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Biomedical subjects

M Borgers

Publications and source records attributed to M Borgers.

At least 127 records · Page 7Linked to original sources
PubMed1990

Class IV Ca2+ antagonists do not affect lipid peroxidation in singlet oxygen challenged cardiomyocytes.

The effects of various Ca2+ antagonists on lipid peroxidation in singlet O2-challenged isolated cardiomyocytes from adult rat heart were investigated. Singlet O2-challenged untreated cells all hypercontracted as a consequence of Ca2+ overload and produced 463.6 +/- 143.6 nM malondialdehyde (MDA; mean +/- SD, n = 8). Protective Ca2+ antagonists reduced the amount of damaged cells, but did generally not affect MDA production. On the other hand, free radical scavengers and antioxidants displayed a good correlation between number of protected cells and MDA produced. It is concluded that flunarizine-like Ca2+ antagonists protect cells against Ca2+ overload without, however, interfering with peroxidative processes.

Animals↗
PubMed1990

Cerebroprotective effects of flunarizine in an experimental rat model of cardiac arrest.

A rat cardiopulmonary arrest model was used to study the effects of flunarizine on survival and on the development of postischemic brain damage. Ischemia was induced by a combination of hypovolemia and intracardiac injection of a cold potassiumchloride solution. To validate the model; survival rate and histological damage were assessed after ischemic periods ranging from 5 to 20 minutes. A 6-minute cardiac arrest period was withheld for further therapeutic investigations. In one group (n = 12), flunarizine was administered successively in doses of 0.5 mg/kg intravenous at 5 minutes, 10 mg/kg intraperitoneal at 1 hour, and 20 mg/kg orally at 16 and 24 hours after recirculation. The second group (n = 13) received only the vehicle. Flunarizine, although not affecting mortality; significantly reduced the mean number of ischemic neurons in CA1 hippocampus from 83% in the control to 44% in the drug-treated series (P = 0.014). The results are indicative of the usefulness of this cardiac arrest model to study morphologic aspects of cerebral injury. The results obtained with flunarizine show the effectiveness of this drug even when it is administered after a severe ischemic insult such as global complete ischemia.

Animals↗
PubMed1990

Evidence for decreased coronary flow reserve in viable postischemic myocardium.

To try to unravel the complexity and heterogeneity of the "no-reflow" phenomenon and its underlying mechanisms, we studied tissue perfusion in reperfused heart muscle by using tracer microspheres in an anesthetized dog model of 90-minute coronary occlusion followed by reperfusion for 2 1/2 hours, 24 hours, or 1 week. Regional myocardial blood flow was determined both in basal flow conditions and during reactive hyperemia. The effect of intracoronary adenosine administration was examined, and the ultrastructure of postischemic myocardium was analyzed. In viable reperfused tissue (as delineated by triphenyltetrazolium chloride staining), reflow in basal conditions is unimpaired. Coronary flow reserve (as approximated by peak reactive hyperemic flow) is intact at the start of reperfusion, decreases by more than half after 2 1/2 hours, and recovers completely within 1 week. This impairment of coronary reserve can be relieved by intracoronary adenosine administration. On ultrastructural examination, the capillaries are patent. On the other hand, in irreversibly damaged myocardium, both the basal reflow impairment and the decrease in coronary flow reserve are severe and permanent. Coronary flow reserve is already decreased at the start of reperfusion, and the pharmacological intervention has no beneficial effect. Ultrastructurally, extracellular and intracellular edema invariably are present, whereas the vascular endothelium is damaged and the capillaries are packed with red blood cells. We conclude that the no-reflow phenomenon (i.e., mechanical obstruction to blood flow) is limited to infarcted tissue. In viable myocardium, however, coronary flow reserve is transiently diminished, probably because of washout and subsequent insufficient availability of the chemical mediator adenosine after breakdown and slow recovery of the precursor ATP pool.

Adenosine↗
PubMed1990

The effect of ketoconazole and itraconazole on the filamentous form of Pityrosporum ovale.

The effect of ketoconazole and itraconazole on the filamentous form of Pityrosporum ovale in vitro was studied. In a recently developed model, using human stratum corneum in vitro, P. ovale transformed into the filamentous form in 25-30% of the cells. Ketoconazole and itraconazole in concentrations of 0.01, 0.1 and 1 microgram/ml were incubated together with P. ovale cells on human stratum corneum pieces placed on a lipid-enriched culture medium. Both agents effectively blocked the production of hyphae. From the low concentration onwards, the changes consisted of a diminishing transformation into hyphae. With transmission electron microscopy, the interior of many cells was often in an advanced stage of necrosis. Exposure to 1 microgram/ml itraconazole causes a disorganization of the internal organelles in 83% of the cells. This model for the production of hyphae of P. ovale in vitro proved very valuable in screening the activity of antimycotic agents against the filamentous form of this yeast.

