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Biomedical subjects

H Haller

Publications and source records attributed to H Haller.

At least 163 records · Page 9Linked to original sources
PubMed1996

Modulation of endothelial function: strategy for long-term cardiovascular protection.

PROPERTIES OF THE ENDOTHELIUM: The endothelium lines all vessels of the body and is the most important communication structure between flowing blood on one hand and the vessel wall, composed of smooth muscle cells and matrix proteins, on the other. Endothelial cells release factors that affect the differentiation and growth of vascular smooth muscle cells; dedifferentiation and subsequent proliferation of vascular smooth muscle cells are important early mechanisms in the pathogenesis of chronic vascular disease. CALCIUM ANTAGONISTS AND THE ENDOTHELIUM: Calcium antagonists primarily affect the cellular interactions of endothelial cells, smooth muscle cells, monocytes and thrombocytes, which are important in the early phases of the development of atherosclerosis. The protective effect of calcium antagonists on the vascular system appears to be low at later stages, which include increased matrix formation and central necrosis of atherosclerotic plaques. CONCLUSION: Present evidence indicates that calcium antagonists may be useful prophylactic agents at an early stage in the development of atherosclerotic vascular changes.

Animals↗
PubMed1996

High permeation of L-type Ca2+ channels at physiological [Ca2+]: homogeneity and dependence on the alpha 1-subunit.

Molecular cloning has identified multiple isoforms of dihydropyridine-sensitive C-class L-type Ca2+ channels. We tested the hypotheses that L-type (C-class) channels exhibit homogeneous high permeation properties at physiological Ca2+ concentrations and membrane potentials. We measured unitary currents through single dihydropyridine-sensitive omega-conotoxin-insensitive endocrine and smooth muscle L-type Ca2+ channels in rat pituitary GH3 and rat aortic A7r5 cell lines. We also measured unitary currents through smooth muscle (Cb) Ca2+ channel alpha 1-subunits in Chinese hamster ovary (CHO) cells. Our results show that single channel conductances of all three L-type (C-class) channels are uniform with high Ba2+ concentrations, e.g., approximately 23 pS with 110 mM Ba2+. The single channel conductances were reduced to similar values when the Ba2+ concentration was lowered to near-physiological values: 11.1, 9.3, and 8.4 pS in GH3, A7r5, and CHO cells at 2 mM Ba2+, respectively. The single channel conductances were not significantly different with near-physiological Ca2+ concentrations: 5.5, 5.9, and 4.9 pS in GH3, A7r5, and CHO cells at 2 mM Ca2+, respectively. The data suggest that L-type (C-class) channels are homogeneous in terms of Ca2+ permeation at physiological charge carrier concentrations and membrane potentials. Furthermore, the data indicate that the relatively high Ca2+ permeation under physiological conditions is determined by the intrinsic properties of the pore-forming Ca2+ channel alpha 1-subunit.

Animals↗
PubMed1996

Hypertension, the endothelium and the pathogenesis of chronic vascular disease.

The endothelium lines all vessels of the body and is the most important structure for communication between the flowing blood and the vessel wall. Healthy endothelium has antiadhesive and antithrombotic properties and is crucial for maintaining blood flow. It serves as a permeability barrier and prevents noxious agents from entering the vessel wall. Endothelial cells have secretory functions and secrete vasorelaxant substances. Therefore, functioning endothelium sustains the homoeostasis of the vessel wall. Endothelial functions are impaired by risk factors for cardiovascular disease such as hypertension, hyperlipidemia and hyperglycemia. Hypertension leads to decreased generation of nitric oxide in endothelial cells, thereby diminishing their vasorelaxant properties. Hypertension also contributes to an increase in endothelial cell permeability leading to intimal edema. Thirdly, hypertension increases the expression of adhesion molecules and increases the adherence of leukocytes to the vessel wall. Hence, hypertension directly contributes to the pathological alterations of the endothelium and it seems that these effects initiate and accelerate the pathogenesis of chronic vascular disease.

Animals↗
PubMed1996

Endothelial cell tyrosine kinase receptor and G protein-coupled receptor activation involves distinct protein kinase C isoforms.

