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Biomedical subjects

F R Bühler

Publications and source records attributed to F R Bühler.

At least 19 recordsLinked to original sources
PubMed1996

Ligand selectivity of 105 kDa and 130 kDa lipoprotein-binding proteins in vascular-smooth-muscle-cell membranes is unique.

Using ligand blotting techniques, with low-density lipoprotein (LDL) as ligand, we have previously described the existence of atypical lipoprotein-binding proteins (105 kDa and 130 kDa) in membranes from human aortic medical tissue. The present study demonstrates that these proteins are also present in membranes from cultured human (aortic and mesenteric) and rat (aortic) vascular smooth-muscle cells (VSMCs). To assess the relationship of 105 and 130 kDa lipoprotein-binding proteins to known lipoprotein receptors, ligand binding specificity was studied. We tested effects of substances known to antagonize ligand binding to either the LDL [apolipoprotein B,E (apo B,E)] receptor (dextran sulphate, heparin, pentosan polysulphate, protamine, spermine, histone), the scavenger receptor (dextran sulphate, fucoidin), the very-low-density-lipoprotein (VLDL) receptor [receptor-associated protein (RAP)], or LDL receptor-related protein (RAP, alpha 2-macroglobulin, lipoprotein lipase, exotoxin-A). None of these substances, with the exception of dextran sulphate, influenced binding of LDL to either 105 or 130 kDa proteins. Sodium oleate or oleic acid, known stimuli for the lipoprotein binding activity of the lipolysis-stimulated receptor, were also without effect. LDL binding to 105 and 130 kDa proteins was inhibited by anti-LDL (apo B) antibodies. LDL and VLDL bound to 105 and 130 kDa proteins with similar affinities (approximately 50 micrograms/ml). The unique ligand selectivity of 105 and 130 kDa proteins supports the existence of a novel lipoprotein-binding protein that is distinct from all other currently identified LDL receptor family members. The similar ligand selectivity of 105 and 130 kDa proteins suggests that they may represent variant forms of an atypical lipoprotein-binding protein.

Adolescent↗
PubMed1996

Prevention of neointima formation by mibefradil after vascular injury in rats: comparison with ACE inhibition.

Cilazapril, an angiotensin-converting enzyme inhibitor, and mibefradil, a selective T-type voltage-operated calcium channel blocker, have been shown to prevent neointima formation after vascular injury. The goal of the present study was to evaluate the mechanism of action of both drugs. For this purpose, the influence of the renin angiotensin system on the effects of mibefradil (30 mg/kg po) and cilazapril (10 mg/kg po) on neointima formation after carotid injury were evaluated in normotensive rats (normal renin angiotensin system) and DOCA hypertensive rats (suppressed renin angiotensin system). In addition, in order to differentiate an effect on cell migration or cell proliferation, both drugs were given either before or after the smooth muscle migration phase. Finally, cilazapril and mibefradil were given in combination. In normotensive rats, mibefradil and cilazapril decreased neointima formation, resulting in neointima/media ratios of 38% (p < 0.05) and 53% (p < 0.01), respectively. However, in DOCA hypertensive rats, mibefradil was active, with a reduction of the neointima/media ratio by 63% (p < 0.001), whereas cilazapril reduced it only slightly (19%) and not significantly. In addition, cilazapril was active only when treatment started before the migration phase (63%, reduction in neointima/media ratio, p < 0.001) but not when started thereafter (13% reduction in neointima/media ratio, n.s.). In contrast, treatment with mibefradil was also active when started after the migration phase (51% reduction in neointima/ media ratio, p < 0.001 when treatment started 1 day before balloon injury and 41%, p < 0.01 when treatment started 5 days after balloon injury). The combination of both drugs was additive (67% reduction in neointima/media ratio, p < 0.001 vs. control). These experiments clearly show that mibefradil and cilazapril have a different mechanism of action after vascular injury. Mibefradil most likely prevents the proliferation of smooth muscle cells. In contrast, cilazapril most likely inhibits the migration of smooth muscle cells. These two different mechanisms of action explain why the effects of both drugs are additive.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Endothelium-modulated proliferation of medial smooth muscle cells: influence of angiotensin II and converting enzyme inhibition.

