Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are many reports on the efficacy of Ca-antagonists for treatment of elderly essential hypertension. In particular, many studies have noted the beneficial effects of antihypertensive therapy on the quality of life (QOL). Nevertheless, there are no reports on antihypertensive therapy regarding the relationship between brain blood flow (BBF) and QOL. Therefore, we examined the efficacy of nitrendipine, a Ca-antagonist, on the brain blood flow and QOL, and its side effects in elderly essential hypertensive patients. The subjects were 17 (males: 4, females: 13) patients with untreated hypertension of WHO stage I or II, aged 70 years or older. The mean dose of nitrendipine was 9.4 +/- 0.4 mg daily. Before and 6 months after treatment, we examined blood pressure (BP), heart rate (HR), echocardiography (left ventricular mass index [LVMI], % fractional shortening [% FS]), plasma noradrenaline (Nad), plasma renin activity (PRA), BBF using the IMP-ARG method with BBF scintigraphy, and QOL was examined with a questionnaire. Two patients were excluded from this study because 1 had no decrease in BP, and another was moved to a different hospital. BP significantly decreased from 178/93 to 137/77 mmHg, but HR was not changed after treatment. BBF significantly increased from 37.0 +/- 4.9 to 41.0 +/- 4.9 ml/dl/min, but % FS, Nad, and PRA did not significantly change. The degree of QOL was improved by 4.2 +/- 1.2 points and there was a significant positive correlation between the changes of BBF and of QOL (r = 0.66, p = 0.04). However, moderate pharmacotherapy for BP seems to be necessary because there were 2 patients whose BBF decreased accompanied by excessive drop in BP after treatment. In conclusion, it is possible to safely use nitrendipine for elderly essential hypertensive patients. Nitrendipine has beneficial effects on BBF, and it was suggested that the increase of BBF is one of the most important factors in improvement of QOL.
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PMID:[Usefulness of nitrendipine and its effects on quality of life and brain blood flow in elderly hypertensive patients]. 1091 29

Non-neuronal monoamine transporters OCT1, OCT2, and EMT, which are all members of the amphiphilic solute facilitator family, control signal transmission by removing released transmitters, such as dopamine, noradrenaline, adrenaline, 5-hydroxytryptamine, and histamine, from the extracellular space. In the current study, we have isolated human EMT (gene symbol SLC22A3) and OCT2 (SLC22A2) genes and report the gene and promoter organization. Both genes consist of 11 coding exons, with consensus GT/AG splice sites and conserved intron locations. The EMT gene is 77 kb, and the OCT2 gene is 45 kb in size. For the EMT gene, two transcription start points were identified by inverse polymerase chain reaction based on mRNA from Caki-1 cells. The EMT promoter, located within a CpG island, lacks a consensus TATA box but contains a prototypical initiator element and a number of potential binding sites for ubiquitous transcription factors Sp1 and NF-1. In contrast, the OCT2 promoter is not associated with a CpG island, contains a putative TATA box, and potential binding sites for specific transcription factors, such as HFH-8 and IK2. Since EMT and OCT2 may play important roles in catecholamine homeostasis and, as such, are candidate genes in human disease, the present results provide a basis for the analysis of genetic variation and the regulation of transcription.
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PMID:Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. 1094 11

Recent studies have shown that maternal hyperinsulinaemia is a risk factor for the development of hypertension in pregnancy. Experimentally, pregnant rats with chronic exogenously induced hyperinsulinaemia (P-INS rats) have increased blood pressure at the end of gestation. This is associated with a blunted elevation of the excretion of the urinary metabolites of nitrate (UNO(x)). In the present study, we aimed to evaluate the mechanism(s) of the increase in blood pressure in this model. Four groups were studied: normal pregnant rats (P rats), P-INS rats, P-INS rats treated with L-arginine (2 g/l in the drinking water) (L-ARG rats) and hyperinsulinaemic virgin rats (V-INS rats). Systolic blood pressure (SBP), UNO(x) excretion (on ingestion of a controlled low-nitrate diet), urine noradrenaline (norepinephrine) and plasma endothelin levels were evaluated. Rats were killed on day 22 of pregnancy. Five P-INS rats were not killed at this time, in order to measure SBP 30 and 60 days after delivery. Fetal number and fetal body weight were evaluated. At the end of pregnancy, a 10+/-3% increase in SBP was found in P-INS rats, contrasting with a fall of -15+/-4% in P rats (P<0.01). In the L-ARG group at the end of pregnancy, SBP values had fallen by -14+/-2%, to values comparable with those of P rats. The increase in UNO(x) excretion was 175+/-38% in P rats, 106+/-12% in L-ARG rats and 41+/-8% in P-INS rats (P<0.01 compared with P and L-ARG groups). No differences were found in the urinary excretion of noradrenaline or in the plasma levels of endothelin-1 between the pregnant groups. Fetal number was similar in all groups, but fetal body weight was lower for P-INS rats compared with P and L-ARG rats. Thus the blood pressure response to L-arginine strongly suggests that a decrease in NO availability may be the main pathogenic mechanism involved in the development of hypertension in this model.
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PMID:Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine. 1135 84