Protein kinase C (PKC) is a family of serine/threonine protein kinase isoforms that is important to intracellular enzymes for both tyrosine kinase receptors and G protein coupled receptors. However, which isoforms are linked to which class of receptors in endothelial cell signaling is not known. Moreover, the PKC isoforms in endothelial cells have not been thoroughly characterized. We tested the hypothesis that specific PKC isoforms are involved in different signaling pathways. PKC isoform expression was assessed by using reverse transcription polymerase chain reaction and Western blotting. The spatial distribution of PKC after stimulation of the cells with basic fibroblast growth factor (bFGF) and thrombin was examined by using confocal microscopy. Expression of PKC alpha, delta, epsilon, theta, and zeta was detectable on both the mRNA and protein levels. In resting cells, PKC alpha and epsilon were mostly distributed in the cytosol, while PKC alpha and epsilon were also present in the nucleus. Nuclear immunoreactivity of PKC alpha and epsilon increased significantly between passages 1 and 3. The phorbol ester TPA induced a rearrangement of PKC delta and a translocation of PKC alpha and epsilon to the nucleus. Treatment of endothelial cells with TPA for 24 hours caused PKC alpha, delta, and epsilon to disappear, while PKC zeta was not influenced by TPA. bFGF induced a rapid assembly of PKC alpha along cytosolic structures, followed by a translocation of the isoform toward the perinuclear region and into the nucleus. bFGF had a smaller effect on PKC epsilon. In contrast, thrombin had a similar effect on nuclear translocation of PKC alpha, did not influence PKC epsilon, and induced a rapid nuclear translocation of PKC zeta. Thus, tyrosine kinase receptor activation via bFGF induced a rapid association of PKC alpha and epsilon with nuclear structures, while activation of the G protein-coupled thrombin receptor increased mostly nuclear PKC zeta. The translocation of PKC isoforms into the nucleus by growth-promoting factors may be important for the induction of endothelial cell growth.

Base Sequence↗
PubMed1996

Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension.

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m2) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8 AM, noon, and 4 PM. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.

Adult↗
PubMed1996

K+ currents in human coronary artery vascular smooth muscle cells.

K+ channels and their currents are important in vascular tone regulation and are potential therapeutic targets; however, K+ channels in human coronary artery vascular smooth muscle cells (VSMCs) have received little attention. We examined K+ currents in freshly isolated VSMCs from human coronary arteries (n=368 from 32 human hearts) with conventional patch-clamp or perforated-patch techniques with nystatin. We detected four different K+ currents: (1) the delayed rectifier K+ current, IK(dr); (2) the Ca2+-activated K+ current, IK(Ca); (3) the nonrectifying noninactivating outward ATP-dependent K+ current, IK(ATP); and (4) the spontaneous transient outward K+ current, IK(STOC). K+ channels underlying spontaneous transient outward currents probably represent a single clustered population of Ca2+-activated K+ channels functionally associated with Ca2+ release channels in the sarcoplasmic reticulum. Inwardly rectifying K+ currents were not observed. K+ currents were unevenly distributed in that they were not uniformly exhibited by all cells. The most prominent K+ currents were IK(Ca) (100%) and IK(dr) (46%). IK(STOC)s, which have not been previously described in humans, were present in 67% of VSMCs. IK(ATP) was small under physiological conditions; however, IK(ATP) increased markedly after cell stimulation with exogenous or endogenous coronary vasodilators. Thus, IK(ATP) may be particularly relevant in ischemia and could be of special importance as a therapeutic target. We conclude that human coronary VSMCs have unique K+ currents that differ sufficiently from those of other species, thus making the investigation of human material clinically relevant. The findings suggest potential avenues for further therapeutic research.

Adenosine Triphosphate↗
PubMed1996

Effects of intracellular angiotensin II in vascular smooth muscle cells.

