Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and... more
Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and vascular function under prolonged hypercholesterolemic conditions in New Zealand White rabbits assigned to one of four groups for 6, 8, or 16 wk of feeding: regular diet (RG), 10% flaxseed-supplemented diet (FX), 0.5% cholesterol-supplemented diet (CH), and 0.5% cholesterol- and 10% flaxseed-supplemented diet (CF). Cholesterol feeding resulted in elevated plasma cholesterol levels and the development of atherosclerosis. The CF group had significantly less atherosclerotic lesions in the aorta and carotid arteries after 6 and 8 wk than the CH animals. However, the anti-atherogenic effect of flaxseed supplementation was completely attenuated by 16 wk. Maximal tension induced in aortic rings either by KCl or norepinephrine was not impaired by dietary choles...
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Prostaglandins, Leukotrienes and Essential Fatty Acids, Volume 34, Issue 7, Pages A3, July 2002, Authors:Anna R. Weber; Richard Mitchell; Bradley P. Ander; Penelope Rampersad; Anton Lukas; James SC Gilchrist; Edwin A. Kroeger; Grant N.... more
Prostaglandins, Leukotrienes and Essential Fatty Acids, Volume 34, Issue 7, Pages A3, July 2002, Authors:Anna R. Weber; Richard Mitchell; Bradley P. Ander; Penelope Rampersad; Anton Lukas; James SC Gilchrist; Edwin A. Kroeger; Grant N. Pierce.
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Downloaded from rstb.royalsocietypublishing.org on December 20, 2010 Phil. Trans. R. Soc. Lond. B. 265, 135-148 (1973) [ 135 ] Printed in Great Britain Adrenergic influences on uterine smooth muscle By Jean M. Marshall and EA Kroeger... more
Downloaded from rstb.royalsocietypublishing.org on December 20, 2010 Phil. Trans. R. Soc. Lond. B. 265, 135-148 (1973) [ 135 ] Printed in Great Britain Adrenergic influences on uterine smooth muscle By Jean M. Marshall and EA Kroeger Division of Biological and Medical ...
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Phosphatidylcholine is the major phospholipid in mammalian tissues and the biosynthesis of phosphatidylcholine in H9c2 cells was previously shown to be stimulated by angiotensin II. In this study, we used the potent AT1 receptor... more
Phosphatidylcholine is the major phospholipid in mammalian tissues and the biosynthesis of phosphatidylcholine in H9c2 cells was previously shown to be stimulated by angiotensin II. In this study, we used the potent AT1 receptor antagonist, losartan, to determine if the angiotensin II-mediated stimulation of phosphatidylcholine biosynthesis was mediated by AT1 receptors. H9c2 cells were incubated with angiotensin II in the absence or presence of various concentrations of losartan. The cells were then incubated with [methyl-3H]choline for an additional 60 min and the radioactivity incorporated into phosphatidylcholine and its choline-containing metabolites determined. Losartan at concentrations which block AT1 receptors did not effect phosphatidylcholine biosynthesis mediated by angiotensin II. In contrast, higher concentrations of losartan inhibited radioactivity incorporated into phosphatidylcholine and its metabolites and this was due to a losartan-mediated reduction in choline uptake. Kinetic studies revealed that the losartan-mediated inhibition of choline uptake was competitive. High concentrations of losartan caused a translocation of CTP:phosphocholine cytidylyltransferase from the cytosolic (inactive) to the membrane (active) fraction likely as a compensatory mechanism for the losartan-mediated reduction in new phosphatidylcholine biosynthesis. Incubation of cells with PD123319, a potent AT2-receptor antagonist, did not block the angiotensin II-mediated stimulation of phosphatidylcholine biosynthesis. The results suggest that angiotensin II stimulates phosphatidylcholine biosynthesis independent of AT1- and AT2-receptor activation and losartan inhibits phosphatidylcholine biosynthesis by reducing choline uptake in H9c2 cells.