Two uptake systems that control the extracellular concentrations of released monoamine neurotransmitters such as noradrenaline and adrenaline have been described. Uptake-1 is present at presynaptic nerve endings, whereas uptake-2 is extraneuronal and has been identified in myocardium and vascular and nonvascular smooth muscle cells. The gene encoding the uptake-2 transporter has recently been identified in humans (EMT), rats (OCT3), and mice (Orct3/Slc22a3). To generate an in vivo model for uptake-2, we have inactivated the mouse Orct3 gene. Homozygous mutant mice are viable and fertile with no obvious physiological defect and also show no significant imbalance of noradrenaline or dopamine. However, Orct3-null mice show an impaired uptake-2 activity as measured by accumulation of intravenously administered [(3)H]MPP(+) (1-methyl-4-phenylpyridinium). A 72% reduction in MPP(+) levels was measured in hearts of both male and female Orct3 mutant mice. No significant differences between wild-type and mutant mice were found in any other adult organ or in plasma. When [(3)H]MPP(+) was injected into pregnant females, a threefold-reduced MPP(+) accumulation was observed in homozygous mutant embryos but not in their placentas or amniotic fluid. These data show that Orct3 is the principal component for uptake-2 function in the adult heart and identify the placenta as a novel site of action of uptake-2 that acts at the fetoplacental interface.
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PMID:Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. 1139 Jun 48

1. The extraneuronal monoamine transporter from rat (EMTr) was heterologously expressed by stable transfection in human embryonic kidney 293 cells and characterized in radiotracer experiments. 2. EMTr-mediated uptake of 1-methyl-4-phenylpyridinium (MPP(+)) was saturable, with a K(m) of 151 micro mol l(-1) and V(max) of 7.5 nmol min(-1) mg protein(-1). 3. Compared to the human orthologue EMTh (gene symbol SLC22A3), EMTr was about two orders of magnitude more resistant to most inhibitors, including disprocynium24 and corticosterone. 4. Strikingly, inhibitors and substrates at low concentration stimulated EMTr-mediated transport above control level with MPP(+) and noradrenaline as substrate, but not with cimetidine. Results were confirmed with EMT from mouse. 5. With different IC(50)-values for different substrates, the standard method to calculate K(i)-values is not applicable. 6. Our experiments suggest that activation is not caused by changes in membrane potential or trans-stimulation. Since the extent of activation depends markedly on the chemical structure of the monitored substrate, involvement of a receptor-mediated signalling pathway or recruitment of transporter reserve are implausible. 7. To explain activation, we present a kinetic model which assumes two binding sites for substrate or inhibitor per transporter entity, possibly resulting from the assembly of homodimers. 8. Activation explains previous reports about inhibitor-insensitive catecholamine transport in rat brain. 9. We speculate that activation may serve to keep the transporter working for specific substrates in the face of inhibitors.
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PMID:Activation of the extraneuronal monoamine transporter (EMT) from rat expressed in 293 cells. 1241 23