Angiotensin (Ang) II is present inside vascular smooth muscle cells (VSMCs); however, its intracellular functions, if any, are unknown. We tested the hypothesis that intracellular Ang II exerts effects on cytosolic Ca2+ ([Ca2+]i) in VSMCs. Ang II was administered via microinjection. Intracellular Ang II localization was demonstrated by fluorescein-labeled Ang II and electron microscopy. [Ca2+]i was monitored by confocal microscopy with fluo 3. Ang II was identified in endosomes and in the nucleus by both localizing techniques. Microinjection of Ang II (10(-10) mol/L) led to a rapid increase in [Ca2+]i in the cytosol and in the nucleus. The [Ca2+]i increase was due to the influx of extracellular Ca2+ ions. The intracellular Ang II effect was totally inhibited by the concomitant injection of the Ang II antagonist CV-11947. Desensitization of extracellular Ang II receptors, on the other hand, did not influence the intracellular effects, nor did extracellular CV-11947. The increase in [Ca2+]i was observed not only in the microinjected cell but also in directly adjacent VSMCs. In contrast to the microinjected cells, the [Ca2+]i increase in the adjacent cells was mostly due to release from intracellular stores. Pretreatment with thapsigargin abolished the Ang II response in adjacent cells. Microinjection of inositol tris-phosphate induced a [Ca2+]i response in adjacent cells that was similar to the Ang II-induced effects. Preincubation of VSMCs with the uncoupling substances dimethyl sulfoxide and heptanol did not decrease the Ang II response but instead prevented a [Ca2+]i surge in adjacent cells. We conclude that intracellular Ang II binds to intracellular Ang II receptors and elicits an increased [Ca2+]i in the injected cell and, thereafter, cells in the immediate neighborhood. Cell-cell contact is necessary for the Ang II-mediated effects. The data suggest that intracellular Ang II may stimulate a cluster of VSMCs from a single cell via the release of second messengers.

Angiotensin II↗
PubMed1996

Circulating leukocyte integrin expression in Wegener's granulomatosis.

Leukocyte adhesion and infiltration are important in the pathogenesis of Wegener's granulomatosis (WG). We tested the hypothesis that the expression of the beta 1-chain integrin VLA-4 (CD49d/CD29) and the beta 2-chain integrins LFA-1 (CD11a/CD18), Mac-1 (CD11a/CD18), and gp150,95 (CD11c/CD18) is increased on leukocytes in patients with active WG. Fifteen patients with active WG as defined by positive antineutrophil cytoplasmic autoantibody (cANCA) titers and biopsy, 30 patients with WG in remission as defined by negative cANCA titers and/or immunosuppressive therapy, 25 normal control subjects, and 12 patients with other inflammatory renal and systemic diseases were studied. Surface expression of LFA-1, Mac-1, p150, 95, and VLA-4 on neutrophils, lymphocytes, and monocytes was measured by fluorescent antibody cell sorting with monoclonal antibodies against CD11a, CD11b, CD11c, CD18, CD49d, and CD29 respectively. Immunocytochemistry and confocal microscopy were also utilized. beta 1 (CD29) and beta 2 (CD18) integrin subunit expression on neutrophils, monocytes, and lymphocytes from patients with acute WG was significantly increased compared with healthy persons and compared with patients with treated vasculitis. Furthermore, the alpha-integrin subunit CD11b expression was increased on granulocytes and monocytes, but not on lymphocytes. Finally, the alpha-integrin subunit CD11a expression was increased on monocytes. Immunocytochemistry showed that the increased immunoreactivity on neutrophils was evenly distributed on the plasma membrane and in the cytosol. Immunosuppression resulted in decreased expression of the beta 1 and beta 2-integrin subunits. It was concluded that the integrin adhesion molecules, particularly Mac-1 (CD11b/CD18), are upregulated on leukocytes in active WG. This finding suggests a role for integrin expression in the pathogenesis of WG and a possible clue for treatment.

Follow-Up Studies↗
PubMed1996

Review: the central role of calcium in the pathogenesis of cardiovascular disease.

