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Biomedical subjects

R Fumagalli

Publications and source records attributed to R Fumagalli.

At least 109 records · Page 6Linked to original sources
PubMed1989

Effects of calcium antagonists on lipids and atherosclerosis.

The arterial accumulation of cholesterol and calcium is a hallmark of atherosclerosis. Calcium antagonists (CAs) lessen the severity of experimentally induced atherosclerosis in cholesterol-fed animals. The reduction of aortic cholesterol is one of the most striking findings. This effect is achieved without a reduction of plasma lipid or blood pressure, and is probably related to an interference of CAs with lipid metabolism in the arterial wall. To what extent these properties of CAs are due to their ability to block calcium channels still remains to be addressed. This report briefly discusses the available in vivo and in vitro evidence for the antiatherosclerotic properties of CAs, and outlines the possible mechanisms by which these compounds affect cellular lipid metabolism.

Animals↗
PubMed1989

Monoclonal antibody 5A binds apolipoprotein B-48 and inhibits the low density lipoprotein-receptor interaction.

In a panel of 10 monoclonal antibodies raised against human LDL we detected three antibodies (named 5A, 6B, and 6E) which recognize both apolipoprotein B-100 and B-48. Antibody 5A inhibited, in a dose dependent manner, the interaction of 125I-LDL with their receptor on human skin fibroblasts. Using thrombolytic fragments, the epitope of antibody 5A was mapped to the carboxy terminal region of apo B-48. MAB 5A was equipotent with MAB Mb 47, an inhibitory antibody whose epitope lies near a putative receptor binding domain of apo B in thrombolytic fragment T2. These findings suggest that areas other than the carboxy terminal portion of apo B-100 may participate in the LDL-receptor interaction, either directly or by determining the exposition of high affinity sites of apo B-100.

Antibodies, Monoclonal↗
PubMed1988

Acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study.

The pulmonary effects of hyperventilation following infusion of sodium salicylate into the cisterna magna was studied in 16 spontaneously breathing adult sheep. We found a fall in PaO2, a decrease in the static compliance of the respiratory system, abnormal chest roentgenographic films, and grossly abnormal lungs following 3.5 to 13 h of hyperventilation. A control group of 15 sheep (10 sheep similarly injected with sodium salicylate, but then sedated and paralyzed and ventilated at normal tidal volume and respiratory rate on a mechanical ventilator, and 5 sheep infused with saline alone and breathing spontaneously) showed no pulmonary or arterial blood gas abnormalities. We conclude that prolonged hyperventilation under the conditions of this experiment precipitated events that resulted in acute lung injury.

Animals↗
PubMed1988

Arachidonic acid metabolism in HEL/30 murine epidermal cell line.

The established mouse epidermis-derived cell line HEL/30 was incubated in the presence of 3H arachidonic acid (AA) for 1 h. After medium removal, cells were reincubated with fresh medium in the presence or absence of the calcium ionophore A23187 and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The AA metabolites formed were extracted from cell-free medium and analyzed using TLC and HPLC. The distribution of the recovered radioactivity showed PGE2, 15-hydroxy-eicosatetraenoic acid (15-HETE), and leukotriene B4 (LTB4), as major products of AA metabolism. The presence of calcium ionophore A23187 increased the release of radioactivity, without affecting the profile of metabolites present in the medium. TPA elicited a preferential increase of cycloxygenase metabolism, this effect being reversed by indomethacin. 5,8,11,14-eicosatetraynoic acid (ETYA) almost completely inhibited LT and HETE formation in A23187 and TPA-treated cells. The results show that HEL/30 cells are able to metabolize AA via both cyclo- and lipoxygenase pathways and that these activities can be modified by chemical means. This cell line might be a suitable tool for studying the involvement of arachidonic acid cascade in cell response to exogenous stimuli.

Animals↗
PubMed1988

Progesterone modulates the expression of HDL binding sites in human skin fibroblasts.

