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Biomedical subjects

C Chen

Publications and source records attributed to C Chen.

At least 649 records · Page 36Linked to original sources
PubMed1998

Altered disposition and antinociception of [D-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice.

This study was undertaken to test the hypothesis that P-glycoprotein (P-gp) modulates opioid peptide pharmacodynamics. [D-Penicillamine2, 5]enkephalin (DPDPE) (10 mg/kg i.v.) was administered to mdr1a(-/-) and wild-type mice to assess systemic disposition and antinociception. A subsequent dose-response experiment examined the impact of P-gp on DPDPE antinociception. In addition, the time course of antinociception was determined after a 0.9-mg/kg [mdr1a(-/-) mice] or 24-mg/kg (FVB mice) i.v. dose. Data were fit with a series of pharmacokinetic-pharmacodynamic models to compare the disposition and action of DPDPE in the two mouse strains. A 10-mg/kg dose produced >80% maximum possible response at all time points in mdr1a(-/-) mice; peak antinociception was <20% maximum possible response in FVB mice. DPDPE systemic disposition did not differ between the two mouse strains. Although brain tissue concentrations were 2- to 4-fold higher in mdr1a(-/-) compared to FVB mice, the dose required to elicit comparable antinociception was nearly 30-fold lower in mdr1a(-/-) mice; brain tissue EC50 differed by an order of magnitude in the two mouse strains. Pharmacokinetic-pharmacodynamic modeling indicated that the difference in antinociception between mdr1a(-/-) and FVB mice was a function of DPDPE distribution within brain, as well as between blood and brain, and not due to differences in intrinsic response. The results of this study suggest that DPDPE is a substrate of P-gp, and that P-gp is responsible, in part, for the low penetration of DPDPE into brain. The substantial difference in brain tissue EC50 in the absence vs. presence of P-gp suggests that P-gp modulates DPDPE-associated antinociception at sites other than the blood-brain interface.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Prevention of chronic rejection in mouse aortic allografts by combined treatment with CTLA4-Ig and anti-CD40 ligand monoclonal antibody.

BACKGROUND: In this study, using a murine model of aortic allotransplantation, the role of blockade of signaling through CD28/B7 and CD40/CD40 ligand costimulatory pathways in the evolvement of posttransplant vasculopathy was examined. METHODS: Aortic allografts were transplanted across C57BL/1OJ (H2b)-->C3H (H2k) strain combinations. Transient or more stable blockade of second signaling was achieved by either a single injection or multiple injections of CTLA4-Ig fusion protein (200 microg/dose i.p.) and/or anti-CD40 ligand (CD40L) monoclonal antibody (250 microg i.m.). At day 30 after transplantation, the grafts were harvested for histopathological and immunohistochemical examination. RESULTS: Similar to allografts of untreated animals, aortic allografts obtained from recipients treated with either CTLA4-Ig or anti-CD40L monoclonal antibody alone exhibited marked narrowing of the lumen primarily due to concentric intimal thickening caused by proliferation of alpha-smooth muscle actin-positive cells. Contemporaneous treatment, however, with either a single injection or multiple injections of CTLA4-Ig and anti-CD40L monoclonal antibody resulted in marked diminution of intimal thickening. Interestingly, concurrent prolonged inhibition of CD28/B7 and CD40/CD40L pathways resulted in complete abrogation of the development of posttransplant arteriopathy. CONCLUSION: These data suggest that a more stable disruption of signaling through costimulatory pathways may be required to obviate the development of posttransplant vasculopathy.

Abatacept↗
PubMed1997

Modulation of intestinal vitamin D receptor by ovariectomy, estrogen and growth hormone.

