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Biomedical subjects

I A Simpson

Publications and source records attributed to I A Simpson.

At least 19 recordsLinked to original sources
PubMed1992

Cell surface accessibility of GLUT4 glucose transporters in insulin-stimulated rat adipose cells. Modulation by isoprenaline and adenosine.

Insulin-stimulated glucose transport activity in rat adipocytes is inhibited by isoprenaline and enhanced by adenosine. Both of these effects occur without corresponding changes in the subcellular distribution of the GLUT4 glucose transporter isoform. In this paper, we have utilized the impermeant, exofacial bis-mannose glucose transporter-specific photolabel, 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-(D-mannos- 4-yloxy)-2-propylamine (ATB-BMPA) [Clark & Holman (1990) Biochem. J. 269, 615-622], to examine the cell surface accessibility of GLUT4 glucose transporters under these conditions. Compared with cells treated with insulin alone, adenosine in the presence of insulin increased the accessibility of GLUT4 to the extracellular photolabel by approximately 25%, consistent with its enhancement of insulin-stimulated glucose transport activity; the plasma membrane concentration of GLUT4 as assessed by Western blotting was unchanged. Conversely, isoprenaline, in the absence of adenosine, promoted a time-dependent (t1/2 approximately 2 min) decrease in the accessibility of insulin-stimulated cell surface GLUT4 of > 50%, which directly correlated with the observed inhibition of transport activity; the plasma membrane concentration of GLUT4 decreased by 0-15%. Photolabelling the corresponding plasma membranes revealed that these alterations in the ability of the photolabel to bind to GLUT4 are transient, as the levels of both photolabel incorporation and plasma membrane glucose transport activity were consistent with the observed GLUT4 concentration. These data suggest that insulin-stimulated GLUT4 glucose transporters can exist in two distinct states within the adipocyte plasma membrane, one which is functional and accessible to extracellular substrate, and one which is non-functional and unable to bind extracellular substrate. These effects are only observed in the intact adipocyte and are not retained in plasma membranes isolated from these cells when analysed for their ability to transport glucose or bind photolabel.

Adenosine↗
PubMed1992

Detection of the GLUT3 facilitative glucose transporter in rat L6 muscle cells: regulation by cellular differentiation, insulin and insulin-like growth factor-I.

The GLUT3 facilitative glucose transporter protein was found to be expressed in rat L6 muscle cells. It was detected at both the myoblast and myotube stage. GLUT3 protein content per mg of total membrane protein increased significantly during L6 cell differentiation. Subcellular fractionation demonstrated that the GLUT3 protein was predominantly localized in plasma membrane-enriched fractions of either myoblasts or myotubes. Short-term exposure of L6 myotubes to IGF-I or insulin caused a redistribution of GLUT3 protein from an intracellular membrane fraction to the plasma membrane, without affecting total membrane GLUT3 protein content. Long-term exposure of L6 myotubes to IGF-I produced an increase of GLUT3 protein in total membranes and all subcellular membrane fractions, especially the plasma membrane. We propose that the GLUT3 glucose transporter may play an important role in glucose metabolism in developing muscle.

Animals↗
PubMed1992

Differential identification and localization of adenylyl cyclase and glucose transporter in brain using iodinated derivatives of forskolin.

Two radioiodinated derivatives of forskolin, [125I]6-IHPP-Fsk and [125I]7-IHPP-Fsk, were synthesized as specific ligands for adenylyl cyclase and glucose transporter, respectively. [125I]6-IHPP-Fsk bound to bovine brain homogenates with a Kd of 9 nM and binding was inhibited by forskolin but not 1,9-dideoxyforskolin, cytochalasin B, or D-glucose. [125I]7-IHPP-Fsk bound to bovine brain homogenates at two classes of binding sites with Kd's of 56 nM and 4.7 microM; cytochalasin B and D-glucose inhibited 75% of the high affinity binding while having no effect on the low affinity binding. [125I]6-IHPP-Fsk and [125I]7-IHPP-Fsk were used to localize adenylyl cyclase and glucose transporter in rat brain by receptor autoradiography. The pattern of binding obtained with [125I]6-IHPP-Fsk was similar to that observed using [3H]forskolin to detect adenylyl cyclase. In contrast, the pattern of binding obtained with [125I]7-IHPP-Fsk was similar to that observed by others using [3H]cytochalasin B to detect glucose transporter. These iodinated ligands are selective for adenylyl cyclase and glucose transporter and require significantly shorter exposure times to yield autoradiographs than tritiated ligands.