This study investigated the role of the endothelium and angiotensin II (Ang II) in regulating medial smooth muscle cell (SMC) proliferation. [3H]-thymidine incorporation into medial SMC of rat arteries was examined in vivo, using ballooned rat carotid arteries, as well as in vitro, using cultures of aortic tissue rings (organoids). In vivo, maximal medial [3H]-thymidine incorporation occurred within 3 days post-ballooning. In endothelium-denuded organoids, maximum medial DNA synthesis was achieved after 7 days of culture. [3H]-thymidine-labelling of SMC in intact organoids (with endothelium) increased minimally during culture, indicating that the endothelium provided protection with respect to medial proliferation under basal conditions (culture in the presence of 1% plasma-derived serum). Inclusion of 10(-7) M Ang II significantly elevated medial [3H]-thymidine incorporation above that in control cultures. The stimulatory effect of Ang II was much more pronounced in intact organoids that in endothelium-denuded organoids, indicating synergistic growth regulation by Ang II and endothelium-derived factors. When organoids were cultured in the combined presence of Ang II and the ACE inhibitor cilazaprilat, labelling indices of intact organoids were also significantly increased above control, but to a lower level than those obtained in the presence of Ang II alone. However, for endothelium-denuded organoids, medial [3H]-thymidine incorporation in the combined presence of Ang II and cilazaprilat was not significantly different from that in untreated controls. Thus, cilazaprilat exerts both endothelium-dependent and endothelium-independent negative regulatory effects on medial SMC proliferation.

Angiotensin II↗
PubMed1995

Mibefradil prevents neointima formation after vascular injury in rats. Possible role of the blockade of the T-type voltage-operated calcium channel.

Mibefradil is a novel calcium antagonist that is selective for the T-type voltage-operated calcium channel rather than the L type. Because T-type calcium channels are present on rapidly proliferating cells and mediate the increase of intracellular calcium induced by some growth factors, such as platelet-derived growth factor, we hypothesized that the blockade of T channels could prevent the excessive smooth muscle cell proliferation that occurs in conditions such as vascular injury. To test this hypothesis, we evaluated in rats the effects of mibefradil (which blocks both L- and T-type channels) on neointima formation after vascular injury, and we compared them with those of equihypotensive doses of amlodipine and verapamil (which block only L-type channels). Mibefradil (30 mg/kg) decreased the area of neointima formed 14 days after balloon injury by 54% (P < .001). In contrast, neither verapamil nor amlodipine had an effect despite a blood pressure reduction at least equal to that of mibefradil. The in vivo effect of mibefradil was indeed an inhibition of smooth muscle cell proliferation, as shown by thymidine incorporation experiments. This antiproliferative effect of mibefradil was also observed in vitro in smooth muscle cells stimulated by fetal calf serum. In this condition also, verapamil was ineffective. We conclude that in rats mibefradil has a potent antiproliferative effect on smooth muscle cells after vascular injury. This effect might be due to blockade of voltage-operated T channels.

Amlodipine↗
PubMed1994

Activation of human peripheral monocytes by angiotensin II.

This study has investigated the ability of the vasoconstrictor peptide angiotensin II to activate human peripheral blood monocytes. Activation was monitored by measuring both the release of tumor necrosis factor alpha from monocytes and their adhesion to monolayers of human endothelial cells. Angiotensin II-elicited activation of monocytes was dose-dependent (half-maximally effective concentration approximately 0.2 nM), saturable (maximally effective concentration approximately 5 nM), and sensitive to inhibition by the angiotensin type 1 receptor antagonist ZD 7155. Such direct actions imply that angiotensin II is an important candidate stimulus for the subendothelial infiltration of monocytes observed in atherogenesis and hypertension.

Angiotensin II↗
PubMed1994

Diminished vascular response to inhibition of endothelium-derived nitric oxide and enhanced vasoconstriction to exogenously administered endothelin-1 in clinically healthy smokers.