Age-related decline in intestinal calcium (Ca) absorption often occur in postmenopausal osteoporotic women. The impaired Ca absorption can be corrected by estrogen (E2) therapy. Growth hormone (GH) therapy has also been reported to increase intestinal absorption of calcium. Since 1,25-dyhydroxyvitamin D (1,25(OH)2D) is the primary regulator of calcium absorption, we explored whether the mechanisms by which E2 and GH enhance Ca absorption involves the vitamin D endocrine system. We measured serum 1,25(OH)2D concentrations and determined the binding characteristics of intestinal vitamin D receptors (VDRs) in four groups of female rats: sham operated (sham), ovariectomized (ovx), ovx + E2, and ovx + GH. Serum 1,25(OH)2D levels were 42.4 +/- 3.4 and 42.5 +/- 3.2 pg/ml in sham and ovx rats, respectively, and decreased by 63 and 34% (P < 0.001) in ovx + E2 and ovx + GH-treated rats, respectively. The numbers of total, unoccupied and occupied VDRs were 116.9 +/- 2.0, 72.1 +/- 1.1 and 44.8 +/- 1.9 fmol/mg protein, respectively, in sham operated rats, and decreased significantly following ovariectomy by 24, 27 and 19% (P < 0.01), respectively. E2 therapy not only significantly increased total, unoccupied and occupied VDRs above those of ovx rats by 55, 58 and 49% respectively, but it increased the levels above those of sham operated controls as well (P < 0.01). In contrast, GH administration prevented the decrease that occurred in ovx rats in the number of total and unoccupied VDRs (111.2 +/- 3.3; 72.6 +/- 1.4 fmol/mg protein, respectively), but it had no significant effect on the number of occupied VDRs. The dissociation constant (Kd) of intestinal VDRs was unaltered by ovariectomy, E2 and GH. We conclude that down regulation of intestinal VDRs may contribute to the Ca malabsorption that occurs in ovarian hormone deficient states such as postmenopausal osteoporosis, and that the stimulation of Ca absorption by E2 and GH may result, in part, from up regulation of intestinal VDRs.

Animals↗
PubMed1997

Nitroglycerin enhances the ability of dobutamine stress echocardiography to detect hibernating myocardium.

BACKGROUND: A biphasic response of wall thickening with initial improvement and subsequent deterioration during dobutamine stress echocardiography (DSE) has been increasingly used for detection of hibernating myocardium. However, the improvement of wall thickening at low-dose DSE may be limited in hibernating myocardium by severe hypoperfusion. Nitroglycerin (NTG) improves myocardial perfusion, reduces oxygen demand, and may enhance low-dose dobutamine to improve wall thickening. METHODS AND RESULTS: A pig model of myocardial hibernation of 24 hours to 7 days was created through severe left anterior descending coronary artery stenosis with coronary flow reductions of approximately 40%, producing severe regional left ventricular dysfunction but no infarction in seven pigs. Myocardial infarction was produced in five pigs with occlusion of the artery. DSE was performed with incremental doses with and without an NTG infusion of 50 to 100 microg/min. In the hibernating group, NTG alone improved wall thickening in the hibernating region modestly from 11.4+/-7.2% at baseline to 19.1+/-7.0%. The improvement was associated with increased regional coronary flow from 0.46+/-0.12 to 0.55+/-0.13 mL x beat(-1) x 100 g myocardium(-1) (P<.05). There was an additive effect of NTG to low-dose (2.5 to 5 microg x kg(-1) x min(-1)) dobutamine on wall thickening in the hibernating region. The improvement of wall thickening of hibernating myocardium with NTG and dobutamine, from 23.7+/-11.1% to 31.1+/-8.9% (P<.001), was associated with an increase in regional coronary flow (P<.01). NTG did not prevent high doses of dobutamine from inducing deterioration of wall thickening in hibernating myocardium. In the infarcted group, no improvement in wall thickening was observed in infarcted regions during NTG infusion, dobutamine infusion, or the combination. CONCLUSIONS: NTG enhances the improvement of wall thickening at low-dose dobutamine and does not prevent high-dose dobutamine from inducing ischemia in hibernating myocardium. Thus, NTG augments the biphasic response of wall thickening and improves the accuracy of DSE for detecting viable myocardium.