Adenylyl Cyclases↗
PubMed1992

Expression of mouse-GLUT3 and human-GLUT3 glucose transporter proteins in brain.

Polyclonal anti-peptide antisera were raised to the C-terminal sequence of mouse- and human-GLUT3 glucose transporter isoforms. GLUT3 protein and mRNA expression were investigated by Western blot and Northern blot assays, in a range of tissues and cell lines. Mouse-GLUT3 protein was detected only in rat brain, where it was present in most regions except adenohypophysis and pineal gland. Mouse-GLUT3 was also detected in primary cultured rat cerebellar neurons and the neuronal cell lines PC12 and NG108-15, but not in cultured astroglia. Human-GLUT3 protein was detected in CHO cells transfected with the human-GLUT3 cDNA and in human brain, but not in human placenta or fat. The expression of GLUT3 in rat brain and neurons indicates it is a major neuronal glucose transporter.

Amino Acid Sequence↗
PubMed1992

Clinical and hemodynamic evaluation of the 19-mm Carpentier-Edwards supraannular aortic valve.

The clinical and hemodynamic performance of the 19-mm Carpentier-Edwards supraannular aortic valve is largely unknown compared with that of the larger valves. Over 4 years we implanted the 19-mm Carpentier-Edwards supraannular aortic valve into 21 patients (20 female) with a mean age of 75 +/- 1.2 years (range, 59 to 86 years) and a mean body surface area of 1.6 +/- 0.03 m2 (range, 1.3 to 1.7 m2). There were four deaths, one operative and three late noncardiac deaths. Follow-up of the 17 survivors for a mean of 20 +/- 3.1 months (range, 2 to 42 months) demonstrated symptomatic improvement in all 17 (all are now in New York Heart Association functional class I or II). There were no valve-related complications and no patient required long-term anticoagulation. Doppler echocardiographic studies were used to assess the in vivo hemodynamic profile of the valve. Mean postoperative aortic valve gradient was 34.1 +/- 2.7 mm Hg (range, 19 to 52 mm Hg). Functional valve orifice area was 1.1 +/- 0.09 cm2 (range, 0.6 to 1.8 cm2). Mean cardiac output was 3.92 +/- 0.17 L/min (range, 3.2 to 5.1 L/min) with a mean cardiac index of 2.5 +/- 0.11 L.min-1 x m-2 (range, 2.1 to 3.2 L.min-1 x m-2). In conclusion, we have demonstrated that aortic valve replacement with the 19-mm Carpentier-Edwards supraannular aortic valve has a low operative mortality and offers major clinical benefits despite moderate transprosthetic gradients. This approach provides an alternative management strategy in elderly patients who would otherwise require low-profile mechanical valves or aortic root enlargement.

Aged↗
PubMed1992

Effects of fluorescein isothiocyanate on insulin actions in rat adipocytes.

The effects of fluorescein isothiocyanate II (FITC) on the actions of insulin in rat adipocytes were studied. When adipocytes were incubated with FITC at pH 7.4 (2 mM agent, 8 min), the cells were completely deprived of their specific insulin-binding activity and rendered unresponsive to the hormone. The effect of FITC on the insulin-binding activity was milder at pH 9.0, and cAMP phosphodiesterase in cells exposed to FITC at pH 9.0 was maximally stimulated if the insulin concentration was increased to 100 nM. Under identical conditions, however, glucose transport activity was rendered not only less sensitive but also less responsive to the hormone. When FITC was added to cells after insulin at pH 9.0, the glucose transport activity that had been stimulated by the hormone was considerably reduced. This reduction was largely, but not entirely, prevented if the cells were deprived of ATP, suggesting that FITC (a) elicited the ATP-dependent reversal of the hormonal effect and, simultaneously, (b) mildly inhibited the transport activity per se. Western blot assay of GLUT-4 (a major isoform of glucose transporter in adipocytes) indicated that FITC (a) partially blocked insulin-dependent translocation of GLUT-4 from the intracellular site to the plasma membrane while it (b) induced a mild "insulin-like" effect. It is concluded that FITC at pH 9.0 (a) renders both glucose transport and phosphodiesterase activities less insulin sensitive presumably by modifying the cellular hormone receptor and (b) makes glucose transport activity less responsive to insulin presumably by (i) blocking hormone-dependent translocation of glucose transporter and (ii) mildly inhibiting intrinsic glucose transport activity.