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Cytosolic phospholipase A 2 (cPLA 2 ) is responsible for the release of arachidonic acid, a precursor for eicosanoid biosynthesis, from cellular phospholipids. The objective of this study is to examine the regulation of cPLA 2 by... more
Cytosolic phospholipase A 2 (cPLA 2 ) is responsible for the release of arachidonic acid, a precursor for eicosanoid biosynthesis, from cellular phospholipids. The objective of this study is to examine the regulation of cPLA 2 by peroxisome proliferator-activated receptor (PPAR) activators in preadipo- cyte SW872 (SW) cells. PPAR belong to the superfamily of nu- clear hormone receptors that heterodimerize
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We have previously shown that in the presence of tetraethylammonium (TEA, 6.7-67 mM) phasic mechanical activity and a myogenic response (MR) to quick stretch are produced in normally multi-unit tracheal smooth muscle. The present studies... more
We have previously shown that in the presence of tetraethylammonium (TEA, 6.7-67 mM) phasic mechanical activity and a myogenic response (MR) to quick stretch are produced in normally multi-unit tracheal smooth muscle. The present studies were designed to investigate the electrophysiological basis for these changes in the mechanical properties of the muscle. Intracellular recordings showed that in the presence of TEA the membrane was partially depolarized and trains of small (8-20 mV), decrementally conducted action potentials were produced spontaneously at a frequency of 15-20/min. Action potentials could also be stimulated by external electrodes, and the conduction velocity over short distances was 0.84 plus or minus 0.2 cm/s. Membrane conductance and rectification, as measured by the magnitude of electrotonic potentials in response to external stimulation, were reduced in the presence of TEA. The length constant was increased from 1.6 plus or minus 0.1 to 2.8 plus or minus 0.2 mm....
The objective of the research project was to investigate whether fenofibrate treatment may alter the biochemical content of the oxidized LDL and consequently its ability to impair the endothelium-dependent relaxation in hyperlipidemic... more
The objective of the research project was to investigate whether fenofibrate treatment may alter the biochemical content of the oxidized LDL and consequently its ability to impair the endothelium-dependent relaxation in hyperlipidemic patients. We hypothesized that fenofibrate treatment of hyperlipidemic patients may attenuate the ability of their oxidized LDL to impair the endothelium-dependent relaxation of the blood vessels as a consequence of fenofibrate-induced changes to the content and composition of lysoPC in the LDL molecule. Hyperlipidemic patients (Type IIb and Type IV) were recruited from the Lipid Clinic, HSC, Winnipeg, Canada, for this study. A blood sample was taken immediately after the recruitment, a second sample was taken after 6 weeks of dietary treatment, and a third sample was taken after 8 weeks of fenofibrate treatment. LDL was isolated from the plasma and oxidized by copper sulfate. Fenofibrate was shown to be highly effect in the reduction of total choleste...
Research Interests: Lipids, Molecular and cellular biology, Humans, Cholesterol, Animals, and 15 moreVascular endothelium, Acetylcholine, Gas Chromatography, Triglycerides, LDL-cholesterol, Rats, Cellular and Molecular Neuroscience, Vasodilation, Blood Vessel, Oxidation-Reduction, Low Density Lipoprotein (LDL), Molecular and Cellular Biochemistry, Fenofibrate, Biochemistry and cell biology, and Oxidized LDL
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The effect of tone on responses of canine tracheal smooth muscle (TSM) to norepinephrine (NE) was studied to elucidate the role of sympathetic innervation and adrenoceptors in the control of the airways. Electrical field stimulation... more
The effect of tone on responses of canine tracheal smooth muscle (TSM) to norepinephrine (NE) was studied to elucidate the role of sympathetic innervation and adrenoceptors in the control of the airways. Electrical field stimulation produced contraction of TSM in vitro which was augmented by eserine, depressed by phentolamine, potentiated by propranolol in the presence of K+ (14 mM) and almost eliminated by tetrodotoxin or atropine. Resting TSM did not contract in response to NE (10(-8) to 10(-4) M) in the presence or absence of propranolol (10(-5)M). The addition of NE (10(-8) to 10(-6) M) at the plateau of contraction produced by K+ (22.8 mM), histamine (10(-6) M) or acetylcholine (5 X 10(-8) M) produced a further phentolamine-sensitive contraction which was potentiated by beta adrenoceptor blockade with propranolol (10(-5) M). The addition of tyramine (10(-5) to 10(-4) M) at the plateau of contraction produced by K+ (22.8 mM) produced a further contraction which was potentiated b...
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The present studies were designed to measure the metabolic cost, in terms of oxygen consumption (QO2) and lactate production, of membrane ion transport, and activation of the contractile apparatus of rat myometrium. The normal QO2 of... more
The present studies were designed to measure the metabolic cost, in terms of oxygen consumption (QO2) and lactate production, of membrane ion transport, and activation of the contractile apparatus of rat myometrium. The normal QO2 of 16.98 +/- 0.84 mumol/g wet tissue per h was reduced to 15.42 +/- 0.66 in the presence of high-K (127 mM) solution. This was further reduced to 14.05 +/- 0.77 and 13.53 +/- 0.76 by the addition of D-600 (10(-5) M), which inhibits Ca influx or in the presence of Ca-deficient high-K solutions, respectively. Ouabain (10(-3) M) reduced QO2 by an amount similar to that produced by high K. Addition of K+ to Na-rich preparations produced an immediate ouabain-sensitive increase of QO2 whose rate was a linear function of [K+]o up to 30 mM in Ca-deficient solution. In all of the above conditions, changes in lactate release paralleled those in QO2. Isoproterenol (10(-6) M), which causes mechanical inhibition of myometrium, had no effect on the QO2 of muscles in nor...