The aim of this work was to study the effects of progesterone on the expression of high density lipoprotein binding sites by cultured human skin fibroblasts. At concentrations ranging between 10(-6)- and 10(-4) M the hormone showed a dose-dependent induction of the HDL binding sites. The effect was maximal at 48 h. The increased HDL binding was only due to an up-regulation of binding sites, without changes of the apparent Kd. This effect was not related to changes of cellular cholesterol content, and was not affected by inhibition of protein synthesis. These data suggest that the expression of binding sites for HDL can be modulated via a mechanism that does not depend upon cellular cholesterol content.

Binding Sites↗
PubMed1988

Relationships between lung computed tomographic density, gas exchange, and PEEP in acute respiratory failure.

Twenty-two patients with acute respiratory failure underwent lung computed tomography (CT) and physiological measurements at 5, 10, and 15 cm H2O positive end-expiratory pressure (PEEP) to investigate the relationship between morphology and function. Lung densities were primarily concentrated in the dependent regions. From the frequency distribution of CT numbers (difference in x-ray attenuation between water and lung) and lung gas volume measurements the authors obtained a quantitative estimate of normally inflated, poorly inflated, and non-inflated lung tissue weight. This estimated average lung weight was increased twofold above normal and excess lung weight correlated with the mean pulmonary artery pressure (P less than 0.01). Venous admixture correlated with the non-inflated tissue mass (P less than 0.01). Increasing PEEP caused progressive clearing of radiographic densities and increased the mass of normally inflated tissue (anatomic recruitment), while reducing venous admixture. The cardiac index decreased after increasing PEEP while oxygen delivery was unchanged. The authors conclude that CT scan lung density and oxygen exchange efficiency are correlated; the main effect of augmenting PEEP is to recruit perfused alveolar units that were previously collapsed.

Acute Disease↗
PubMed1988

Pulmonary microthrombosis in severe adult respiratory distress syndrome.

Pulmonary microvascular occlusive disease has been investigated using balloon occlusive pulmonary angiography in 31 patients with severe adult respiratory distress syndrome (ARDS) of different origins (14 patients with pneumonia, nine with multiple injury, eight with sepsis). Multiple pulmonary artery filling defects (PAFD) were detected in 13 (42%) patients, with a seven (78%) in nine incidence among those with posttraumatic ARDS. The presence of PAFD did not correlate with the severity of the respiratory failure, with the pulmonary hemodynamic alterations (pulmonary hypertension and increased vascular resistance), or with the final outcome (mortality rate was 54% among patients with PAFD and 61% among those with normal angiograms). These findings suggest that widespread pulmonary microthrombosis is a common event in patients with polytrauma and respiratory failure, with an important pathophysiologic role in the onset of posttraumatic ARDS.

Adolescent↗
PubMed1988

Calcium antagonists and low density lipoprotein receptors.

The effect of different calcium antagonists on receptor-mediated LDL catabolism by human cells in culture was investigated. The calcium antagonists have been recently classified in six types, based on their pharmacological activities. The three types selective for the slow calcium channels (types I, II, and III), and the nonselective type IV have been investigated in respect to LDL metabolism. Calcium antagonists of type I (verapamil-related compounds) and type III (diltiazem) induce an increase of receptor-mediated uptake of human LDL. In contrast, calcium antagonists of type II (nifedipine-related compounds) and type IV (flunarizine) are inactive. Verapamil and diltiazem stimulate LDL receptor activity in normal fibroblasts, in fibroblasts obtained from a hypercholesterolemic type IIa heterozygous patient, in the human hepatoma cell line HepG2, but not in receptor-negative cells. The stimulatory effect depends on drug concentrations in the culture medium. Cycloheximide and alpha-amanitin prevent the stimulating effect of calcium antagonists on LDL uptake. The possible mechanisms of this action of calcium antagonists and the relationship between the in vitro stimulation of LDL receptor activity and the in vivo inhibition of lipid deposition in the arterial wall elicited by calcium antagonists are discussed. Calcium antagonists may exert part of their antiatherosclerotic activity by counteracting the inhibition of receptor-mediated lipid metabolism induced by calcium deposition in the cellular components of the arterial walls.