Animals↗
PubMed1997

Solar ultraviolet radiation exposure does not appear to exacerbate HIV infection in homosexual men. The Multicenter AIDS Cohort Study.

OBJECTIVE: To determine the effect of sun exposure on HIV progression. DESIGN: Cross-sectional survey nested within a longitudinal cohort study. SETTING: The Multicenter AIDS Cohort Study. PARTICIPANTS: A total of 1155 white HIV-seronegative and 496 white HIV-seropositive homosexual men, of whom 142 seroconverted during the study. MAIN OUTCOME MEASURES: T-helper lymphocyte decline and AIDS. RESULTS: No positive correlation was found between the development of AIDS or loss of T-helper lymphocytes and (i) phenotypic characteristics associated with enhanced ultraviolet radiation (UVR) sensitivity (hair or eye color, skin type), or (ii) reported UVR exposure (sun lamp/tanning bed use, frequency of beach vacations, sunscreen use), or (iii) composite score of UVR sensitivity and exposure history. The composite scores and individual measures of risk were not correlated with rate of T-helper lymphocyte decline (slope) based upon rank correlation (correlation coefficient, 0.04; P = 0.32). In fact, individuals purposefully seeking the sun had slower T-helper lymphocyte declines. Sensitivity to UVR was also not significantly associated with AIDS [odds ratio (OR), 1.11 per unit of higher composite score; 95% confidence interval (CI), 0.66-1.88; P = 0.63]. Among individuals who were HIV-infected at baseline, those who have been purposely seeking sun exposure were less likely to have AIDS (OR, 0.67; 95% CI, 0.39-1.11; P = 0.12). CONCLUSIONS: These data suggest that phenotypic characteristics of high UVR sensitivity and exposure are not highly correlated with decline in T-helper lymphocyte count or with progression to AIDS.

Adult↗
PubMed1997

The mechanism of cAMP-mediated enhancement at a cerebellar synapse.

Increases in cAMP have been shown previously to enhance the strength of the granule cell to Purkinje cell synapse. We have examined the mechanisms underlying this enhancement in rat cerebellar brain slices. Elevation of cAMP levels by forskolin increased synaptic currents in a dose-dependent manner. Fluorometric calcium measurements revealed that forskolin did not affect presynaptic calcium influx or resting calcium levels. The waveform of the presynaptic volley was also unaltered, indicating that changes in the presynaptic action potential did not contribute to synaptic enhancement. However, forskolin enhanced the frequency but not the size of spontaneous miniature EPSCs. There was a one-to-one correspondence between increases of spontaneous and evoked neurotransmitter release. These results suggest that forskolin increases release at this synapse via presynaptic mechanisms that do not alter calcium influx. The effect of forskolin on paired-pulse facilitation was examined to assess the relative contributions of changes in the probability of release (p) and changes in the number of functional release sites (n) to this form of enhancement. These experiments suggest that although small changes in n cannot be excluded, most of the enhancement arises from increases in p.

Action Potentials↗
PubMed1997

Left ventricular remodeling in myocardial hibernation.