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In multi-unit tracheal smooth muscle (TSM), quick stretches applied at a velocity of 5 times the measured maximum velocity of isotonic shortening of the muscle, of a magnitude 3 times the measured extension of the series-elastic component... more
In multi-unit tracheal smooth muscle (TSM), quick stretches applied at a velocity of 5 times the measured maximum velocity of isotonic shortening of the muscle, of a magnitude 3 times the measured extension of the series-elastic component when the muscle contracts maximally, and at optimal muscle length (L-o) were unable to elicit any myogenic response (MR). Experimental conditions such as hypoxia (P-O2 smaller than 60 mmHg) and acidosis (pH equals 6.8) or the presence of Ba2+ (2 mM), acetylcholine (10-6 M), or high (K+)-o (59 mM) were also unable to elicit the MR. However, tetraethylammonium chloride (TEA, 0.4-67 mM) produces 1) spontaneous phasic contractions and 2) a MR to quick stretch. The ionic basis for these changes was then investigated by studying the Ca and Mg dependence of the response to TEA. The dose-response relationship to TEA was shifted to the left by decreasing external Mg2+ from 2.5 to 0.5 mM. The ability of TSM to produce a MR was absolutely dependent on externa...
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Research Interests: Life Sciences, Lipids, Nitric oxide, Animals, Male, and 15 moreAcetylcholine, Liver Function, Risk factors, Rats, Risk Factors, Lipid Profile, Liver Disease, Blood Vessel, Muscle Relaxation, Potassium Chloride, Biochemistry and cell biology, Low density lipoprotein cholesterol, Bile ducts, Ligation, and Pharmacology and pharmaceutical sciences
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Equine airway smooth muscle is innervated by vagal efferents and, in addition, displays spontaneous mechanical activity. The preparation thus appears to contain at least two discrete excitable components, the cholinergic neural elements... more
Equine airway smooth muscle is innervated by vagal efferents and, in addition, displays spontaneous mechanical activity. The preparation thus appears to contain at least two discrete excitable components, the cholinergic neural elements and the smooth muscle membrane. Indomethacin (INDO), a cyclooxygenase (CO) inhibitor, exerts a considerable potentiation of function in this preparation. The latter may be effected indirectly, through loss of the inhibitory effect of endogenous prostaglandin E2 (PGE2) on neural acetylcholine release and through direct effects on smooth muscle of the generally antagonistic CO and lipoxygenase (LO) metabolites. The present studies were designed to assess the relative contributions of altered arachidonic acid metabolism on those respective elements. The utility of the model, in terms of distinguishing neural and myogenic components, was assessed by examining the effects of the muscarinic antagonist atropine (ATR) and the neurotoxin tetrodotoxin (TTX) on...
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A decrease in the cellular utilization of glucose produced by several glucose antimetabolites and especially by 2 deoxy-D-glucose considerably stimulates food intake. An analysis of this phenomenon is presented in terms of the available... more
A decrease in the cellular utilization of glucose produced by several glucose antimetabolites and especially by 2 deoxy-D-glucose considerably stimulates food intake. An analysis of this phenomenon is presented in terms of the available experimental evidence. Experiments in which glucose antimetabolites have been administered so as to influence selectively the central and peripheral glucosensitive loci suggest a possible mechanism for the action of the substances. The mechanisms by which glucose antimetabolites and exogenous insulin induce cellular glucoprivation and the subsequent changes in food intake are compared and discussed.
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ABSTRACT The changes in cAMP levels in the hippocampus, cerebral cortex and the neostriatum were investigated at different times after the cerebroventricular administration of SRIF. An early significant increase in cAMP levels (at 5... more
ABSTRACT The changes in cAMP levels in the hippocampus, cerebral cortex and the neostriatum were investigated at different times after the cerebroventricular administration of SRIF. An early significant increase in cAMP levels (at 5 minutes) in the hippocampus induced by SRIF was eliminated by pretreatment with sotalol. However, the overall behavioral response to SRIF was not affected by sotalol. Sotalol itself significantly reduced cAMP levels in control experiments. In cerebral cortex, an SRIF-induced increase in cAMP levels was significantly lowered by sotalol pretreatment at both 5 and 15 minutes post-SRIF. In neostriatum, a sustained elevation in cAMP levels was observed at 5 and 15 minutes after the intraventricular infusion of SRIF. Sotalol pretreatment failed to reduce the cAMP levels although it lowered its increase at 15 min. post-SRIF. The results appear to show a beta adrenergic involvement in the cAMP response to SRIF and an apparent independence of the behavioral response from cAMP changes.
