Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrphostins are low-molecular-weight synthetic inhibitors of protein tyrosine kinase, which block cell proliferation. Since platelet-derived growth factor (PDGF) is thought to figure prominently in disorders of vascular smooth muscle cells (VSMC), such as atherosclerosis, hypertension, and restenosis, we examined whether tyrphostins would inhibit PDGF-induced mitogenesis in VSMC. In this communication, we demonstrate that tyrphostins with the benzenemalononitrile nucleus inhibited PDGF-dependent growth of VSMC as well as PDGF-dependent DNA synthesis in these cells, with the concentrations for 50% inhibition ranging from 0.04 to 9 microM. Up to 30-fold higher tyrphostin concentrations were required to inhibit serum-stimulated DNA synthesis of VSMC. The effect of the tyrphostins is reversible, since on their removal a normal proliferative response to PDGF was resumed. Tyrphostins also inhibited PDGF-receptor autophosphorylation and PDGF-induced phosphorylation of intracellular substrates, including the phosphorylation of phospholipase C-gamma, with a potency ratio similar to their antimitogenic activity. The expression of c-fos mRNA, a mitogenic nuclear signal, was also reduced in PDGF-stimulated VSMC treated with tyrphostins at concentrations which inhibit PDGF-induced mitogenesis. It is concluded that tyrphostins are potent reversible inhibitors of PDGF-induced mitogenesis which act by inhibiting the tyrosine kinase activity of the PDGF receptor and the subsequent signaling cascade. Tyrphostins may be useful in the study and treatment of VSMC proliferation disorders.
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PMID:Tyrphostins inhibit PDGF-induced DNA synthesis and associated early events in smooth muscle cells. 185 Jan 95

Insulin regulates cellular metabolic reactions by its action on the plasma membrane, intracellular enzymes and the nucleus. The first stage in the propagation of the insulin signal is the coupling of insulin to specific receptors at the cell surface. The exact mechanism whereby the transmembrane signalling mechanism (s) results in different insulin-mediated cellular effects is not known. However, the insulin receptor tyrosine kinase, the expression of second messengers, and the action of protein kinase C may, either individually or in combination, mediate some of the insulin effects, such as translocation and activation of glucose transporter proteins. Insulin resistance in clinical conditions such as insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), hypertension and obesity may be acquired to a large extent, and is thus partially reversible. Regulatory factors in insulin sensitivity, such as free fatty acids, counterregulatory hormones and blood glucose level, play an important role in the metabolic control and pathogenesis of insulin resistance in man.
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PMID:Regulation of insulin action at the cellular level. 204 21

Several ion fluxes are stimulated when mitogenic polypeptides are added to cells. The precise mechanism by which this activation takes place is not understood, but compelling evidence exists in the case of the activation of sodium-hydrogen exchange that it requires the tyrosine kinase activity associated with the mitogen receptor. The activation of sodium-hydrogen exchange by mitogens is associated with changes in intracellular pH that appear to be permissive but not causal in allowing cells to proceed through the cell cycle. When added to cells, mitogens also activate protein kinase C, which acts as part of a feedback loop to control the activity of the mitogen receptor. Possible mechanisms for this control are discussed.
Hypertension 1987 Nov
PMID:Control of ion fluxes by mitogenic polypeptides. 244 80

Insulin might play a role in the hypertension occurring in insulin-resistant diabetes. In addition, insulin has recently been shown to potentiate norepinephrine (NE) induced vascular tone. We used ring segments of the rabbit facial artery mounted in a myograph to test the hypothesis that potentiation of NE-induced tone by insulin may be related to activation of protein kinase C (PKC) and tyrosine kinase (TK). NE-induced contractions in the presence of insulin (1 mU/mL) were 200% (NE 0.1 and 0.3 microM), 252% (NE 1 microM), and 129% (NE 3 microM) of control. Insulin (1 mU/mL) had no effect on NE (10 and 100 microM) induced contractions. The potentiation by insulin of NE-induced tone was not altered by endothelium removal and could be mimicked by phorbol-12-myristate-13-acetate (PMA, 0.1 microM). Histamine-induced contractions were not altered by insulin (1 mU/mL). Insulin potentiation of NE-induced tone was suppressed by pretreatment of the rabbit facial artery with the PKC inhibitor calphostin C (0.1 microM) or the TK inhibitor genistein (10 microM). 45Ca2+ influx due to NE (3 microM) did not change in the presence of insulin (1 mU/mL) or PMA (0.1 microM) despite a higher contractile response, so that wall force per unit of 45Ca2+ influx was increased by insulin (1 mU/mL) and PMA (0.1 microM). Calphostin C (0.1 microM) and genistein (10 microM) both prevented the increase in wall force per unit of 45Ca2+ influx due to insulin (1 mU/mL). Our study shows that insulin potentiates NE-induced tone through a TK- and PKC-dependent mechanism.
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PMID:Insulin potentiates norepinephrine-induced vascular tone by activation of protein kinase C and tyrosine kinase. 753 May 92