Adipose Tissue↗
PubMed1992

Cholera and pertussis toxins modify regulation of glucose transport activity in rat adipose cells: evidence for mediation of a cAMP-independent process by G-proteins.

Adenylyl cyclase in rat adipose cells is stimulated by ligands for Rs receptors (e.g. isoproterenol) and inhibited by ligands for Ri receptors (e.g. adenosine). In contrast, Rs receptors mediate inhibition and Ri receptors mediate augmentation of insulin-stimulated glucose transport activity by a process independent of changes in cellular cAMP-dependent protein kinase activity [Kuroda M., Honnor R. C., Cushman S. W., Londos C. and Simpson I. A. (1987) J. biol. Chem. 262, 245-253]. The present study examines the possible role of G-proteins in the regulation of insulin-stimulated glucose transport activity by Rs and Ri receptors. First, conditions were established that permit intoxication of isolated rat adipocytes by cholera and pertussis toxins without compromising cell integrity. Effectiveness of toxin treatment was monitored by examining adenylyl cyclase activity in isolated plasma membranes. Secondly, neither toxin interfered with the ability of a maximal concentration insulin to initiate the glucose transport response. Thirdly, pertussis toxin eliminated the augmenting effects of adenosine on insulin-stimulated glucose transport activity, but enhanced the inhibitory effects of isoproterenol. Findings with ligands for other Ri receptors (nicotinic acid and prostaglandin E2) mirrored those with adenosine. Finally, cholera toxin elicited a modest depression of transport activity, and only in the absence of an Ri ligand (e.g. adenosine). Furthermore, in contrast to the enhanced stimulation of adenylyl cyclase by isoproterenol and GTP, cholera toxin eliminated the inhibitory effect of isoproterenol on transport activity. The augmentative effects of adenosine on transport activity were unchanged. Measurements of (-/+cAMP) cAMP-dependent protein kinase activity ratios reinforce the notion that modulation of glucose transport activity is independent of changes in cAMP. We conclude that regulation of glucose transport activity by Rs and Ri receptors is mediated by the G-proteins, Gs and Gi (or other toxin substrates), respectively. Inasmuch as such regulation occurs at the plasma membrane and appears to be cAMP-independent, it is suggested that glucose transporters may be direct targets for receptor: G-protein interactions.

Adenylate Cyclase Toxin↗
PubMed1992

Intravascular ultrasound imaging of the coronary arteries: an in vitro evaluation of measurement of area of the lumen and atheroma characterisation.

OBJECTIVE: To assess the accuracy of measurement of area of the lumen, and sensitivity, and specificity of detection of atheroma in coronary arteries in vitro with a commercially available 20 MHz intravascular ultrasound system. SETTING: A teaching hospital department of cardiology with the support of the department of cardiovascular pathology. PROCEDURE: 10 segments of coronary artery were removed from cadaver hearts. Intravascular ultrasound imaging was performed at fixed levels and the vessels were then sectioned and photographed before histological preparation. An independent blinded observer measured luminal area and assessed the presence of atheroma on the intravascular ultrasound images of 76 vessel sections (304 quadrants). The sensitivity and specificity of detection of atheroma was assessed in comparison with the histologically prepared sections. Luminal areas from intravascular ultrasound, photographs of cross sections of the vessels and histological sections were compared with the technique of limits of agreement. RESULTS: Overall 36% of the 304 quadrants studied histologically had identifiable atheroma. Intravascular ultrasound sensitivity for atheroma was 0.593 and the specificity was 0.839. The positive predictive value was 0.674, and the relative risk 3.139. Values for area of the vessel lumen were on average 9.4 mm2 (confidence interval (CI) 8.6-10.2 mm2) larger than those measured from photographs and 10.7 (CI 9.8-11.6 mm2) larger than those measured from the histological sections. CONCLUSIONS: The intravascular ultrasound system assessed in this study significantly overestimated coronary vessel luminal area and had low sensitivity and specificity for detection of atheroma. Improvements in image resolution are required before this system can provide useful information on coronary artery size and morphology.