BACKGROUND: Left ventricular (LV) remodeling as a consequence of extensive myocardial infarction has been well established in animal and human studies. This study was designed to determine whether regional LV dysfunction with myocardial hibernation without transmural or extensive infarction could initiate the remodeling process. METHODS AND RESULTS: A severe left anterior descending coronary artery stenosis was created to reduce resting flow by approximately 40% (from 0.99+/-0.10 to 0.56+/-0.11 mL x min(-1) x g[-1]) and was maintained for 7 days in 13 pigs. The reduction of regional coronary flow initially produced acute myocardial ischemia, as evidenced by reduced regional wall thickening, from 37+/-3% at baseline to 9+/-7%, regional lactate production and a decrease in regional coronary venous pH. All pigs had significant regional LV dysfunction and reduced LV ejection fraction (41+/-11%). The LV end-diastolic volume increased from 59+/-9 mL at baseline to 74+/-13 mL immediately after placement of the stenosis and to 78+/-17 mL 7 days later with hibernating myocardium. The LV mass did not change immediately (60+/-8 g baseline versus 59+/-11 g immediately after creation of the stenosis) but increased modestly yet significantly to 67+/-15 g after 7 days of myocardial hibernation subtending the severe LAD stenosis. The reductions of coronary flow and wall thickening were unchanged at 7 days, whereas myocardial lactate production recovered. By 4 weeks after restoration of LAD flow, regional function had recovered in all 7 pigs with follow-up. Of the 13 pigs, 6 were free from any evidence of myocardial infarction, and 4 had patchy necrosis involving less than 6% of the area at risk. CONCLUSIONS: LV remodeling, which is commonly associated with extensive myocardial infarction, can be initiated by regional dysfunctional hibernating myocardium resulting from a severe coronary stenosis. Myocardial necrosis is not a prerequisite for LV remodeling in response to regional dysfunction.

Animals↗
PubMed1997

Myocardial cell death and apoptosis in hibernating myocardium.

OBJECTIVES: This study was designed to study apoptosis in hypoperfused hibernating myocardium subtending severe coronary stenosis. BACKGROUND: Apoptosis contributes to myocyte death in acute myocardial infarction. METHODS: A left anterior descending coronary artery stenosis was created in 13 pigs and maintained for 24 h (n = 4), 7 days (n = 5) and 4 weeks (n = 4) to reduce coronary blood flow by a mean of 34% with severe regional myocardial systolic dysfunction, as documented by echocardiography. Apoptosis was detected with an in situ end-labeling method and confirmed by "deoxyribonucleic acid laddering" on agarose-gel electrophoresis. The severity of apoptosis was expressed as the percentage of apoptotic myocyte nuclei and nonapoptotic myocardial nuclei. RESULTS: Myocardial blood flow of the anterior left ventricular wall was reduced from 1.00 +/- 0.18 to 0.66 +/- 0.21 ml/min per g (p < 0.01), with a severe reduction of anterior regional wall thickening from a mean (+/-SD) of 39 +/- 4% to 9 +/- 8% (p < 0.01). There was no myocardial infarction in five pigs and minimal patchy infarction of < or = 6% of the area at risk in eight pigs. Apoptotic myocytes were observed in the hibernating myocardial region in all pigs (4.8 +/- 2.3%). Myocyte apoptosis was patchy in distribution and was found predominantly in the subendocardial myocardium (9.8 +/- 4.6%) and rarely in the subepicardial myocardium (0.32 +/- 0.45%). Apoptosis was found not only around focal fibrosis areas, but also in areas without fibrosis or patchy infarction. Apoptosis was found not only in 24-h hypoperfused myocardium, but also in 4-week hypoperfused myocardium. The severity of myocyte apoptosis correlated significantly with regional coronary blood flow reduction (r = 0.75, p < 0.01). No apoptosis was found in the normal control region. CONCLUSIONS: This study demonstrates that there is ongoing myocyte death through myocyte apoptosis in hypoperfused hibernating myocardium.

Animals↗
PubMed1997

Heat shock factor 1 represses Ras-induced transcriptional activation of the c-fos gene.

Heat shock factor 1, the critical molecular regulator of the stress response is conserved throughout eukaryotic organisms and activates the transcription of heat shock genes. We now show that heat shock factor 1 inhibits the expression of c-fos, an immediate early gene that controls responses to extracellular stimuli for growth and differentiation. Heat shock factor 1 inhibits the transcription of the c-fos gene and antagonizes the activating effects of the signal transducing protein Ras on the c-fos promoter and on the promoter of another Ras responsive gene uPA. This property was specific for heat shock factor 1; c-fos repression was not seen with the structurally related protein heat shock factor 2. Repression involved different molecular mechanisms compared with those involved in transcriptional activation by heat shock factor 1 and specifically did not require binding to the c-fos promoter. Thus, in addition to its known role as a transcriptional activator of the cellular heat shock response, heat shock factor 1 also antagonizes the expression of Fos, a key component of the ubiquitous AP-1 transcription factor complex and as such could influence multiple aspects of cell regulation.