The quinazoline family of alpha1-blockers (prazosin, doxazosin, and terazosin) induce apoptosis of prostate cells through an alpha1-adrenoceptor-independent mechanism. The objective of this study was to gain insight into the non-adrenergic, apoptotic mechanism of action of doxazosin in the prostate and the induction of anoikis by doxazosin. Primary cultures of benign prostate stromal and epithelial cells and the LNCaP (androgen sensitive) and PC-3 (androgen insensitive) prostate carcinoma cell lines were treated with doxazosin (0-50 microM). The effects of doxazosin on cell morphology, caspase-3 activity, and the expression levels of focal adhesion kinase (FAK) and integrin-linked kinase (ILK) were examined. Doxazosin induced changes in morphology consistent with anoikis in both benign and cancerous prostatic cells and increased caspase-3 activity. The effects were similar comparing benign cells (which express alpha1-adrenoceptors) and cancer cells (which do not express alpha1-adrenoceptors), but were more robust in benign cells. Norepinephrine had no effect on doxazosin-induced cell morphology or caspase-3 activity. Treatment of PC-3 cells with doxazosin significantly reduced the protein levels of FAK but did not significantly affect the levels of ILK. These findings suggest that doxazosin induces apoptosis and anoikis of prostate cancer cells by a mechanism of action that is alpha1-adrenoceptor independent. The apoptosis of cancer cells induced by doxazosin counteracts cell proliferation and may have the potential of retarding or reversing prostate cancer cell growth.
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PMID:Induction of anoikis by doxazosin in prostate cancer cells is associated with activation of caspase-3 and a reduction of focal adhesion kinase. 1522 Dec 43

Dynamic remodeling of the actin cytoskeleton occurs during agonist-induced smooth muscle contraction. Tyrosine phosphorylation of the adaptor protein paxillin has been implicated in regulation of actin filament formation and force development. We have investigated the role of the actin cytoskeleton in noradrenaline (NA)-induced and endothelin (ET)-induced activation of the calcium-dependent nonreceptor tyrosine kinase PYK2 and subsequent phosphorylation of paxillin in rat small mesenteric arteries. NA and ET induced a rapid and prolonged activation of PYK2, as shown by increased phosphorylation at Y402 and Y881, and a concomitant association of the kinase with a Triton X-100 insoluble membrane (cytoskeleton) compartment. Both agonists also increased phosphorylation of paxillin at Y31 and Y118 with a similar time course as PYK2 phosphorylation, and induced its association with the same membrane compartment as PYK2. Treatment of arteries with cytochalasin D disrupted stress fibers and inhibited NA-induced and ET-induced force in a myosin light chain 20 phosphorylation independent and reversible manner. However, cytochalasin D treatment had no effect on NA-induced and ET-induced phosphorylation of either PYK2 or paxillin but did prevent their association with the TritonX-100 insoluble membrane compartment. These results show that in mesenteric arteries an intact cytoskeleton and force development are not prerequisites for G-protein--coupled receptor--induced activation of PYK2 and paxillin, by tyrosine phosphorylation, in vascular tissue, but are necessary for the translocation of PYK2 and paxillin to the membrane.
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PMID:Role of the actin cytoskeleton in G-protein-coupled receptor activation of PYK2 and paxillin in vascular smooth muscle. 1591 46

The non-neuronal monoamine transporters OCT1, OCT2 and EMT (human gene symbols SLC22A1-A3) efficiently transport a number of positively-charged monoamines and some small organic cations across the plasma membrane, and thus are implicated in the inactivation of released monoamine transmitters (e.g. noradrenaline, histamine, agmatine) in vivo. Although prostaglandins are full anions at physiological pH, data from a recent publication suggest efficient transport of the prostaglandins PGE2 and PGF2alpha by OCT1 and OCT2. In the present study we have reexamined transport of PGE2 by OCT2 from human (OCT2h). Uptake of substrate into monolayers of 293 cells, stably transfected to express OCT2h, was compared to uptake into non-transfected control cells. Efficiency of transport of the established substrate 3H-1-methyl-4-phenylpyridinium (MPP+), expressed as clearance, was high at 81 microl min(-1) mg protein(-1) on average. By contrast, uptake of 3H-PGE2 was virtually identical for control cells and OCT2h cells. The efficiency of transport was 0.1+/-0.6, 1.0+/-0.3, and 0.7+/-0.4 microl min(-1) mg protein(-1) for cell lysis with methanol, HClO4, and Triton X-100 respectively. Similar results were obtained with unlabeled MPP+ (192+/-12 microl min(-1) mg protein(-1)) and PGE2 (0.3+/-0.1 microl min(-1) mg protein(-1)) in LC-MS/MS analysis. We conclude that OCT2h is not capable of transporting prostaglandins. The data from the previous report may represent binding rather than transport. Our comparison of transport efficiencies confirms the notion that relevant substrates of OCT1, OCT2, and EMT must carry a positive charge.
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PMID:Are organic cation transporters capable of transporting prostaglandins? 1621 6