The goal of this study was to determine the role of tyrosine phosphorylation in transducing deformation-stimulated vascular smooth muscle growth. Rat aorta-derived vascular smooth muscle cells were cultured on flexible silicone elastomer membranes and subjected to cyclic deformation (15 cycles per minute, deformed 2 seconds, relaxed 2 seconds). Deformation significantly increased proto-oncogene expression, [3H]thymidine incorporation, [3H]leucine incorporation, and cell number. Time course studies showed an 8-hour lag between initiation of cell deformation and onset of [3H]thymidine incorporation, with peak levels achieved after 18 to 24 hours. Western analysis of protein blots from deformed cells (10 minutes) demonstrated increased levels of phosphotyrosine-containing proteins having molecular weights of 110 to 130 and 70 to 80 kD. Deformation-stimulated tyrosine phosphorylation was prevented by the tyrosine kinase inhibitor Herbimycin A. Tyrosine kinase inhibition also prevented deformation-stimulated vascular smooth muscle cell growth as measured by [3H]thymidine incorporation. Cyclic deformation stimulates vascular smooth muscle proliferation through activation of tyrosine kinases. Inhibition of tyrosine phosphorylation is an effective means of preventing deformation-induced vascular smooth muscle growth in vitro.
Hypertension 1994 Dec
PMID:Tyrosine kinase inhibition prevents deformation-stimulated vascular smooth muscle growth. 799 27

In previous studies, we related increased elastolytic activity in pulmonary arteries (PA) with endothelial injury to the later development of PA hypertension in rats. As the mechanism causing the increased PA elastase was unknown, we hypothesized that serum factors which are accessible to vascular smooth muscle cells (SMC) following endothelial injury stimulate their elastolytic activity. To test this, we developed an in vitro assay in which we added [3H]-elastin to cultured vascular SMC after 24 h serum starvation and monitored elastolysis following a further 24 h incubation with fetal bovine serum (FBS). We observed that serum induced increased elastolytic activity in both PA and aorta-derived SMC but not in endothelial cells or SMC with low basal levels of elastolytic activity. Maximum stimulation of SMC elastolytic activity occurred with a concentration as low as 1% FBS and despite elastase inhibitors in serum, suggesting that the activity is confined to the immediate pericellular region where enzyme concentration is high. Serum-stimulated elastolytic activity was not reproduced by growth factors or cytokines known to be associated with vascular disease or to induce release of elastases in other cells. The serum inducing elastolytic activity was heat and acid labile. It was associated with increased elastin adhesion to the 67 kD elastin binding protein on SMC surfaces and was prevented by tyrosine kinase inhibitors but not protein kinase C or A inhibitors. Our studies therefore suggest a mechanism whereby serum induction of SMC elastase requires signalling through the elastin binding protein and activation of tyrosine kinase.
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PMID:Serum-induced vascular smooth muscle cell elastolytic activity through tyrosine kinase intracellular signalling. 802 Dec 92

The mechanisms of vascular structural alterations in hypertension were studied in cultured adventitial fibroblasts isolated from aortas of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Basic fibroblast growth factor (bFGF)-, epidermal growth factor (EGF)-, or platelet-derived growth factor (PDGF)-induced DNA synthesis and phospholipase C activity were estimated by determining 3H-thymidine incorporation and 3H-inositol phosphate production, respectively. The role of protein tyrosine kinases was assessed by stimulating the cells in the presence of tyrphostin, a protein tyrosine kinase inhibitor. Both the mitogenic potency of bFGF, EGF, and PDGF and the phospholipase C activity elicited by these factors were increased markedly in SHR (v WKY) fibroblasts. SHR fibroblasts were significantly less sensitive to tyrphostin inhibition of bFGF-induced 3H-thymidine incorporation than WKY fibroblasts, whereas when the cells were stimulated with EGF, PDGF, or 5% serum, SHR and WKY fibroblasts were equally sensitive to tyrphostin inhibition. At doses that abolished bFGF-induced 3H-thymidine incorporation, tyrphostin did not affect bFGF-induced 3H-inositol phosphate production. These results indicate that in aortic fibroblasts phospholipase C activation is not sufficient for bFGF-induced DNA synthesis. They suggest that tyrosine kinase activation is a necessary step in the transduction of bFGF mitogenic signal and plays an important role in the enhanced DNA synthesis exhibited by SHR (v WKY) cells. Therefore, one may envisage that bFGF contributes, through paracrine/autocrine mechanisms, to the vascular smooth muscle hyperplasia/hypertrophy in SHR.
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PMID:Signaling mechanisms of basic fibroblast growth factor in arterial cells from genetically hypertensive rat. 803 51