Calcium↗
PubMed1988

Effect of derivatives of trapidil on the expression of LDL receptors.

The influence of trapidil and some of its derivatives (AR 12456, AR 12463, AR 12465) on the LDL receptor mediated uptake and degradation of 125 I-LDL by human skin fibroblasts (HSF) and human hepatic cells (HEP G2) was investigated. AR 12456 enhanced the uptake and degradation of 125 I-LDL in HEP G2, but inhibited this pathway in HSF. When this drug was preincubated with HEP G2 cells, and then the incubation medium was transferred to HSF, a stimulation of specific LDL pathway occurred also in this cell line. Trapidil, AR 12463 and AR 12465 were inactive under the same experimental conditions. These findings suggest that a metabolite of AR 12456 might be responsible for the enhanced expression of LDL receptors in human cells.

Antihypertensive Agents↗
PubMed1988

(5Z)-carbacyclin displays agonist-antagonist properties on prostacyclin-receptors in platelets and vascular myocytes.

(5E)- and (5Z)-carbacyclin are chemically stable analogues of prostacyclin (PGI2), which mimic PGI2 actions. In particular, they inhibit platelet aggregation and relax vascular smooth muscle, through the activation of adenylate cyclase (AC) being, however, less potent than PGI2. The characteristics of AC activity modulation by the two isomeric carbacyclins in membranes of human platelets and of myocytes cultured from rabbit mesenteric artery have been investigated. In human platelet membranes, both carbacyclins stimulated AC activity with the same efficacy as PGE1 and PGI2; in addition, these two prostaglandins inhibited the aggregation of human and rabbit platelets to the same extent as PGE1. On the contrary, in myocytes (5Z)-carbacyclin fails to produce the same degree of stimulation of AC elicited by PGI2, (5E)-carbacyclin and PGE1, nor does it induce the maximal relaxation of rabbit mesenteric artery attained with the other prostaglandins. (5Z)-carbacyclin is also able to antagonize the activation of AC by PGE1, PGI2 or (5E)-carbacyclin, acting therefore as a partial agonist. In conclusion, (5Z)-carbacyclin is a full agonist at the platelet level both in human and rabbit, thus excluding possible interspecies differences, but it is a partial agonist on myocytes. Therefore, (5Z)-carbacyclin appears to discriminate between PGI2 -receptors in the two target cells.

Adenylyl Cyclases↗
PubMed1987

Regulation of low density lipoprotein metabolism by 26-hydroxycholesterol in human fibroblasts.

Oxygenated derivatives of cholesterol are believed to play a role in cellular cholesterol homeostasis through the feed-back control of its biosynthesis. We report that 26-hydroxycholesterol inhibits the specific binding, uptake and degradation of 125I-LDL in human fibroblasts. The effect is dose-dependent, and saturation kinetics indicates a reduction of LDL-binding sites with no effect on ligand affinity. The results support a possible role of 26-hydroxycholesterol, a physiological oxysterol, in the regulation of cellular cholesterol homeostasis.

Cells, Cultured↗
PubMed1987

Lipophilic beta-adrenoceptor antagonists stimulate cholesterol biosynthesis in human skin fibroblasts.

The effect of a series of beta-adrenoceptor antagonists on cholesterol biosynthesis was studied in vitro in normal human skin fibroblasts. Some, but not all, of the drugs studied stimulated the incorporation of [2-14C]-acetate into cell sterols in a dose-dependent manner. This effect was unrelated to beta-blocking potency, selectivity for beta 1 or beta 2 adrenoceptors and partial agonistic activity of the drugs, thus ruling out a beta-receptor mediated mechanism. A positive, statistically significant correlation was found, however, between the drug lipophilicity and the stimulation of sterol biosynthesis. Propranolol, the most effective agent in increasing [2-14C]-acetate incorporation into cellular sterols, also enhanced the conversion of 3-hydroxy-3-methylglutaryl CoA (HMGCoA) into mevalonic acid, suggesting an interference of lipophilic beta-adrenoceptor antagonists with HMHCoA-reductase, the feed-back regulated rate limiting step of cholesterol biosynthesis.