Animals↗
PubMed1997

Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma.

In normal animals, peripheral nerve injury produces a persistent, neuropathic pain state in which pain is exaggerated and can be produced by nonpainful stimuli. Here, mice that lack protein kinase C gamma (PKCgamma) displayed normal responses to acute pain stimuli, but they almost completely failed to develop a neuropathic pain syndrome after partial sciatic nerve section, and the neurochemical changes that occurred in the spinal cord after nerve injury were blunted. Also, PKCgamma was shown to be restricted to a small subset of dorsal horn neurons, thus identifying a potential biochemical target for the prevention and therapy of persistent pain.

Animals↗
PubMed1997

The CRF1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist.

Corticotropin releasing factor (CRF) is the key coordinator of the neuroendocrine and behavioral responses to stress. In the central nervous system, CRF excites select neuronal populations, and infusion of CRF into the cerebral ventricles of infant rats produces severe age-dependent limbic seizures. These seizures, like other CRF effects, result from activation of specific receptors. Both of the characterized members of the CRF receptor family (CRF1 and CRF2), are found in the amygdala, site of origin of CRF-induced seizures, and may therefore mediate these seizures. To determine which receptor is responsible for the excitatory effects of CRF on limbic neurons, a selective, non-peptide CRF1 antagonist was tested for its ability to abolish the seizures, in comparison to non-selective inhibitory analogues of CRF. Pretreatment with the selective CRF1 blocker (NBI 27914) increased the latency and decreased the duration of CRF-induced seizures in a dose-dependent manner. The higher doses of NBI 27914 blocked the behavioral seizures and prevented epileptic discharges in concurrent electroencephalograms recorded from the amygdala. The selective CRF1 blocker was poorly effective when given systemically, consistent with limited blood-brain barrier penetration. Urocortin, a novel peptide activating both types of CRF receptors in vitro, but with preferential affinity for CRF2 receptors in vivo, produced seizures with a lower potency than CRF. These limbic seizures, indistinguishable from those induced by CRF, were abolished by pretreatment with NBI 27914, consistent with their dependence on CRF1 activation. In summary, CRF induces limbic seizures in the immature rat, which are abolished by selective blocking of the CRF1 receptor. CRF1-messenger RNA levels are maximal in sites of seizure origin and propagation during the age when CRF is most potent as a convulsant. Taken together, these facts strongly support the role of the developmentally regulated CRF1 receptor in mediating the convulsant effects of CRF in the developing brain.

Animals↗
PubMed1997

Expression of transforming growth factor beta type III receptor suppresses tumorigenicity of human breast cancer MDA-MB-231 cells.

Transforming growth factor beta (TGF-beta) promotes tumor progression in some model systems including human breast cancer cells. In this study, we report that human breast cancer cell lines express reduced amounts of TGF-beta type III receptor (RIII) when compared with untransformed human mammary epithelial cells. Consequently, we examined whether expression of RIII in human breast cancer MDA-MB-231 cells could reduce TGF-beta's tumor promoting activity by sequestering active TGF-beta isoforms produced by the cells. A tetracycline-repressible human RIII expression vector was stably transfected into the cell line. RIII expression in a pool of transfected clones and a single clone was found to be reversibly repressed by tetracycline treatment. Expression of RIII reduced the amount of active TGF-beta1 and TGF-beta2 in the conditioned medium. The medium conditioned by control cells showed a significantly higher growth inhibitory effect than that conditioned by RIII-transfected cells on the growth of the mink lung epithelial CCL64 cells. A conditioned medium collected from RIII-transfected cells treated with tetracycline significantly increased its growth inhibitory activity to that of control cells. Expression of RIII also reduced tumor incidence and growth rate in two separate experiments when the cells were inoculated in athymic nude mice. Treatment of the mice with tetracycline repressed RIII expression in the tumors generated by RIII-transfected cells and increased tumor incidence and growth rate. These results suggest that TGF-beta RIII can reduce tumorigenicity of MDA-MB-231 cells apparently by sequestering TGF-beta isoforms produced by these cells.