High blood pressure is one of the major risk factors for atherosclerosis. In this study, we examined the effects of pressure on cell proliferation and DNA synthesis in cultured rat vascular smooth muscle cells. Pressure without shear stress and stretch promotes cell proliferation and DNA synthesis in a pressure-dependent manner. Pressure-induced DNA synthesis was inhibited significantly by the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, the protein kinase C inhibitor H-7, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine, staurosporine, and the tyrosine kinase inhibitor ([3,4,5-trihydroxyphenyl]methylene)propanedinitrile. To clarify whether activation of PLC and calcium mobilization are involved in pressure-induced DNA synthesis, production of 1,4,5-inositol trisphosphate (IP3) and intracellular Ca2+ was measured. Pure pressure increased IP3 and intracellular Ca2+ in a pressure-dependent manner. The increases in both IP3 and intracellular Ca2+ were inhibited significantly by 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate. This study demonstrates a novel cellular mechanism whereby pressure regulates DNA synthesis in vascular smooth muscle cells, possibly via activation of PLC and protein kinase C.
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PMID:Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. 818 28

Intracellular calcium may be a mediator of insulin action in vascular smooth muscle cells. This study investigates effects of physiological concentrations of insulin on intracellular free calcium concentrations in primary unpassaged vascular smooth muscle cells derived from 3- and 17-week-old normotensive rats (Wistar and Wistar-Kyoto) and spontaneously, hypertensive rats (SHR). Underlying mechanisms responsible for insulin-evoked calcium responses were also studied. Basal calcium was significantly higher in 17-week SHR cells (134 +/- 8 nmol/L) compared with cells from Wistar-Kyoto (98 +/- 12 nmol/L) and Wistar (99 +/- 10 nmol/L) rats. Insulin (70 microU/mL) significantly increased calcium in all cells. Responses from 3-week rat cells were similar. The increase was amplified in 17-week SHR cells (177 +/- 7 nmol/L) compared with Wistar-Kyoto (130 +/- 14 nmol/L) and Wistar (132 +/- 16 nmol/L) cells. Genistein (0.1 mumol/L) and tyrphostin 23 (0.1 mumol/L) (tyrosine kinase inhibitors) completely abolished insulin-induced calcium effects. Stimulatory effects of insulin were significantly inhibited by 0.1 mumol/L diltiazem, staurosporine, calphostin C, and thapsigargin. The inhibitory effects of diltiazem (calcium channel antagonist) and the protein kinase C inhibitors staurosporine and calphostin C were significantly lower in cells from hypertensive compared with those from normotensive rats. Calcium recovery after insulin administration was delayed in SHR cells. In conclusion, insulin increases vascular smooth muscle cell calcium concentrations, possibly via calcium channel activation, protein kinase C-mediated mechanisms, and intracellular calcium mobilization. Alterations of these pathways as well as impaired calcium recovery to baseline may be associated with increased insulin-sensitive calcium responses in cells from SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Jun
PMID:Insulin-induced Ca2+ transport is altered in vascular smooth muscle cells of spontaneously hypertensive rats. 820 30

Epidermal growth factor (EGF) is not only a cell mitogen but a potent vasoconstrictor that shares many properties with angiotensin II. Because EGF is localized in the kidney, we have studied the direct effects of EGF on renin secretion using both static incubations and perifusions of rat renal cortical slices. EGF at 5 x 10(-9) M significantly inhibited renin secretion in static incubations (control, 100 +/- 3%; EGF, 72 +/- 3%; p < 0.001). When added to perifusions, EGF acted rapidly, reducing renin secretion at the earliest time period (10 minutes). Similarly, transforming growth factor-alpha, which can bind to the EGF receptor, also inhibited renin secretion (control, 92 +/- 8%; transforming growth factor-alpha [2 x 10(-9) M], 63 +/- 4%; p < 0.02). Because both prostaglandins and lipoxygenase products of arachidonic acid have been shown to play a role in some EGF-mediated actions, we examined these possible mechanisms of EGF action. Meclofenamate, a cyclooxygenase blocker, and BW755c and baicalein, both lipoxygenase blockers, were studied. None of these agents altered EGF-mediated renin inhibition. EGF action has also been coupled to the stimulation of tyrosine kinase activity; therefore, we examined the effects of the tyrosine kinase inhibitors genistein and quercetin. Both genistein (10(-5) M) and quercetin (10(-5) M) abolished the inhibition of renin by EGF (control, 100 +/- 3%; EGF, 82 +/- 4%; EGF plus genistein, 110 +/- 7%; p < 0.01; EGF, 75 +/- 4%; EGF plus quercetin, 92 +/- 4%; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 May
PMID:Epidermal growth factor is a potent inhibitor of renin secretion. 849


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