Low density lipoprotein and calcium homeostasis in human vascular smooth muscle cells.
Explore the source record for details and available documents.
Calcium↗
Biomedical subjects
M Schachter
Publications and source records attributed to M Schachter.
A comparison of calcium channel currents in vascular smooth muscle cells from Watanabe hereditary hypercholesterolaemic and New Zealand white rabbits.
Explore the source record for details and available documents.
Animals↗
Growth inhibition of human vascular smooth muscle cells by fenofibrate: a possible therapy for restenosis.
OBJECTIVE: The aim was to assess the growth inhibitory effect of fibrates on human vascular smooth muscle cells. Restenosis is the most important factor limiting the long term success of invasive vascular interventions and there is as yet no effective preventive treatment. Platelet derived growth factor (PDGF) is considered to be an important growth promoting agent for vascular smooth muscle cells (VSMC) and fenofibric acid (a hypolipidaemic drug) has been reported to be a PDGF antagonist. METHODS: The effect of the fibrate drugs fenofibrate, clofibrate, bezafibrate, and gemfibrozil were examined on the proliferation of cultured human vascular smooth muscle cells derived from saphenous vein (n = 20) and graft stenoses (n = 7). RESULTS: Fenofibrate (100 microM) produced potent inhibition (48%) of VSMC proliferation at a concentration equivalent to that of its circulating metabolite fenofibric acid, but none of the other drugs produced any significant effect on growth. VSMC derived from graft stenoses were equally sensitive to inhibition as saphenous vein derived controls, in contrast to our previous work which reported that graft stenosis derived VSMC were resistant to growth inhibition by the physiological inhibitor heparin. The antiproliferative effect of fenofibrate was independent of inhibition of cellular cholesterol synthesis or toxicity. Fenofibrate inhibited VSMC growth induced by 15% fetal calf serum, PDGF, and basic fibroblast growth factor to a similar degree, indicating that it is not a specific PDGF antagonist. CONCLUSIONS: Fenofibrate is not a specific PDGF antagonist. Fenofibric acid, one of the principal metabolites of fenofibrate, did not produce any inhibition of growth, suggesting that oral administration of fenofibrate would not be efficacious. Fenofibrate is the first potent inhibitor to be described for VSMC derived from human myo-intimal hyperplastic lesions.
Bezafibrate↗
Hypertension and blood vessels.
The arterial wall undergoes many changes in hypertension. These changes affect the endothelium, vascular smooth muscle cells and the extracellular matrix of the blood vessel. Current evidence regarding both functional and structural aspects of these changes in the blood vessel wall is reviewed in this article.
Animals↗
Effect of calcium channel blockers on the growth of human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses.
Vascular restenosis after invasive interventions is an important clinical problem for which no preventive pharmacologic therapy exists. Calcium channel blockers have been shown to inhibit myointimal hyperplasia in animal models of restenosis and in some small and flawed clinical coronary restenosis trials. We examined the inhibitory effect of amlodipine, verapamil, and diltiazem on the growth of cultured human vascular smooth muscle cells (VSMC) derived from saphenous vein (n = 20) and graft stenoses (n = 7), in 14-day proliferation assays and [methyl 3H]thymidine uptake studies. Amlodipine and verapamil produced significant inhibition (30%) of VSMC proliferation and DNA synthesis at 10 microM but not at 500 nM-1 microM. To our knowledge, this is the first study to examine the antiproliferative effect of calcium channel blockers in VSMC derived from human graft stenoses. Growth inhibition of VSMC from graft stenoses was not significantly different from that of control saphenous vein-derived cells. We conclude, therefore, that calcium channel blockers inhibit human VSMC proliferation in vitro, regardless of whether the cells were grown from graft stenoses or saphenous vein. However, the concentrations at which these calcium channel blockers elicit antiproliferative effects may not be attainable during therapeutic dosing in humans.
Amlodipine↗
Potassium channel opening properties of thiazide diuretics in isolated guinea pig resistance arteries.