BACKGROUND: Smoking is a major risk factor for the development of atherosclerosis. Because endothelial dysfunction may be a marker for future atherosclerosis, we investigated the effects of smoking on endothelium-dependent control of vascular tone. METHODS AND RESULTS: The effects of brachial arterial infusions of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthesis inhibitor; sodium nitroprusside; endothelin-1; and norepinephrine on forearm blood flow (strain-gauge plethysmography) were compared in 29 long-term smokers and 16 nonsmokers. The acute effects of smoking on systemic hemodynamics, plasma catecholamines, and forearm vascular responses to these compounds were investigated in smokers only. Smokers did not differ from nonsmokers (n = 16) regarding the vascular effects of sodium nitroprusside (n = 13) or vasoconstriction due to norepinephrine and endothelin-1 (n = 16). Low-dose endothelin-1-induced vasodilation, believed to reflect endothelial prostacyclin or nitric oxide release, was absent in smokers (n = 16), and their increase of forearm vascular resistance (FVR) after L-NMMA (n = 13) was impaired (35.6 +/- 27.9% versus 118.8 +/- 43.2%, P < .001). Short-term smoking (n = 11) increased blood pressure, heart rate, and plasma epinephrine concentrations (P < .05 or less); enhanced endothelin-1-induced vasoconstriction (delta FVR, 457 +/- 192% versus 254 +/- 143%, P < .01); and decreased norepinephrine-induced vasoconstriction (P < .05), but had no effect on the other interventions. CONCLUSIONS: Long-term smoking is associated with a diminished nitric oxide-dependent component of basal vascular tone and an impaired endothelium-dependent vasodilator response to low-dose endothelin-1 and short-term smoking enhances endothelin-1-induced vasoconstriction. Impaired endothelial control of vascular tone might reflect impairment of normal antiatherosclerotic endothelial functions in smokers, but the relevance of smoking-induced enhancement of endothelin-1 vasoconstriction remains to be determined.

Adult↗
PubMed1994

A repressive coping style protecting from emotional distress in low-renin essential hypertensives.

OBJECTIVE: To investigate the relationship between the behavioural characteristics and specified subgroups of patients with essential hypertension. DESIGN AND METHODS: Fifty-four patients were classified into groups with a high (n = 9), normal (n = 35) or low plasma renin activity (n = 10), and were compared with 20 normotensive subjects by psychological tests. Standardized tests were used to measure anger expression, defensiveness and the subjects' psychological status (e.g. anxiety, depression). RESULTS: A repressive coping style, defined by a high defensiveness and low anxiety levels, was found significantly more often in patients with low than in patients with high plasma renin activity and normotensive subjects. The patients with high plasma renin activity scored significantly higher on suppressed anger, anxiety and interpersonal sensitivity than did those with low plasma renin activity. The scores of the normal plasma renin activity group were similar to those of the normotensive group. CONCLUSIONS: The results underline that there is not one hypertensive 'personality'. Whereas the patients with a high plasma renin activity appear to be more susceptible to emotional conflicts, the patients with low plasma renin activity report low emotional distress and maintain an apparently well-adjusted facade.

Adaptation, Psychological↗
PubMed1994

Characteristics of low and high density lipoprotein binding and lipoprotein-induced signaling in quiescent human vascular smooth muscle cells.

Low density lipoprotein (LDL) and high density lipoprotein (HDL) have been shown to stimulate signal transduction events in a number of cell types, including cultured vascular smooth muscle cells (VSMC), but it is not known whether these events are mediated through distinct lipoprotein receptors for transmembrane signaling. This study has used confluent quiescent cultures of human microarteriolar VSMC to investigate the relationship between the characteristics of 125I-LDL and 125I-HDL3 binding and those of LDL- and HDL3-stimulated cell signaling. Two distinct binding sites for LDL (Kd1 approximately 2 micrograms/ml and Kd2 approximately 40 micrograms/ml) and a single class of sites for HDL3 (Kd approximately 30 micrograms/ml) were identified. The Kd1 for high affinity 125I-LDL binding in quiescent VSMC was comparable to the value for heparin-sensitive binding of 125I-LDL to apolipoprotein B/E receptors in fibroblasts (Kd approximately 1 microgram/ml). Concentrations of lipoproteins required for half-maximal stimulation (EC50) of phosphoinositide catabolism and intracellular calcium mobilization in VSMC were approximately 35 micrograms/ml for HDL3 and approximately 40 micrograms/ml for LDL. Both LDL- and HDL3-stimulated signaling responses in VSMC, as well as 125I-HDL3 binding and low affinity 125I-LDL binding to VSMC, were insensitive to heparin. Competition binding studies (with unlabeled lipoproteins at 2.5-200 micrograms/ml) showed partial displacement of 125I-LDL by HDL3 and of 125I-HDL3 by LDL, whereas complete displacement of 125I-LDL or 125I-HDL3 by their homologous lipoproteins was achieved. Thus, the binding sites for HDL3 are distinct from those for LDL. Because the response of VSMC to combinations of LDL and HDL3 was additive, LDL and HDL3 also exert their signaling effects through distinct sites. Further investigation is required to unequivocally demonstrate that the heparin-insensitive HDL3 and low affinity LDL binding sites in VSMC are those through which LDL and HDL3 stimulate transmembrane signaling.