Calcium-dependent processes play a central role in several different cells of the cardiovascular system including vascular smooth muscle and endothelial cells and also in monocytes, macrophages and platelets. In response to extracellular stimuli cytosolic calcium concentration increases. The increase is composed of two distinct phases. Firstly, calcium is released from intracellular stores via IP3. In the second phase calcium influx across the cell membrane is mostly responsible for the sustained rise in intracellular calcium concentration. This phase of the peak increase in cytosolic calcium is a prerequisite for sustained activation of the cell and the processes of vascular smooth muscle contraction and the activation of nuclear transcription factors for protein biosynthesis. Under ischemic conditions the regulatory systems which control the intracellular free calcium concentration consume a major portion of the cell's physiological energy supply (90%) and a decreased oxygen supply under ischemic conditions rapidly reduces the cell's capacity for intracellular calcium storage or outward transport across its membrane. Calcium antagonist drugs principally act on L-type calcium channels to reduce the influx of calcium into the the cells of the body. Since calcium antagonist drugs are able to influence a wide range of cellular processes which have been implicated in atherosclerosis, glomeruloscierosis, left ventricular hypertrophy and insulin resistance there are strong grounds for their use in a range of clinical disease states.

Calcium↗
PubMed1996

Effect of strenuous exercise on agonist-induced platelet cytosolic calcium in man.

Hypertension, which is attenuated by regular aerobic exercise, is associated with an increase in cytosolic platelet calcium [Ca+2]i. How aerobic exercise might lower blood pressure is unknown. We tested the hypothesis that exercise would influence the agonist-induced effect on platelet cytosolic calcium [Ca+2]i. Twenty, healthy normotensive men between 20 and 60 years of age (five per decade) were studied while resting supine for 30 min and after bicycle ergometry at a work load sufficient to achieve a heart rate of 200 beats per min minus age in years. On the next day, the protocol was repeated with the subjects exercising at 75% their maximum heart rate for 6 min. Venous blood was obtained from an indwelling cannula. Exercise had no effect on total or ionised serum calcium values. Adrenaline values increased from 0.2 +/- 0.03 to 0.55 +/- 0.1 (s.e.m.) nmol/l (P < 0.05), while noradrenaline increased from 1.46 +/- 0.18 to 4.72 +/- 0.44 nmol/l (P < 0.05). Resting platelet [Ca+2]i concentrations were 95.4 +/- 3.9 and 94.4 +/- 3.0 nmol/l on the two study days. The values were not correlated with age or level of fitness. The platelet [Ca+2]i was 99.2 +/- 4.2 nmol/l after exercise, not different from the resting values. Platelet activation with adrenaline and thrombin across a wide range of doses resulted in prompt increases in [Ca+2]i, which were 50% less in platelets after exercise than at rest (P < 0.05). Activation with angiotensin (Ang) II, on the other hand, was less pronounced and less clearly influenced by exercise. We conclude that exercise influences the platelet activation state and reactivity. The decreased [Ca+2]i responses to adrenaline and thrombin suggest that [Ca+2]i stores were in part depleted at exercise compared to rest, an effect not observed with Ang II perhaps because of the smaller number of Ang II-operative receptors on platelets.

Adult↗
PubMed1996

The role of hyperglycemia and hyperinsulinemia in the pathogenesis of diabetic angiopathy.

The small and large vessel disease associated with diabetes mellitus is responsible for its morbidity and mortality. Although much of the pathogenesis remains to be clarified, the role of hyperinsulinemia and hyperglycemia per se in the progression of vascular disease is beginning to emerge. Hyperinsulinemia increases the release of very low density lipoprotein (VLDL) and may also be responsible for the low HDL cholesterol levels in patients with diabetes. Hyperinsulinemia also contributes to increased blood pressure, which independently promotes vascular disease. High glucose concentrations have direct influence on intracellular signal transduction, including effects on sorbitol pathway and associated changes of pyridine nucleotides, the de novo synthesis of diacylglycerol with subsequent stimulation of protein kinase C, and possibly changes in the cellular generation of myoinositol. Hyperglycemia also exerts long-lasting changes in cellular function, which result from non-enzymatic glycosylation of matrix and membrane proteins with subsequent binding of these proteins to specific receptors. These receptors are termed the advanced glycosylation end-products (AGE) receptors. Their activation leads to an increased release of cytokines and growth factors including PDGF, interleukins, TNF-alpha, and TGF-beta, all of which may act concomitantly in the disease process.

Arteriosclerosis↗
PubMed1995

Bradykinin induces rise of free calcium in nuclei of neuroblastoma x glioma hybrid NG 108-15 cells.