Antifungal Agents↗
PubMed1990

Beta-cyclodextrins as vehicles in eye-drop formulations: an evaluation of their effects on rabbit corneal epithelium.

Beta-cyclodextrins are cyclic molecules with a hydrophilic outer side and a central hydrophobic cavity. Through the inclusion of drug molecules into their cavities, i.e. the formation of inclusion complexes, cyclodextrins are able to modify the physical and chemical properties of these molecules. When used in pharmaceutical formulations, they can improve the aqueous solubility, stability, dissolution rate, bioavailability and/or local tolerance of certain drugs. To make an initial evaluation of the potential use of beta-cyclodextrins as vehicles in ophthalmic eye-drop formulations, we studied the effect of a single and of multiple applications of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) 12.5% and of dimethyl-beta-cyclodextrin (DM-beta-CD) 5 and 12.5% solutions on the corneal epithelium of albino and pigmented rabbits with slit lamp biomicroscopy (SLB) and scanning electron microscopy (SEM). We can conclude from this study that DM-beta-CD at concentrations of 5 and 12.5% is not a suitable vehicle for ophthalmic formulations since it is toxic to the corneal epithelium and that HP-beta-CD at a concentration of 12.5% is well tolerated by the rabbit eye and is not toxic to the corneal epithelium when evaluated by SLB and SEM.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1989

Favourable effect of flunarizine on the recovery from hemiparesis in rats with intracerebral hematomas.

In 25 rats, an intracerebral hematoma was created in the foreleg area of the motor cortex by injection of 50 microliters blood. After the lesion, 13 were treated with flunarizine and 12 with the solvent. Neurological testing was performed by measuring the running time on a rotating platform. In animals with hemiparesis, the flunarizine group (n = 7) showed a significantly (P less than 0.05) better recovery than the control group (n = 8). No significant differences occurred in animals without neurological deficits (flunarizine: n = 6, control: n = 4). So the effect of the drug is not due to a non-specific activation; it may partially cure neurological deficits caused by intracerebral hematoma.

Animals↗
PubMed1989

Mitochondrial hydrogen peroxide generation by NADH-oxidase activity following regional myocardial ischemia in the dog.

Recently, an exogenous NADH-oxidase has been shown to be a source of oxygen derived toxic species in heart mitochondria. This enzyme uses NADH and oxygen to form superoxide radicals and hydrogen peroxide. Growing evidence suggests that oxygen radicals and hydrogen peroxide may contribute to cardiac damage during ischemia or hypoxia. The activity of the enzyme NADH-oxidase could play an important role in the damage caused by oxygen derived toxic species, especially since cellular defense mechanisms against free radicals are depleted under ischemic conditions. In this study, a cytochemical method was used to visualize hydrogen peroxide, the reaction product of NADH-oxidase activity, in normal and ischemic dog myocardium. The NADH-oxidase reaction product was present in weak amounts in mitochondria from normoxic myocardium. In viable ischemic areas a high degree of activity was observed in the mitochondria. In infarcted tissue mitochondria contained few or no reaction product at all. The results support the hypothesis that hydrogen peroxide and oxygen radicals produced in the mitochondria by a high NADH-oxidase activity may contribute to the mitochondrial damage observed during ischemia when NADH is no longer oxidized by the respiratory chain and cellular defense mechanisms are impaired.

Animals↗
PubMed1989

Mode of action of itraconazole: morphological aspects.

The broad spectrum of antifungal activity of itraconazole is verified by morphologic criteria at the light and electron microscopical level. Yeast and fungal species examined are Candida albicans, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Pityrosporum ovale, Trichophyton rubrum and Aspergillus fumigatus. Exposures of cultures of these yeasts and fungi to itraconazole results in dose- and time-dependent alterations which vary in nature and intensity from one species to another. The most striking gross morphological change is seen in the biphasic species and consists of the abolishment of morphogenic development of the blastospore into the hyphal forms (C. albicans and P. ovale) and of the hyphal into the yeast forms (P. brasiliensis). Furthermore, the outgrowth and development of inoculated A. fumigatus hyphae into sporulating vesicles is almost completely abolished. The above mentioned effects on morphogenesis are achieved in the 10(-10)-10(-7) M range. Except for P. ovale, the earliest ultrastructural changes after itraconazole consist of abnormalities at the plasma membrane, the cell wall and cytoplasmic vacuoles. They precede a marked increase in cell volume, defective cell division, abortive hyphal outgrowth and loss of cell viability. These changes are identical to those previously described after miconazole and ketoconazole treatment. However, when compared to the other available azole-derivatives sharing the same basic mechanisms of action, itraconazole displays an exceptionally strong activity against A. fumigatus which can be morphologically translated by a potent necrotizing action on hyphae and inhibition of vesicle formation and sporulation. The in vitro effects of itraconazole are supported by data obtained from microscopic examinations of samples derived from patients with experimental animals infected with various fungal organisms.