Adrenergic beta-Antagonists↗
PubMed1987

(5Z)-carbacyclin discriminates between prostacyclin-receptors coupled to adenylate cyclase in vascular smooth muscle and platelets.

(5E)- and (5Z)-carbacyclin are prostacyclin (PGI2) analogues endowed with antiaggregating and vasodilator properties, which stimulate adenylate cyclase activity in membranes from human platelets and cultured myocytes from rabbit mesenteric artery. In platelets they display the same efficacy as prostaglandin E1 (PGE1), and hence PGI2 both as activators of adenylate cyclase and as inhibitors of aggregation. In contrast, in vascular smooth muscle cells (5Z)-carbacyclin fails to produce the same degree of stimulation of the enzyme as PGI2, (5E)-carbacyclin and PGE1, nor does it induce the maximal relaxation of the mesenteric artery as do the other prostaglandins. (5Z)-carbacyclin is also able to antagonize the activation of adenylate cyclase and the relaxation elicited by PGE1 or PGI2 in the mesenteric artery, and therefore it displays partial agonist properties in these cells. We conclude that the receptors for PGI2 coupled to adenylate cyclase in platelets and vascular smooth muscle cells are different from each other, because (5Z)-carbacyclin can discriminate between them, being a partial agonist at myocyte but not at platelet level.

Adenylyl Cyclases↗
PubMed1987

Lipophilic beta-adrenoceptor antagonists stimulate low density lipoprotein receptor activity in human skin fibroblasts.

The effect of beta-adrenoceptor antagonists on the receptor-mediated low density lipoprotein (LDL) binding and internalization was studied in vitro in human skin fibroblasts. The cellular uptake of 125I-labeled human LDL was dose dependently elevated by some, but not all, of the drugs used. This effect of beta-adrenoceptor antagonists was positively related to their lipophilicity, and was prevented by cycloheximide and by alpha-amanitin. Scatchard analysis of the saturable LDL binding indicates an increased number of LDL binding sites. Our studies show that the stimulating effect of beta-adrenoceptor antagonists on the high affinity LDL binding and internalization in human skin fibroblasts involves DNA transcription and new protein synthesis, and identify drug lipophilicity as a major determinant of this action. This effect could be relevant in vivo in adipose tissue which accumulates lipophilic drugs and derives its cholesterol mainly from circulating LDL.

Adrenergic beta-Antagonists↗
PubMed1987

Severe impairment in lung function induced by high peak airway pressure during mechanical ventilation. An experimental study.

We explored the pulmonary effects of continuous mechanical ventilation (MV) at a peak inspiratory pressure of 50 cm H2O in healthy, paralyzed, and anesthetized adult sheep during a period of 48 h. The 9 control sheep (Group A) were ventilated with 40% oxygen at a tidal volume of about 10 ml/kg and a peak inspiratory pressure of 15 to 20 cm H2O. All these animals remained stable throughout the 48 h of MV with no change in lung function. The 7 sheep in Group B were ventilated with 40% oxygen using a pressure-controlled ventilator at 50 cm H2O peak inspiratory pressure, at a VT of 50 to 70 ml/kg. All sheep in Group B developed severe respiratory failure and died or were killed within 2 to 35 h, and showed parenchymal consolidation at autopsy. The 9 sheep in Group C were ventilated as in Group B, except that 3.8% CO2 was added to the inspired gases: the Group C animals deteriorated more slowly, with little change in PaO2 but with a severely reduced FRC, VT, total static lung compliance, and grossly abnormal lungs at autopsy. We conclude that in this model, mechanical ventilation at peak airway pressure of 50 cm H2O will lead to progressive impairment in pulmonary mechanics, lung function, acute respiratory failure, and alveolar cellular dysfunction, as demonstrated by highly abnormal minimal surface tension values of saline lung lavage fluid in both study groups.

Animals↗