Confocal fluorescence microscopy was used to study the bradykinin-induced calcium signals in the neuroblastoma x glioma cell line NG 108-15. We found that bradykinin induced a rise in free calcium, not only in the cytoplasm but also in the nucleus. The nuclear and cytosolic calcium concentrations were not significantly different and rose to about 1.2 microM. The signal was mediated by the B2-receptor subtype as confirmed using the specific antagonist Hoe 140. Both the onset and the intensity of the calcium signals were concentration-dependent. The rise of nuclear calcium level was independent of extracellular calcium and suppressed by thapsigargin which is known to deplete inositol 1,4,5-trisphosphate-sensitive calcium stores. Bradykinin-induced calcium increase desensitizes rapidly. This desensitization was shown not to involve activation of protein kinase C.

Animals↗
PubMed1995

Fetal transverse cerebellar diameter/abdominal circumference ratio in assessing fetal size.

OBJECTIVE: To test the usefulness of the fetal transverse cerebellar diameter/abdominal circumference (TCD/AC) ratio in predicting known small-for-gestational-age (SGA) infants. METHOD: The relationship between fetal TCD and AC throughout the second half of pregnancy was investigated in 635 well-dated, normal pregnancies and examined with regard to gestational age and infant birth weight percentiles. RESULTS: One hundred eighteen (19%) fetuses were excluded due to inadequate visualization of the fetal cerebellum. A strong correlation was noted between gestational age determined by the last menstrual period and both fetal TCD (r2 = 0.91338) and AC (r2 = 0.89361) in fetuses with birth weights between the 10th and 90th percentiles (n = 407; mean 14.4, S.D. 1.2). Although the TCD/AC ratio showed a poor correlation with gestational age (r2 = 0.15788), a slight increase was noted during gestation. A TCD/AC ratio greater than 15.5 was present in 80% of SGA infants when measurements were performed within 1 week of delivery. CONCLUSION: Fetal TCD/AC ratio as a gestational age-independent method could improve diagnostic sensitivity and specificity in the early detection of fetal growth abnormalities.

Abdomen↗
PubMed1995

Cholecystokinin induced signaling in rat glioma C6 cells.

We investigated the effect of sulphated cholecystokinin octapeptide (CCK-8S) on free intracellular calcium concentration, phosphatidylinositol metabolism, and protein phosphorylation in C6 cells, a rat glioma cell line which was shown to express CCKB type receptors. Increase in [Ca2+]i by both influx across the cell membrane and release from internal stores was demonstrated by utilizing a laser confocal imaging system. Because CCK-8S produced a transient elevation of inositol triphosphate level participation of InsP3 in calcium signaling in C6 cells is very likely. Protein kinase C seems to be involved in CCK-8S induced signaling in rat glioma C6 cells as demonstrated by using in vivo phosphorylation experiments.

Animals↗
PubMed1995

Decidual-trophoblast interactions: decidual lymphoid cell populations in basal and parietal decidua.

Immunohistochemical analysis of tissue specimens from human pregnancy decidua basalis in contact with invasive trophoblast of chorion frondosum and decidua parietalis in contact with non-invasive chorion laeve do not differ in the frequency of lymphoid cells of the following phenotypes (CD2, CD4, CD8, CD14, CD21 and gamma/delta TCR). A practical implication of this observation is that the collection of lymphoid cells from whole decidua by curettage for functional studies is justified.

Antigens, CD↗
PubMed1995

Tumefactive megalocytic interstitial nephritis in a patient with Escherichia coli bacteremia.

Megalocytic interstitial nephritis is rare and primarily affects the cortex in an otherwise normal kidney. We recently encountered a patient with Escherichia coli bacteremia and oliguric acute renal failure who died of gram-negative septicemia. At autopsy, this patient's kidneys displayed typical features of megalocytic interstitial nephritis. We were able to perform special stains suggesting that the histiocytic interstitial cells originated from infiltrating macrophages. Our patient illustrates that macrophage proliferation can result in interstitial inflammation sufficiently severe to cause anuric acute renal failure.

Acute Kidney Injury↗