Animals↗
PubMed1989

Photochemical stroke model: flunarizine prevents sensorimotor deficits after neocortical infarcts in rats.

We produced unilateral photochemical infarcts in the hindlimb sensorimotor neocortex of 186 rats by intravenous injection of the fluorescein derivative rose bengal and focal illumination of the intact skull surface. Infarcted rats showed specific, long-lasting deficits in tactile and proprioceptive placing reactions of the contralateral limbs, mostly the hindlimb. Placing deficits were most prominent during transition to immobility and/or when independent limb movements were required. Administration of flunarizine, a Class IV calcium antagonist, 30 minutes after infarction resulted in marked sparing of sensorimotor function in 30 rats. In contrast to 20 vehicle-treated rats, which remained deficient for at least 21 days, 15 (75%) of the rats treated with 1.25 mg/kg i.v. flunarizine showed normal placing on Day 1 after infarction, whereas the remaining five (25%) recovered within 5 days. Oral treatment of 10 rats with 40 mg/kg flunarizine was also effective. Neocortical infarct volume and thalamic gliosis, assessed 21 days after infarction, did not differ between 30 flunarizine- and 30 vehicle-treated rats. However, when 4-hour-old infarcts were measured in 16 rats, posttreatment with intravenous flunarizine reduced infarct size by 31%. In combination with appropriate behavioral analyses, photochemical thrombosis may constitute a relevant stroke model, in which flunarizine preserved behavioral function during a critical period, corresponding to the spread of ischemic damage.

Animals↗
PubMed1989

Structural degeneration of Aspergillus fumigatus after exposure to saperconazole.

Saperconazole is a newly synthesized triazole antifungal with potent activity against Aspergillus fumigatus. Exposure of spores inoculated into BHI agar medium to saperconazole doses as low as 35 ng ml-1, resulted in complete suppression of germination (hyphal outgrowth) when treatment started simultaneously with inoculation. Cultures which were grown for 24 or 48 h in the absence of drug and were then exposed to saperconazole showed a block in the development of hyphae, sporophores, vesicles, sterigmata and spores. Moreover, a substantial proportion of the pre-existent hyphae became necrotic during exposure to the drug. The latter was most obvious with the 70 ng ml-1 dose. Although treatment with lower doses yielded severely altered but non-necrotic cells, an abolishment of further outgrowth and differentiation was achieved.

Antifungal Agents↗
PubMed1988

Purine nucleoside phosphorylase: a histochemical marker for glial cells.

The distribution of purine nucleoside phosphorylase activity has been investigated histochemically in rat and guinea-pig brain. At the light microscopical level, enzyme activity was most pronounced in glial cells in various anatomical regions of the rat brain. In contrast, the guinea-pig brain presented only a weak activity. Endothelial cells of both species were also reactive. These findings were confirmed by electron microscopy. Based upon anatomical position and morphologic characteristics, positive glial cells were identified as astrocytes. Precipitate-rich astrocytic processes could be easily demonstrated in between barely reactive neuronal fibers and around microvessels. A minority of astrocytes was devoid of reaction product. The present method may offer a valuable tool for the histopathological study of several types of disorders in which glial cells play a functional role.

Animals↗
PubMed1988

A new method to study activated oxygen species induced damage in cardiomyocytes and protection by Ca2+-antagonists.

It has been proposed that oxygen derived free radicals contribute to reperfusion injury in ischemic tissue: radical induced lipid peroxidation is believed to cause membrane destruction, eventually evolving to cell death. A method is introduced which investigates the effect of exogenously generated reactive O2 species on isolated Ca2+-tolerant rat cardiomyocytes. Singlet oxygen (O2(1)), generated by photo-excitation of the photosensitive dye rose bengal, induced the transformation of elongated rod-shaped cells into hypercontracted rounded cardiomyocytes. These shape changes were prevented by removal of extracellular Ca2+ or by addition of radical scavengers. Pre-treatment with various classes of Ca2+-antagonists dose-dependently reduced the number of hypercontracted cardiomyocytes after exposure to O2(1). Compounds not active on the slow Ca2+-channel (e.g. flunarizine-like) provided a better degree of protection than the genuine slow Ca2+-channel blockers (e.g. dihydropyridines). Ultrastructurally, cardiomyocytes exposed to O2(1) showed a loss of cytochemically demonstrable sarcolemma-associated Ca2+ and the presence of clustered Ca2+-deposits in the mitochondria. Drug pre-treated cells displayed a Ca2+-distribution pattern comparable to unchallenged control cells.

