inactivation once absorbed. Its selective toxicity for yeasts and fungi is found to be primarily linked to the inhibition of ergosterol biosynthesis and to interference with other membrane lipids. In vitro growth studies revealed that ketoconazole's activity was more pronounced against the invasive morphogenetic form than against the saprophytic form of Candida albicans, which at least partly explains its prominent in vivo potency. At extremely low concentrations (10 ng/ml-1) ketoconazole prevents the development of the very form that is responsible for the expression of clinical symptoms. In contrast to other imidazoles, ketoconazole's action on the morphogenesis of the organism is not influenced by serum. The synergistic action with host defense cells, as demonstrated in culture systems, is another inherent property of this drug and may have a great impact on the eradication of systemic fungal infections. These effects of ketoconazole have been studied in a variety of fungal organisms with the aid of phase-contrast, scanning, and transmission electron microscopy in order to characterize ketoconazole's profile in comparison to the other imidazole derivatives.

Animals↗
PubMed1983

The role of calcium in cellular dysfunction.

In order to study the effects of substances with selective Ca2+ entry blocking properties which enhance the tolerance to ischemia by preventing a toxic calcium overload, attempts are made to localize calcium ultrastructurally. Under normoxic conditions, a mobile pool of Ca2+ is localized in synaptic vesicles and in mitochondria of brain cells; in mitochondria of cardiac, skeletal and vascular smooth muscle; and in the junctional SR of fast skeletal muscle. A plasmalemmabound pool of Ca2+ is present in cardiac and slow skeletal muscle. Ischemia or hypoxia induce marked shifts in calcium of both the mobile and the plasmalemma-bound pools. Cardiac and skeletal muscle mitochondria scavenge huge amounts of calcium, especially during the reperfusion period following prolonged circulatory arrest. The membrane-bound Ca2+ is lost under these conditions. In the hypoxic brain, the amount of intracellular calcium clearly parallels the degree of damage. Observations made on peripheral and brain blood vessels show that high amounts of precipitated Ca2+ cover the myofilaments upon induction of spasm. The antispasmodic effect of the selective Ca2+-entry blockers flunarizine and lidoflazine is morphologically characterized by the absence of Ca2+ over the myofilaments in muscle treated as such whereas the extracellular Ca2+ remained the same. This observation indicates that the entry of Ca2+ is blocked at the level of the plasma membrane. In the heart and brain these drugs preserve the structural integrity of the plasmalemma-surface coat complex and thereby protect the cells against the devastating consequences of cellular calcium overload.

Animals↗
PubMed1983

Localization of calcium in red blood cells.

The distribution of calcium is demonstrated in human red blood cells (RBC) with a combined phosphate-pyroantimonate technique (PPA). Freshly collected blood and tissue biopsies were initially fixed in potassium phosphate-glutaraldehyde and the complexed calcium was subsequently visualized on Vibratome sections with potassium pyroantimonate. The majority of cells, both in isolated as well as "in situ" preparations, show a fine granular precipitate located at the inner leaflet of the plasma membrane. A minority of cells lack these membrane-associated deposits, exhibiting instead a random distribution of very fine precipitate in their cytoplasm. Capillary endothelial cells and pericytes are devoid of plasma membrane-bound precipitate. When irreversible crenation of RBC is induced by exposure to ionophore A 23187 and calcium, the sphero-echinocytes loose their membrane-bound precipitate, whereas the cells that retain their discocyte shape demonstrate the usual pattern of membrane-bound deposits. Contrarily, cells showing reversible shape changes induced by either A 23187-Ca2+ challenge, by adenosine triphosphate depletion during aging, or contact with lysolecithin, retain or regain the membrane-bound calcium. This cytochemical demonstrable calcium at the inner leaflet of the plasma membrane is probably bound to acidic phospholipids, since it is readily extractable with the nonionic detergent Triton X-100.

Calcimycin↗
PubMed1983

Cardioprotective effects of lidoflazine in extensive aorta-coronary bypass grafting.

The cardioprotective effects of lidoflazine, a calcium entry blocker, were tested in patients undergoing multiple aorta-coronary bypass grafting (at least four grafts). Intermittent aortic cross-clamping at 25 degrees to 28 degrees C was used. Mean cross-clamp time was 11 minutes for one distal anastomosis. Patients were randomized into three groups: a control group (I), a group (II) pretreated with 0.5 mg . kg-1 lidoflazine intravenously before cardiopulmonary bypass (CPB), and a group (III) pretreated with 1 mg . kg-1 lidoflazine intravenously. The following markers of ischemia are used: (1) adenosine triphosphate (ATP), creatine phosphate (CP) and glycogen determined in transmural left ventricular biopsy specimens taken at the beginning and end of CPB; (2) ultrastructure in a similar pair of specimens; and (3) hemodynamic recovery 15 minutes after cessation of CPB. At the end of the intervention, ATP decreased to 73% in Group I but remained unchanged in Groups II (98%) and III (88%). CP decreased to 82% in Group I and remained unaltered in Groups II (100%) and III (110%). Glycogen decreased in Group I (to 44%) and in Group II (78%) but remained unchanged in Group II (138%). Ultrastructural study showed better preservation of the glycocalyx and sarcolemma in Group III than in Group I. Left ventricular stroke work index remained unaltered after CPB in Group III but decreased in Groups I and II to about 60% of its initial value. Thus lidoflazine pretreatment protects the myocardium in a dose-dependent manner against deterioration of myocardial function and structure.

Adenosine Triphosphate↗
PubMed1983

Protection with flunarizine against hypoxic-ischaemic damage of the rat cerebral cortex. A quantitative morphologic assessment.

The protective effect of flunarizine against cerebral cortical damage was evaluated in the "Levine preparation" after 24 hr of a combined hypoxic-ischaemic insult. Ligation of the right carotid artery, followed by intermittent exposure of the rats to pure nitrogen resulted in two major types of cellular damage in the ipsilateral hemisphere: coagulative necrosis of neurones (ischaemic cell change) and extreme cellular swelling (severe cell change). Quantification of the degree of damage was obtained by calculating the number of both types of cell change per mm3 of cortex. Flunarizine given orally at doses of 20 mg/kg and 10 mg/kg 5 hr before mild hypoxia and at doses of 40 mg/kg and 10 mg/kg 5 hr before severe hypoxia, led to a significant reduction of ischaemic and severe cell change. The calcium entry blocking properties of flunarizine are held responsible for these beneficial effects.

Animals↗