Coronary Artery Disease↗
PubMed1992

Ventricular fibrillation in hypertrophic cardiomyopathy is associated with increased fractionation of paced right ventricular electrograms.

BACKGROUND: Intraventricular conduction in hypertrophic cardiomyopathy (HCM) has been characterized to test the hypothesis that myofibrillar disarray will cause dispersion of activation throughout the ventricular myocardium. METHODS AND RESULTS: Of 37 patients with HCM, four had spontaneous ventricular fibrillation (VF), five had nonsustained ventricular tachycardia (VT), 13 had no risk factors, and 15 had a family history of sudden death. These patients and four controls were studied by pacing one site in the right ventricle and recording electrograms from three other right ventricular sites. These electrograms were high-pass filtered to emphasize small deflections due to activation of small bundles of myocytes close to the electrode. Intraventricular conduction curves were obtained with S1S2 coupling intervals decreasing in 1-msec steps from 479 msec to ventricular effective refractory period (VERP). These curves were repeated by pacing each RV site in turn and were characterized by two parameters: the point at which latency increased by 0.75 msec/20 msec reduction of the S1S2 coupling interval and an increase in electrogram duration between an S1S2 of 350 msec and VERP. Patients with VF, VT, and family history of sudden death had a mean increase in electrogram duration of 12.8 (2.9-32.3) msec versus 4.6 (-4.2 to 14.0) msec in low-risk patients and controls. Electrogram latency increased at an S1S2 of 363 msec in the VF group (342-386), 269 msec in the controls (266-279), and 326 msec in the non-VF group (260-399). Discriminant analysis separated VF patients from the remainder (p less than 0.0001) and VF, VT, and family history of sudden death patients from the low-risk and control groups (p less than 10(-6)). CONCLUSIONS: Patients with HCM who are at risk of sudden death have increased dispersion and inhomogeneity of intraventricular conduction, and this may create the conditions for reentry and arrhythmogenesis.

Adolescent↗
PubMed1992

Echocardiographic study of the morphology and growth of the aortic arch in the human fetus. Observations related to the prenatal diagnosis of coarctation.

BACKGROUND: In a study of normal and abnormal growth of the aorta before birth, high-resolution echocardiographic imaging of the aortic arch in 92 normal fetuses aged 16-38 weeks was used to establish normal values for aortic arch dimensions at varying gestational ages. METHODS AND RESULTS: From long-axis views of the aortic arch, the internal diameter of the aortic root, ascending aorta, transverse aortic arch, aortic isthmus, proximal descending thoracic aorta, and left common carotid artery were measured. Correlation coefficients for the diameter of each aortic arch segment when related to gestational age varied from r = 0.87 to r = 0.94 (p less than 0.001 for each), and growth curves were derived from the third and 97th percentiles around each linear regression analysis. In most of the fetuses, there was progressive tapering of the aortic arch, with the smallest diameter being at the isthmus. The ratio of the transverse aorta, isthmus, descending aorta, and aortic root to the ascending aorta remained relatively constant with gestational age, with mean values of 0.94, 0.81, 0.96, and 1.13, respectively. In five fetuses in whom a prenatal diagnosis of aortic coarctation was confirmed postnatally, transverse aortic and isthmic measurements fell on or below the third percentile for gestational age from the above data. In each case, the ratio of left common carotid artery to transverse aorta was greater than or equal to 0.73 compared with less than or equal to 0.62 for the 92 normal fetuses (mean ratios, 0.77 +/- 0.05 [SD] for coarctation versus 0.48 +/- 0.08 for normal fetuses; p less than or equal to 0.001). CONCLUSIONS: Use of normal growth curves for the developing aortic arch should facilitate the prenatal diagnosis of left heart and aortic arch abnormalities, particularly aortic coarctation, which until recently has been a difficult prenatal diagnosis to make with certainty.

Aorta, Thoracic↗
PubMed1991

Phosphorylation state of the GLUT4 isoform of the glucose transporter in subfractions of the rat adipose cell: effects of insulin, adenosine, and isoproterenol.