Electrical field stimulation (EFS) produced a biphasic contractile response; viz. initial rapid phasic contraction and second slow tonic contraction, in isolated guinea pig vas deferens. Pretreatment with the substrate of nitric oxide (NO) synthase (NOS), 1 mM L-arginine (L-ARG), augmented both the initial rapid and the second slow contractile responses to EFS (5 Hz, 0.5 msec, 30 V, for 30 sec). The increase of stimulation frequency from 5 Hz to 10 Hz or 20 Hz tended to attenuate the augmented responses. On the contrary, pretreatment with an inhibitor of NOS, 0.1 mM NG-nitro-L-arginine (L-NNA) suppressed both the initial rapid and the second slow contractile responses to EFS. The suppressive effect on the initial rapid contraction was also attenuated by the increase of stimulation frequency from 5 Hz or 10 Hz to 20 Hz. Contractile response to exogenously administered 1 mM adenosine triphosphate (ATP) tended to be slightly increased and decreased by the treatment with 1 mM L-ARG and 0.1 mM L-NNA, respectively. Contractile response to exogenously administered 10 microM noradrenaline (NA) was almost unaffected by the treatment with 1 mM L-ARG, while the treatment with 0.1 mM L-NNA slightly depressed the response. Potentiated contractile response to 1 mM ATP in the presence of 10 microM NA was further potentiated by the treatment with 1 mM L-ARG, while the response was almost unaffected by the treatment with 0.1 mM L-NNA. These findings may indicate that NO acts mainly on presynaptic site and increases the release of chemical transmitter, ATP or prevents the inactivation of ATP. Also, NO may act, at least in part, on postsynaptic site and potentiates the contractile response to ATP in the presence of NA.
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PMID:Nitric oxide modulates biphasic contractile response of guinea pig vas deferens to electrical field stimulation. 1742 55

Central angiotensin II plays a critical role in the regulation of cardiovascular function and autonomic activity, in part, via angiotensin type 1 receptors in the rostral ventrolateral medulla (RVLM). Increasing evidence indicates that angiotensin II can also act on angiotensin type 2 receptors (AT(2)Rs) to exert antagonistic effects. In the current study we determined the effects of overexpression of AT(2)R in the RVLM on sodium and water excretion and on blood pressure in conscious rats. The overexpression of AT(2)R was induced by bilateral microinjection of the AT(2)R adenovirus (Ad5-SYN-AT2R-IRES-EGFP, 2.5 x 10(6) infection units in 0.5 microL; Ad5-SYN-EGFP as the control, 2.5 x 10(6) infection units in 0.5 microL) into the RVLM of rats. Immunofluorescence staining showed that microinjection of AT(2)R adenovirus into the RVLM evoked local overexpression. Significant overexpression of AT(2)R in the RVLM began at 24 hours and was sustained up to 12 days after microinjection. Overexpression of AT(2)R in the RVLM significantly decreased the nocturnal arterial blood pressure and increased the 24-hour urine excretion at days 2, 3, and 4 after gene delivery compared with the control rats. These alterations were abolished by the microinfusion of captopril into the RVLM and were enhanced by angiotensin II infusion. Overexpression of AT(2)R in the RVLM also significantly decreased the urine concentration of noradrenaline and 24-hour noradrenaline excretion (1.1+/-0.5 microg in control rats and 2.4+/-0.5 microg in AT(2)R rats; P<0.05). These results suggest that overexpression of AT(2)R in the RVLM induced a diuresis that may be mediated, in part, by sympathoinhibition.
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PMID:Effects of angiotensin type 2 receptor overexpression in the rostral ventrolateral medulla on blood pressure and urine excretion in normal rats. 1808 51


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