We examined the role of K+ channels in mediating the acute vascular actions of hydrochlorothiazide, indapamide, cicletanine, and cromakalim, studying the effect of K+ channel blockers on drug-induced relaxation and drug-induced 86Rb efflux in guinea pig mesenteric arteries. Cromakalim-induced relaxation was unaffected by charybdotoxin, apamin, or phencyclidine (PCP) but was reduced by 75% (with 30 microM cromakalim) by glibenclamide (p < 0.001). Cromakalim increased 86Rb efflux from guinea pig vessels, an effect that was abolished by glibenclamide. Hydrochlorothiazide and cicletanine-induced relaxations have been shown to be inhibited by charybdotoxin by unaffected by glibenclamide, apamin, or PCP. Hydrochlorothiazide and cicletanine increased 86Rb efflux from guinea pig mesenteric arteries. These increases were abolished by charybdotoxin. Indapamide-induced relaxation was not affected by incubation with any of the K+ channel blockers. Indapamide did not alter basal 86Rb efflux. The results suggest that in guinea pig mesenteric arteries indapamide-induced relaxation is not mediated by an action on K+ channels. Cromakalim-induced effects are mediated by KATP. Large conductance KCa mediates the hydrochlorothiazide and cicletanine-induced vascular effects in part.
Animals↗
Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis.
Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced [methyl 3H]-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.
Adenine↗
Cutaneous permeability responses to bradykinin and histamine in the guinea-pig: possible differences in their mechanism of action.
1. Plasma protein extravasation (PPE) responses in guinea-pig skin have been measured using accumulation of intravenously injected 125I-labelled human serum albumin (125I-HSA). 2. The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.1 mumol/site) significantly reduced responses to bradykinin (BK; 0.5 nmol/site) or histamine (4.5 nmol/site) when co-injected with the inflammatory mediators. D-NAME (0.1 mumol/site) had no significant effect. 3. L-NAME (0.01-0.1 mumol/site) appeared to produce greater shifts of the dose-response curve to BK (0.1-3 nmol/site) than of that to histamine (2.3-27 nmol/site). Both 0.01 and 0.1 mumol L-NAME/site significantly reduced the response to BK (0.5 nmol/site) whereas only the higher dose of L-NAME produced a significant reduction in the response to histamine (4.5 nmol/site). 4. The inhibitory effect of L-NAME (0.1 mumol/site) on the response to BK but not on that to histamine was significantly reversed by L-arginine (L-Arg; 10 mumol/site). D-arginine (D-Arg; 10 mumol/site) had no significant effect in either case. 5. L-Arg (10 mumol/site) significantly enhanced the response to BK but inhibited that to histamine. D-Arg (10 mumol/site) had no significant effect on BK but significantly inhibited histamine. L-Lysine (L-Lys: 10 mumol/site) had no significant effect on the response to either BK or histamine. 6. L-Arg (100 mM) had a significant inhibitory effect on isometric contractions to histamine, but not BK in guinea-pig ileum in vitro. D-Arg (100 mM) also significantly inhibited histamine responses whereas L-Lys (100 mM) had no effect. 7. The alpha-adrenoceptor agonist, phenylephrine (0.3 or 6 nmol/site) inhibited matched responses to BK (0.5 nmol/site) or histamine (5.4 nmol/site) to comparable degrees, but gave significant inhibition only at the higher dose. 8. The Beta-adrenoceptor agonist, isoprenaline (0.5 or 10 nmol/site) had a significant inhibitory effect on the response to histamine (5.4 nmol/site) whereas a comparable response to BK (0.5 nmol/site) was significantly reduced by the higher dose only.9. Our results with L-NAME suggest that local production of NO is involved in the modulation of mediator-induced vascular permeability. It is possible that NO may play a greater role in the extravasation response to BK than to that induced by histamine.10. The differential effects of L-NAME and isoprenaline on BK- and histamine-induced PPE raise the possibility that BK and histamine may induce vascular permeability via different mechanisms in guinea-pig skin.