Arterioles↗
PubMed1993

Effects of peptide vasoconstrictors on vessel structure.

The peptide vasoconstrictors angiotensin II and endothelin-1, originally described as being derived exclusively from the plasma renin-angiotensin system and vascular endothelium, respectively, have been demonstrated to be produced independently of these sources. Local tissue angiotensin-generating systems are well documented and endothelin production has been demonstrated for a variety of nonendothelial cells, including vascular smooth muscle cells. There is increasing evidence that these locally produced vasoconstrictor peptides may contribute to blood vessel homeostasis, as well as the development of vascular pathologic conditions. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In addition to their vasoconstrictor properties, angiotensin II and endothelin-1 act as potent biologic effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in vascular smooth muscle cells. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The most well-established autocrine feedback loops of vascular smooth muscle cells are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of angiotensin II and endothelin-1. The effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural importance, since both vasoconstrictors (via autocrine growth modulators) may influence the composition of the extracellular matrix of vascular smooth muscle cells. This includes effects on the synthesis and secretion of thrombospondin, fibronectin, tenascin, etc. The secretion of extracellular matrix glycoproteins themselves and incorporation into extracellular matrix in vitro appear to be linked to the activity of the autocrine feedback loops: e.g., stimulation of thrombospondin mRNA results in secretion of the glycoprotein only in the concomitant presence of exogenous platelet-derived growth factor, whereas the expression of fibronectin and tenascin may be directed by transforming growth factor-beta. The influence of angiotensin II and endothelin-1 on vascular smooth muscle cell surface receptor expression may represent a secondary mode of action of these vasoconstrictor peptides. Endothelin-1, for instance, can rapidly down-regulate platelet-derived growth factor-alpha receptor mRNA and both angiotensin II and endothelin-1, via induction of transforming growth factor-beta, may interrupt the platelet-derived growth factor based autocrine feedback loop. In vivo, the highly complex interactions between local and systemic vasoconstrictor production, autoregulated feedback loops, and extracellular matrix (which also serves as a reservoir for growth and differentiation modulators) are central to vessel homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin II↗
PubMed1993

Expression of soluble and insoluble fibronectin in rat aorta: effects of angiotensin II and endothelin-1.

This study has investigated the influence of the vasoconstrictor peptides angiotensin II (Ang II) and endothelin-1 (ET-1) on fibronectin expression by vascular smooth muscle cells (VSMC). In confluent, quiescent cultures of VSMC, Ang II and ET-1 elevated fibronectin mRNA levels in a time- and dose-dependent fashion. ET-1 and Ang II also induced a time-dependent expression of immunoreactive fibronectin in cultures of aortic organoids, and for both peptides the fibronectin immunoreactivity was most prominent within those medial smooth muscle cell layers close to the vessel lumen. Immunoprecipitation of biosynthetically labelled fibronectin elaborated by cultured VSMC revealed a predominant expression of soluble fibronectin in response to Ang II, whereas for ET-1 the newly synthesized fibronectin was predominantly incorporated into the extracellular matrix deposit of the cells. These findings indicate that Ang II and ET-1 may exert disparate effects on smooth muscle cell phenotype and migration.

Angiotensin II↗
PubMed1993

Evidence for the involvement of G proteins in the modulation of 22Na and 45Ca fluxes in myogenic L6 and aortic smooth muscle cells.

Preincubation of rat skeletal muscle derived L6 myoblasts with 10 mM NaF increased, the activity of Na+/H+ exchanger, and the uptake of 45Ca by 2 and 5 folds, respectively. In cultured vascular smooth muscle cells (CVSMC) of rat aorta, NaF increased the activity of Na+,K(+)-pump, Na+/H+ exchanger, passive permeability for Na+, and 45Ca uptake by 1.6, 9, 2, and 9 folds, respectively. Both, in CVSMC and L6 cells, the effect of NaF on the Na+/H+ exchanger and 45Ca uptake were significantly augmented by 20 microM AlCl3. No effect of AlCl3 on the NaF dependent changes in ion flux was seen in rat erythrocytes. The results suggest that in L6 and CVSMC cells, the Na+/H+ exchanger and Ca++ uptake pathway(s) are activated by GTP-binding proteins.

Aluminum↗
PubMed1993

The renin-angiotensin system and extracellular matrix.