Animals↗
PubMed1997

Cell-growth regulation of the hamster dihydrofolate reductase gene promoter by transcription factor Sp1.

The dihydrofolate reductase (DHFR) gene (dhfr) promoter contains cis-acting elements for the transcription factors Sp1 and E2F. Given the ability of Sp1 to activate the dhfr promoter, we have evaluated the contribution of Sp1 to the cell-growth regulation of the dhfr gene. Using gel-mobility assays performed with DNA probes from the minimal promoter of the hamster dhfr gene and nuclear extracts from cultured hamster cells (CHO K1) we show that the binding of Sp1 to the dhfr promoter is cell-growth-phase regulated. Accordingly, dhfr transcription and mRNA levels in K1 cells increase upon serum stimulation. Cytological detection of Sp1 by immunofluorescence reveals a decrease of this protein in the process leading to the G0 state, and an increase upon serum stimulation of quiescent cells. These results were confirmed by western blot analysis. It is concluded that Sp1 progressively binds to the hamster dhfr promoter after stimulation of cell proliferation, which can account for the transcriptional regulation of the dhfr gene during the cell cycle. The role of Sp1 in the specific control of dhfr during the cell cycle was confirmed in vivo using cell lines derived from dhfr-negative cells transfected with dhfr plasmids carrying either the wild-type or mutated Sp1-binding or E2F-binding sites in the dhfr minimal promoter.

Animals↗
PubMed1997

Direct comparison of arbutamine and dobutamine stress testing with myocardial perfusion imaging and echocardiography in patients with coronary artery disease.

Arbutamine, a new sympathomimetic compound, appears to elicit a more balanced inotropic and chronotropic response than dobutamine, currently used as a pharmacologic stress agent. The present study was performed to compare standard dobutamine stress testing with arbutamine for the detection of myocardial ischemia with technetium (Tc)-99m sestamibi tomographic imaging and 2-dimensional echocardiography in patients with coronary artery disease. Twenty-six patients with evidence of coronary artery disease underwent dobutamine infusion of 5 to 40 microg/kg/min in 3-minute stages. On a separate day, arbutamine was administered by an automated, computerized, closed-loop device monitoring both heart rate and blood pressure. Both infusions were terminated upon achievement of target heart rate, completion of maximal infusion dose (dobutamine), heart rate saturation (arbutamine), or standard clinical end points. Tc-99m sestamibi was injected before termination of both infusions followed by tomographic myocardial perfusion imaging, whereas echocardiography was performed at baseline and throughout the infusions. There were no significant differences in maximal heart rate, blood pressure, and rate-pressure product as well as in the development of anginal symptoms or electrocardiographic changes during both infusions. The location and severity of myocardial perfusion defects and echocardiographic wall motion abnormalities were similar between both agents. It is concluded that arbutamine produces similar imaging results compared with standard dobutamine stress with both Tc-99m sestamibi single-photon emission computed tomographic myocardial perfusion imaging and 2-dimensional echocardiography.

Adult↗
PubMed1997

Sensitive analysis of [D-Pen2,5]enkephalin in rat serum by capillary electrophoresis and laser-induced fluorescence detection.