Animals↗
Abnormal growth regulation of vascular smooth muscle cells by heparin in patients with restenosis.
Proliferation of vascular smooth muscle cells (VSMC) underlies myointimal hyperplasia, which can lead to restenosis after angioplasty and vascular surgery. We propose that some individuals have an intrinsic capacity for this exaggerated response to vascular injury, partly through decreased sensitivity to the physiological growth inhibitor heparin. We investigated the effect of heparin on VSMC from restenotic lesions and from apparently normal vessels of the same patients, and VSMC from control patients undergoing primary bypass procedures. Cells from patients with restenosis (both restenotic lesion and undiseased vein) showed much lower sensitivity to growth inhibition by heparin than the controls (median inhibition 8 [95% Cl -2 to 25] vs 22 [15-44]%, p < 0.001); this finding suggests aberrant growth regulation in these cells.
Arterial Occlusive Diseases↗
Cellular biology of human intimal hyperplastic stenosis.
Restenosis after angioplasty and vascular surgery remains a major unsolved clinical problem. Vascular smooth muscle cell (VSMC) hyperplasia is an invariable response, but in 20-50% of cases proceeds to compromise the vessel lumen. We sought to identify cellular characteristics of human VSMC which are associated with restenosis. Human VSMC were grown from 135 samples of vascular tissue derived from patients undergoing primary cardiovascular surgery and revision surgery for restenosis. Cells derived from normal vein and artery, atherosclerotic plaques and from stenotic lesions were studied for successful proliferation in cell culture. Furthermore, growth rates were measured in response to 15% foetal calf serum +/- inhibition with heparin (100 micrograms/ml). Significantly fewer cells from atherosclerotic plaques progress to the third passage in cell culture than those derived from stenoses and controls (p < 0.001, Chi square) and growth rates after the third passage could not be studied in these cells. Of cells that progress to this stage, growth rates do not differ between stenosis-derived and normal cells under standard conditions. VSMC from mature atherosclerotic plaques may have undergone senescent changes. Stenosis-derived cells do not grow more rapidly than normal cells, but are significantly less sensitive to heparin (p < 0.001, Mann-Witney test), which is a major physiological inhibitor of VSMC growth. Differences in biological characteristics of human VSMC, observed in cell culture, may provide important insights into human vascular disease.
Actins↗
Inhibition of pancreatic cancer cell growth in vitro by the tyrphostin group of tyrosine kinase inhibitors.
Tyrphostins are a group of low molecular weight synthetic inhibitors of protein tyrosine kinases (PTK). The intracellular domains of the receptors for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), insulin-like growth factor 1 (IGF-1) possess PTK activity. Since EGF, TGF-alpha and IGF-1 are considered to play an important role in the proliferation of pancreatic cancer cells, we studied the effects of tyrphostins on the growth of three human pancreatic cancer cell lines (MiaPaCa-2, Panc-1 and CAV). The tyrphostins AG17, T23 and T47 all inhibited EGF and serum-stimulated DNA synthesis. AG17 was found to be the most potent of these agents and caused a dose-dependent but reversible inhibition of cell growth. Furthermore using an immunoblotting procedure we also found AG17 to inhibit EGF-induced tyrosine phosphorylation in the MiaPaCa-2 cell line. Tyrosine kinase inhibitors may prove to be useful agents for the treatment of pancreatic cancer.
Catechols↗
Effect of oxidants on vascular smooth muscle proliferation.
Explore the source record for details and available documents.
Animals↗
Competition between atomic and molecular Auger decays: Study of the resonant Auger decay of HBr after the Br 3d--> sigma * transition.
Explore the source record for details and available documents.
Journal Article↗
Isolated tubal torsion: clinical and ultrasonographic correlation.
Explore the source record for details and available documents.
Adolescent↗
Ion channel involvement in the acute vascular effects of thiazide diuretics and related compounds.