The acute effects of insulin, adenosine, and isoproterenol on the activity, subcellular distribution, and phosphorylation state of the GLUT4 glucose transporter isoform were investigated in rat adipocytes under conditions carefully controlled to monitor changes in cAMP-dependent protein kinase (A-kinase) activity. In contrast to GLUT1, which has not been shown to be phosphorylated even when cells are exposed to any of the above agents, GLUT4 was partially phosphorylated (0.1-0.2 mol/mol) when the activity of the A-kinase was suppressed, and remained unchanged in response to insulin. Isoproterenol elicited a 64% inhibition of insulin-stimulated glucose transport activity in the absence, but not the presence, of adenosine receptor agonists. However, in either the presence or the absence of agonists, A-kinase was activated as assessed by examining the phosphorylation of the major adipocyte A-kinase substrate, perilipin. Similarly, under either condition, phosphorylation of GLUT4 was enhanced 1.4-fold in the intracellular membranes, but no significant change was observed in the plasma membrane. In the absence of adenosine receptor agonists, isoproterenol exerted a small (14%) but significant inhibition of the insulin-induced translocation of GLUT4 but had no effect on the translocation of GLUT1. Thus, changes in the phosphorylation state and/or subcellular distribution of GLUT4 cannot account for the inhibition of insulin-stimulated glucose activity induced by isoproterenol.

Adenosine↗
PubMed1991

Role of protein kinase C in the regulation of glucose transport in the rat adipose cell. Translocation of glucose transporters without stimulation of glucose transport activity.

The possible role of protein kinase C in the regulation of glucose transport in the rat adipose cell has been examined. Both insulin and phorbol 12-myristate 13-acetate (PMA) stimulate 3-O-methylglucose transport in the intact cell ein association with the subcellular redistribution of glucose transporters from the low density microsomes to the plasma membranes, as assessed by cytochalasin B binding. In addition, the actions of insulin and PMA on glucose transport activity and glucose transporter redistribution are additive. Furthermore, PMA accelerates insulin's stimulation of glucose transport activity, reducing the t1/2 from 3.2 +/- 0.4 to 2.1 +/- 0.2 min (mean +/- S.E.). However, the effect of PMA on glucose transport activity is approximately 10% of that for insulin whereas its effect on glucose transporter redistribution is approximately 50% of the insulin response. Immunoblots of the GLUT1 and GLUT4 glucose transporter isoforms in subcellular membrane fractions also demonstrate that the translocations of GLUT1 in response to PMA and insulin are of similar magnitude whereas the translocation of GLUT4 in response to insulin is markedly greater than that in response to PMA. Thus, glucose transport activity in the intact cell with PMA and insulin correlates more closely with the appearance of GLUT4 in the plasma membrane than cytochalasin B-assayable glucose transporters. Although these data do not clarify the potential role of protein kinase C in the mechanism of insulin action, they do suggest that the mechanisms through which insulin and PMA stimulate glucose transport are distinct but interactive.

3-O-Methylglucose↗
PubMed1991

Subcellular distribution and phosphorylation state of insulin receptors from insulin- and isoproterenol-treated rat adipose cells.

Rat adipose cells treated with insulin followed by isoproterenol exhibit a change in glucose transporter intrinsic activity (lowered maximal activity) and a decrease in insulin sensitivity (rightward shift of the concentration-response curve) when assayed for 3-O-methylglucose transport. To investigate the latter phenomenon, the distribution and phosphorylation state of insulin receptors was examined. Isoproterenol augmented the effect of insulin to reduce cell surface receptors by 20-30%. These receptors were recovered in microsomal fractions. Isoproterenol also markedly reduced insulin-stimulated [32P]phosphate incorporation into the plasma membrane receptor beta-subunit. These effects may account for the effect of isoproterenol to decrease the sensitivity of the glucose transport response to insulin.

Adipose Tissue↗
PubMed1991

Transcoronary atrioventricular nodal modification using microvascular collagen.