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The purpose of the present study was to examine the effects on cataractogenesis of daily sc administration of the Ca2+ antagonist drug verapamil to diabetic rats. Streptozotocin-induced diabetic rats were given verapamil half-way through... more
The purpose of the present study was to examine the effects on cataractogenesis of daily sc administration of the Ca2+ antagonist drug verapamil to diabetic rats. Streptozotocin-induced diabetic rats were given verapamil half-way through the 8-week experimental period or during the full 8 weeks of diabetes. Verapamil administration had no effect on the high blood glucose values, low circulating insulin levels, or elevated triglyceride and cholesterol concentrations in the diabetic rats. Untreated diabetic rats had a 90% incidence of cataracts. Four weeks of verapamil administration reduced this incidence to 41%, and a full 8 weeks of drug treatment further lowered the incidence to 20%. Diltiazem, another Ca2+ antagonist, lowered the incidence of cataracts in the diabetic rats to a similar extent. Verapamil administration to the diabetic animals also partially protected against the presence of retinal microangiopathy in the diabetic animals. Lenticular hydration and lipid accumulation were only indirectly related to cataractogenesis in the diabetic rats and its protection by verapamil treatment. Lenticular electrolyte imbalance, particularly Ca2+, in the diabetic animals was closely correlated with cataract formation, and verapamil significantly reduced the alterations in these ion concentrations. The present results demonstrate the efficacy of verapamil as a protective agent against cataractogenesis and some retinal damage in diabetic animals. Most importantly, this occurs in the absence of any change in the glycemic status of the diabetic animals. The findings strongly support a role for lenticular Ca2+ imbalance in cataract development in diabetes and provide initial evidence to suggest its clinical use in the diabetic population at risk for blindness.
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Page 1. AMERICAN JOURNAL OF PHYSIOLOGY Vol. 225, No. 6, December 1973. Printed in USA Beta-adrenergic effects on rat myometrium: mechanisms of membrane hyperpolarization EA KROEGER AND JM MARSHALL ...
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... concerning the function of the ASM in disease. A canine model of allergic asthma (11) was used to study the role of changes in contractile properties of ASM in the pathogenesis of asthma. ASM tone is known to depend upon the ...
Research Interests: Asthma, Dogs, Smooth muscle, Applied, Animals, and 3 moreImmunoglobulin E, Trachea, and Muscle contraction
Hypoxia impairs contractility in canine tracheal smooth muscle (TSM). This is attributed to intracellular lactacidosis. The present studies were undertaken to confirm this. Lactate was found to be significantly increased in hypoxic TSM... more
Hypoxia impairs contractility in canine tracheal smooth muscle (TSM). This is attributed to intracellular lactacidosis. The present studies were undertaken to confirm this. Lactate was found to be significantly increased in hypoxic TSM (65.36 +/- 7.37 mg/100 g wet tissue), compared to normoxic (29.83 +/- 5.05). Intracellular pH (pHi) was, however, significantly increased in hypoxic active TSM to 7.71 +/- 0.05 as compared to 7.30 +/- 0.03 in normoxic active muscle. pHi of resting normoxic muscle (7.20 +/- 0.04) was statistically not different from that of resting hypoxic muscle. The pHi's of resting normoxic and active hypoxic muscles were significantly different. These results show that under in vitro, hypoxic conditions: 1) an increase in glycolysis in TSM is indicated by the increased lactate production, 2) there is a surprising, concomitant rise in pHi rather than a decrease as previously expected, and 3) it is mechanical activity of the muscle which leads to this paradoxical...