The involvement of calcium and potassium channels in mediating the vascular actions of hydrochlorothiazide, indapamide and cicletanine were investigated in guinea pig small vessels mounted on the Mulvany myograph. Hydrochlorothiazide (10 microM) and cicletanine (10 microM) were weak calcium antagonists shifting the calcium dose-response curve half a log unit to the right. Indapamide was a far more potent inhibitor, a 10 microM concentration shifting the calcium dose-response curve 3 log units to the right and reducing maximal calcium contraction by 72% (P < .001). Relaxations to hydrochlorothiazide and cicletanine were reduced in the presence of charybdotoxin, a blocker of calcium-activated potassium channels (KCa). Maximal relaxation induced by hydrochlorothiazide (30 microM) was reduced by 91% and cicletanine-induced relaxation by 63%. In the presence of iberiotoxin, a more selective KCa inhibitor, maximal hydrochlorothiazide and cicletanine-induced relaxations were reduced by 73 and 60%, respectively. Neither drug's action was affected by incubation with glibenclamide, which inhibits ATP-sensitive K+ channels. Incubation with glibenclamide, charybdotoxin or iberiotoxin had no effect on the indapamide-induced relaxation. These results show differences in the involvement of ion channels in the acute vasorelaxation produced by these drugs. Hydrochlorothiazide and cicletanine-induced relaxations appear to be mediated via KCa, whereas indapamide is a potent calcium antagonist.
Animals↗
Tyrosine kinase inhibitors block calcium channel currents in vascular smooth muscle cells.
Selective inhibitors of tyrosine kinases, tyrphostin 23 and genistein, produced concentration-dependent inhibition of voltage-operated calcium channel currents in vascular smooth muscle cells isolated from rabbit ear artery. The potency of these two structurally dissimilar inhibitors was similar to that reported for their action as inhibitors of tyrosine kinases. Daidzein, an inactive analogue of genistein, had little inhibitory effect on calcium channel currents at concentrations below 300 microM consistent with an action of these agents at a tyrosine kinase. However, tyrphostin 1, a reportedly less active tyrphostin derivative, also inhibited calcium channel currents with a potency similar to tyrphostin 23. These findings suggest that voltage-operated calcium channels in vascular smooth muscle may be modulated by endogenous tyrosine kinase(s) which display different sensitivities to inhibitors compared with the epidermal growth factor (EGF) receptor. Alternatively the possibility of direct blocking actions of these inhibitors at voltage-operated calcium channels cannot be excluded.
Animals↗
Direct vascular actions of hydrochlorothiazide and indapamide in isolated small vessels.
The mechanism by which thiazides lower peripheral resistance is unresolved. The aim of this study was to investigate the mechanisms of the acute vasodilator action of hydrochlorothiazide and the 'thiazide-like' diuretic indapamide on human, guinea pig and rat small arteries. Vessels were mounted on a myograph and the relaxation profile of both drugs and interactions with K+ channels and the vascular eicosanoid system were studied. Neither drug had any relaxant effect in rat mesenteric vessels and indapamide did not relax human arteries. Hydrochlorothiazide in both human and guinea pig vessels produced significantly more relaxation of noradrenaline than K(+)-constricted vessels (P less than 0.001). Relaxation to hydrochlorothiazide was reduced in the presence of charybdotoxin. Maximal-induced hydrochlorothiazide relaxation was reduced by 64% in human arteries (P less than 0.001) and by 91% in guinea pig vessels (P less than 0.001). Incubation with glibenclamide and indomethacin had no effect on the relaxant activity of hydrochlorothiazide and indapamide. Indapamide-induced relaxation was unaffected in the presence of charybdotoxin. These results show marked differences in the acute vasodilator action of hydrochlorothiazide and indapamide. There appears to be involvement of Ca(2+)-activated K+ channels in the acute vasorelaxant activity of hydrochlorothiazide.
Animals↗