Surgical and catheter based techniques for atrioventricular (AV) nodal modification have recently been described. Similarly, transcoronary embolization for the treatment of arrhythmias has recently emerged as a potentially useful approach. This report reviews our experience of a novel technique using embolization of the AV node with an inert agent, cross-linked collagen, for the treatment of AV nodal reentrant tachycardia. Three patients with refractory nodal tachycardia received 0.1-0.5 mL cross-linked collagen (2 mg/mL) delivered via a catheter placed within the nodal artery. All developed transient complete AV block with subsequent recovery of conduction. Two patients have had no further tachycardia and were noninducible at restudy. One patient required electrical modification because of recurrent symptoms. One patient sustained a limited posterior infarct due to back-spill of collagen into the distal right coronary artery. This novel technique provides an alternative approach to a cure for AV nodal tachycardia without producing long-term heart block.

Atrioventricular Node↗
PubMed1991

Alcohol ablation of atrioventricular conduction.

Transcoronary ablation of atrioventricular conduction by dehydrated alcohol was attempted in 14 patients with refractory atrial arrhythmias. Alcohol (0.5 or 1.0 ml) was delivered after selective catheterisation of the atrioventricular nodal artery in the 10 patients in whom the artery could be identified by cineangiography. The other four patients underwent electrical ablation when the nodal artery could not be catheterised. Temporary atrioventricular block induced by dilute contrast and cold saline (0.9%) confirmed that the catheter was in the correct position before the alcohol was delivered. In all 10 patients complete atrioventricular block developed after alcohol ablation. The block persisted in all four patients given 1.0 ml alcohol but not in four of the six given 0.5 ml. The mean (SD) creatine kinase (MB fraction) at four to six hours after ablation was 76.5 (49.5) IU after 1.0 ml and 75.5 (43.1) IU after 0.5 ml alcohol (normal less than 20 IU). The overall success rate of alcohol ablation in the whole group on an "intention to treat" basis was 43%. The procedure was a technical success in six of the 10 patients in whom the nodal artery was identified. Transcoronary alcohol ablation of atrioventricular conduction should be considered in patients in whom electrical techniques have been unsuccessful.

Aged↗
PubMed1991

Pericardial haemorrhage causing right atrial compression after cardiac surgery: role of transoesophageal echocardiography.

After cardiac surgery transoesophageal echocardiography showed a large thrombus compressing the right atrium in three hypotensive patients. No satisfactory images were obtained by transthoracic imaging, which is often difficult in ventilated patients after cardiac surgery. Transoesophageal echocardiography, however, provided rapid diagnostic information and permitted prompt surgical intervention.

Aged↗
PubMed1991

A new method for quantification of regurgitant flow rate using color Doppler flow imaging of the flow convergence region proximal to a discrete orifice. An in vitro study.

While color Doppler flow mapping has yielded a quick and relatively sensitive method for visualizing the turbulent jets generated in valvular insufficiency, quantification of the degree of valvular insufficiency has been limited by the dependence of visualization of turbulent jets on hemodynamic as well as instrument-related factors. Color Doppler flow imaging, however, does have the capability of reliably showing the spatial relations of laminar flows. An area where flow accelerates proximal to a regurgitant orifice is commonly visualized on the left ventricular side of a mitral regurgitant orifice, especially when imaging is performed with high gain and a low pulse repetition frequency. This area of flow convergence, where the flow stream narrows symmetrically, can be quantified because velocity and the flow cross-sectional area change in inverse proportion along streamlines centered at the orifice. In this study, a gravity-driven constant-flow system with five sharp-edged diaphragm orifices (ranging from 2.9 to 12 mm in diameter) was imaged both parallel and perpendicular to the direction of flow through the orifice. Color Doppler flow images were produced by zero shifting so that the abrupt change in display color occurred at different velocities. This "aliasing boundary" with a known velocity and a measurable radial distance from the center of the orifice was used to determine an isovelocity hemisphere such that flow rate through the orifice was calculated as 2 pi r2 x Vr, where r is the radial distance from the center of the orifice to the color change and Vr is the velocity at which the color change was noted. Using Vr values from 54 to 14 cm/sec obtained with a 3.75-MHz transducer and from 75 to 18 cm/sec obtained with a 2.5-MHz transducer, we calculated flow rates and found them to correlate with measured flow rates (r = 0.94-0.99). The slope of the regression line was closest to unity when the lowest Vr and the correspondingly largest r were used in the calculation. The flow rates estimated from color Doppler flow imaging could also be used in conjunction with continuous-wave Doppler measurements of the maximal velocity of flow through the orifice to calculate orifice areas (r = 0.75-0.96 correlation with measured areas).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