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Atorvastatin is an established HMG-CoA reductase inhibitor which effectively reduces the plasma low density lipoprotein (LDL)-cholesterol level in hyperlipidemic patients. The present study was designed to investigate whether atorvastatin... more
Atorvastatin is an established HMG-CoA reductase inhibitor which effectively reduces the plasma low density lipoprotein (LDL)-cholesterol level in hyperlipidemic patients. The present study was designed to investigate whether atorvastatin treatment can modify the biochemical content of oxidized LDL in hyperlipidemic patients and the ability of oxidized LDL to impair the endothelium-dependent relaxation of blood vessels. With atorvastatin (10 mg/day) treatment for 4 weeks in 19 type IIa hyperlipidemic patients, total cholesterol level was lowered by 23%, LDL-cholesterol was lowered by 32% and triacylglycerol was lowered by 19% as compared with dietary therapy alone. High density lipoprotein levels increased by approximately 9%. The ability of oxidized LDL from hyperlipidemic patients after atorvastatin treatment to impair the endothelium-dependent relaxation was significantly reduced as compared with dietary intervention alone. Analysis of the biochemical contents of oxidized LDL fro...
Research Interests: Phospholipids, Humans, Diet Therapy, Vascular endothelium, LDL-cholesterol, and 10 moreAdult, Drug Therapy, High Density Lipoprotein, Blood Vessel, Oxidation-Reduction, Low Density Lipoprotein (LDL), Total Cholesterol, Molecular and Cellular Biochemistry, Biochemistry and cell biology, and Combined Modality Therapy
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Tracheal smooth muscle (TSM) from an ovalbumin sensitized canine model of allergic asthma showed hypersensitivity and hyper-reactivity to histamine (H) when compared to that from littermate controls in vitro. Mepyramine abolished H... more
Tracheal smooth muscle (TSM) from an ovalbumin sensitized canine model of allergic asthma showed hypersensitivity and hyper-reactivity to histamine (H) when compared to that from littermate controls in vitro. Mepyramine abolished H responses in TSM of both groups; it also abolished the allergic response to obalbumin of TSM from sensitized dogs. The H2 receptor agonist, 4-methyl histamine (4-MH) caused small dose-related decreases in H contractures but had no effect on carbachol- or K+-induced tension. Metiamide, an H2 antagonist, did not enhance the H contracture, suggesting the 4-MH may not be exerting a relaxant effect since H2 receptors were absent. The maximum H-induced isometric tension was potentiated when the sensitized and control muscle strips were pre-equilibrated with 4-MH. These observations are consistent with the presence in canine TSM of H1 but not relaxant H2 receptors, the release of endogenous H to the tissue during the antigen-antibody reaction, and the competitio...
Research Interests: Pharmacology, Asthma, Histamine, Dogs, Smooth muscle, and 4 moreAnaphylaxis, Animals, Trachea, and Muscle contraction
Perfusion of the rat right ventricular wall muscle for 4 min with a Ca2(+)-free medium followed by perfusion with a Ca2(+)-containing solution resulted in a 42% recovery of developed tension, contracture, and a massive release of creatine... more
Perfusion of the rat right ventricular wall muscle for 4 min with a Ca2(+)-free medium followed by perfusion with a Ca2(+)-containing solution resulted in a 42% recovery of developed tension, contracture, and a massive release of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) from the muscle. High concentrations (1-5 mM) of amiloride partially protected the ventricular wall from Ca2+ paradox-induced dysfunction. The inclusion of benzamil, an amiloride analogue, 2 min before and during the Ca2(+)-free perfusion period prevented contracture development, restored force development, and almost totally eliminated the release of CPK and LDH from the muscle. Contractile function was best protected by 10-50 microM benzamil. The results demonstrate the efficacy of benzamil as a protective agent against Ca2+ paradox-induced myocardial dysfunction and damage. In view of the known capacity of benzamil to block transsarcolemmal Na(+)-Ca2+ exchange, this study supports the involveme...
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The effects of two smooth muscle relaxants, isoproterenol and D-600, on calcium movements in rat myometrium were investigated. Both relaxants caused a nonspecific increase in 45-Ca efflux due to changes in mechanical tension but the... more
The effects of two smooth muscle relaxants, isoproterenol and D-600, on calcium movements in rat myometrium were investigated. Both relaxants caused a nonspecific increase in 45-Ca efflux due to changes in mechanical tension but the additional net loss expected on the basis of previous studies with isoproterenol could not be demonstrated due to a high background of calcium exchange. Analysis of 45-Ca and 40-Ca residual in the muscle after efflux experiments and washing of the tissue in a Ca-deficient solution containing LaCl3 (2.0 mM) showed that the specific activity ratio 45-Ca/40-Ca was unaltered with isoproterenol and, thus, the net loss of calcium occurred equally from slowly and rapidly exchanging compartments. "Pulse label" experiments in which 45-Ca and either isoproterenol or D-600 were added simultaneously for a 2-minute period demonstrated that both relaxants decreased the 45-Ca space; however, the specific activity ratio 45-Ca/40-Ca in the tissue was reduced wh...