A hallmark of vascular disease is the inappropriate proliferative and synthetic behaviour of vascular smooth muscle cells. This phenotypically immature behaviour arises as a consequence of the myocytes undergoing phenotypic conversion and/or clonal proliferation of a "fetal" type of smooth muscle cell preexisting in the vessel wall. De-differentiation and initiation of proliferation is not only induced by endothelial desquamation and acute exposure of smooth muscle cells to platelet-derived mitogens, but also occurs in the uninjured blood vessel. Therefore normal components of the blood vessel are implicit in the pathological process. These include vasoconstrictor peptides, growth factor peptides and extracellular matrix molecules. In vitro and in vivo experimentation has indicated that while some of these compounds individually are only mild stimulators of smooth muscle proliferative metabolism, they may act synergistically to induce robust responses. Here we discuss the effects of the vasoconstrictor peptide angiotensin II, which can be locally generated within the vessel wall itself, on the expression of extracellular matrix molecules in vitro and in vivo. We focus on the angiotensin II-modulated expression of extracellular matrix glycoproteins, e.g. thrombospondin, tenascin, fibronectin and laminin.

Angiotensin II↗
PubMed1993

Ischemic ECG changes are found more often in asymptomatic men with a coronary prone behaviour pattern.

Type A behaviour has been related to coronary heart disease (CHD) as an independent risk factor. Therefore, ischemic electrocardiographic (ECG) changes may be more prominent in Type A than in Type B individuals. ECG abnormalities were assessed by the Cardiac Infarction Injury Score (CIIS), which has predictive power for sudden death. In 100 healthy men aged 30-45 yr, the CIIS was related to cardiovascular risk factors such as age, blood pressure, smoking, family history of CHD and behaviour pattern groups defined by the Structured Interview (46 Type A, 20 Type X and 34 Type B subjects). The distribution of the CIIS was different among the behaviour pattern groups (p < 0.05) and was shifted towards higher ischemic scores in Type A subjects. These findings suggest that clinically asymptomatic persons with Type A behaviour have a greater probability of suffering ischemic heart disease and possible sudden death.

Adult↗
PubMed1993

Acetylsalicylic acid, at high concentrations, inhibits vascular smooth muscle cell proliferation.

The growth of human smooth muscle cells in culture is inhibited by acetylsalicylic acid (ASA). In comparison to control, the proliferation of cells treated with 270 mg/L lysinmono(acetylsalicylate)/30 mg/L glycine was inhibited by 50-90% under different culture conditions. Cell numbers per well (control vs. treated) were as follows: (a) 470,500 +/- 55,890 vs. 24,750 +/- 4,030 (p < 0.002) after 6 days in the presence of 10% fetal calf serum (FCS), (b) 160,500 +/- 9,920 vs. 74,000 (p < 0.001) after 8 days in the presence of 10% human serum; and (c) 387,000 +/- 29,420 vs. 35,250 +/- 1,110 (p < 0.001) after 8 days in the presence of 5% FCS. Significant inhibition of growth by lysinmono(acetylsalicylate) at 90 mg/L was noted only for cultures grown with 10% FCS. Lower concentrations of this drug were ineffective under all culture conditions. Higher dosages of ASA, which would prevent not only platelet aggregation but also smooth muscle cell growth, may therefore be indicated in therapy of patients who undergo percutaneous transluminal coronary angioplasty (PTCA) or coronary artery transplantation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Peptide vasoconstrictors, vessel structure, and vascular smooth-muscle proliferation.

The peptide vasoconstrictors angiotensin II (Ang II) and endothelin-1 (ET-1), originally thought to derive exclusively from the plasma renin-angiotensin system and vascular endothelium, respectively, have been demonstrated to be produced independently of such sources. Local tissue angiotensin-generating systems are well documented, and endothelin production has been demonstrated for a variety of nonendothelial cells, including vascular smooth-muscle cells (VSMC). There is increasing evidence from in vitro studies that local production of these vasoconstrictor peptides may contribute to blood vessel homeostasis and the development of vascular pathologies. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In addition to their vasoconstrictor properties, Ang II and ET-1 act as potent biological effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in VSMC. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The best-recognized autocrine feedback loops of VSMC are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of Ang II and ET-1. Because both vasoconstrictors (via their induction of autocrine growth modulators) may influence the composition of the extracellular matrix of VSMC, the effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural importance. Ang II and ET-1 promote the synthesis and secretion of the glycoproteins thrombospondin, fibronectin, and tenascin.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