Animals↗
PubMed1988

Ultrastructural localization of calcium in the myocardium of cardiomyopathic syrian hamsters.

Cardiomyopathy of the Syrian hamster is characterized by myocardial calcium overload and focal myocardial necrosis. The cause of the myocardial calcium overload is not yet fully understood. In this study, the ultrastructural localization of calcium was determined in normal hamster hearts and in non-necrotic and necrotic myocardium of cardiomyopathic hamsters (strain BIO 82.62). In many cells from the non-necrotic myocardium of the cardiomyopathic hamsters the calcium deposits, visible as 20 nm particles, were confined to the inner leaflet of the plasma membrane, the T-tubules and the intercalated disks. This corresponds to the calcium distribution found in normal hamsters and other mammalian species. A number of morphologically normal cells, however, displayed an increased amount of calcium precipitate in the mitochondria as well as at the sarcolemma indicating that, in the cardiomyopathic hamster, focal calcium overload is detectable cytochemically in cells which otherwise do not show gross abnormalities. In cells showing morphological signs of myolytic degeneration a marked redistribution of calcium precipitate took place. Sarcolemma became devoid of calcium deposits whereas an enormous amount of clustered precipitate occurred in largely swollen mitochondria. These data are in support of a relationship between impaired ion homeostasis and degeneration events in cardiomyopathy. Furthermore, there appears to be a clear parallelism in calcium redistribution between hypoxic and cardiomyopathic myocardium.

Animals↗
PubMed1988

Phospholipid composition and amphiphile content of isolated sarcolemma from normal and autolytic rat myocardium.

Sarcolemmal vesicles were purified to a similar extent, 50- to 60-fold on a protein basis, from normal rat hearts and hearts subjected to 30 or 60 min of autolysis at 37 degrees C (total ischemia in vitro). Electron microscopic examination of the autolytic hearts revealed sarcolemmal discontinuities and other morphological characteristics typical of irreversible cell injury. Total contents and percentage composition of phospholipid classes did not differ between normal and autolytic hearts or between sarcolemmal preparations from these hearts. There was no increase in lysophospholipid contents of whole hearts or of purified sarcolemma after autolysis. Long chain acyl-CoAs or acylcarnitines did not accumulate in autolytic hearts under our experimental conditions. The molar long chain acyl-CoA: phospholipid ratio in isolated sarcolemma was extremely low (1:100,000). It increased 3-fold after autolysis but the increase was most probably the result of an increase in mitochondrial contamination of the sarcolemmal preparations from autolytic hearts. The molar long chain acylcarnitine: phospholipid ratio of isolated sarcolemma was much larger (1:100), but it did not change after autolysis. Experiments, in which radioactive amphiphiles were incorporated in isolated sarcolemma that was subsequently repeatedly washed, indicated that the lysophospholipid and acylcarnitine contents of isolated sarcolemma reflect the contents of sarcolemma in situ, but that sarcolemmal acyl-CoA is used for re-acylation reactions during purification, explaining the low acyl-CoA content of isolated sarcolemma. Na/K-ATPase and Na/Ca-exchange activities were markedly depressed in isolated sarcolemma from autolytic hearts. Our results suggest that sarcolemmal phospholipid breakdown and sarcolemmal amphiphile accumulation are not responsible for the structural and functional defects of the sarcolemma after autolysis.

Acetylcarnitine↗
PubMed1988

Histology of the postischaemic myocardium and its relation to left ventricular function.

The relation between the histology of the myocardium and left ventricular function was studied in 23 dogs submitted to 90 min of coronary artery occlusion followed by reperfusion for up to 1 week. It was shown that 32% of the perfusion area of the occluded coronary artery was irreversibly damaged. There was, however, no significant correlation between the decrease in left ventricular function (ejection fraction assessed by angiography) and the extent of myocardial necrosis. Upon reperfusion, salvage of 68% of the perfusion area of the occluded vessel was obtained. Viability of the myocardium in this area was demonstrated by electron microscopy. However, postischaemic regional function was completely lost in the first 24 h, in spite of this considerable amount of viable tissue. Nevertheless, regional function recovered after 1 week of reperfusion, which suggests a stunned myocardium in the early postischaemic phase. These results show that histological examination of postischaemic tissue has prognostic value in terms of recovery of function, but a direct correlation between structure and function does not exist in the early reperfusion phase.

Actin Cytoskeleton↗