A highly sensitive analytical method based on capillary zone electrophoresis (CZE) coupled with a laser-induced fluorescence (LIF) detector was explored for the analysis of [D-Pen2,5]enkephalin (DPDPE) in rat serum. DPDPE and the internal standard Phe-Leu-Glu-Glu-Ile (P9396) were extracted from serum samples with C18 solid-phase extraction disk cartridges, followed by derivatization with tetramethylrhodamine-5-isothiocyanate (TRITC) isomer G before introduction onto the capillary column. Complete resolution of DPDPE and the internal standard from other serum components was achieved within 20 min on a 140 cm x 50 microns I.D. capillary column with borate buffer (25 mM. pH 8.3). With the current method, it is possible to detect 1.3E-18 mol of DPDPE on column. The results suggest that CZE-LIF is a promising method for the sensitive and specific quantitation of therapeutic peptides in biological matrices.

Animals↗
PubMed1997

Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase.

The c-Jun N-terminal kinase (JNK), or stress-activated protein kinase plays a crucial role in cellular responses stimulated by environmental stress and proinflammatory cytokines. However, the mechanisms that lead to the activation of the JNK pathway have not been elucidated. We have isolated a cDNA encoding a novel protein kinase that has significant sequence similarities to human germinal center kinase (GCK) and human hematopoietic progenitor kinase 1. The novel GCK-like kinase (GLK) has a nucleotide sequence that encodes an ORF of 885 amino acids with 11 kinase subdomains. Endogenous GLK could be activated by UV radiation and proinflammatory cytokine tumor necrosis factor alpha. When transiently expressed in 293 cells, GLK specifically activated the JNK, but not the p42/44(MAPK)/extracellular signal-regulated kinase or p38 kinase signaling pathways. Interestingly, deletion of amino acids 353-835 in the putative C-terminal regulatory region, or mutation of Lys-35 in the putative ATP-binding domain, markedly reduced the ability of GLK to activate JNK. This result indicates that both kinase activity and the C-terminal region of GLK are required for maximal activation of JNK. Furthermore, GLK-induced JNK activation could be inhibited by a dominant-negative mutant of mitogen-activated protein kinase kinase kinase 1 (MEKK1) or mitogen-activated protein kinase kinase 4/SAPK/ERK kinase 1 (SEK1), suggesting that GLK may function upstream of MEKK1 in the JNK signaling pathway.

Amino Acid Sequence↗
PubMed1997

Impact of acute propranolol administration on dobutamine-induced myocardial ischemia as evaluated by myocardial perfusion imaging and echocardiography.

Beta-blocker therapy may delay or completely prevent myocardial ischemia during exercise testing, as assessed by ST-segment shifts, myocardial perfusion defects, or echocardiographic wall motion abnormalities. However, the impact of beta-blocker therapy on these end points during dobutamine stress testing has not been well established. The purpose of this study was to determine the impact of propranolol on dobutamine stress testing with ST-segment monitoring, technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) imaging, and echocardiography. In 17 patients with known reversible perfusion defects, dobutamine stress tests with and without propranolol were performed in randomized order and on separate days, following discontinuation of oral beta blockers and calcium antagonists. Propronolol was administered intravenously to a cumulative dose of 8 mg or to a maximum heart rate reduction of 25% and dobutamine was infused in graded doses in 3 minute stages until a standard clinical end point or the maximum dose of 40 microg/kg/min was achieved. The dobutamine stress test after propranolol was associated with a lower maximum heart rate (83 +/- 18 vs 125 +/- 17, p <0.001) and rate pressure product (14,169 +/- 4,248 vs 19,894 +/- 3,985, p <0.001) despite a higher infusion dose. The SPECT myocardial ischemia score was also lower (6.9 +/- 5.8 vs 10.1 +/- 7.1, p = 0.047) and fewer echocardiographic segments were abnormal (3.4 +/- 3.0 vs 4.6 +/- 3.4, p = 0.042). In 4 of 17 patients, reversible perfusion defects and echocardiographic wall motion abnormalities were detected during the control but not during the propranolol test. Thus, during dobutamine stress testing, beta-blocker therapy attenuates, and in some cases eliminates, evidence of myocardial ischemia.

Aged↗