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J T Saari

Publications and source records attributed to J T Saari.

At least 37 records · Page 2Linked to original sources
PubMed1995

Defects of copper deficiency in rats are modified by dietary treatments that affect glycation.

We examined the hypothesis that nonenzymatic glycosylatin of proteins (glycation) contributes to the defects of copper deficiency. We studied copper-adequate and -deficient rats while altering two factors known to affect glycation: type of dietary carbohydrate and amount of food intake. Copper deficiency caused cardiac enlargement and anemia, decreased erythrocyte osmotic fragility, enhanced heart lipid peroxidation, increased the percentage of glycated hemoglobin (Hb A1) and reduced staining of lens crystallins on SDS-PAGE gels (suggestive of glycation). Increasing dietary sucrose reduced organ copper concentration, exacerbated the rise in Hb A1 and worsened the anemia caused by copper deficiency. Food restriction ameliorated heart and erythrocyte defects, reduced the percentage of glycated hemoglobin and heart peroxidation and also improved heart and liver copper status in copper-deficient rats. These findings indicate that copper deficiency enhances glycation and that sucrose may exacerbate some defects of copper deficiency by enhancing glycation. Inhibition of defects of copper deficiency by food restriction suggests that glycation and/or peroxidation may contribute to those defects.

Analysis of Variance↗
PubMed1995

Intracranial aneurysms: MR angiographic screening in 400 asymptomatic individuals with increased familial risk.

PURPOSE: To evaluate the accuracy and limitations of magnetic resonance (MR) angiographic screening for incidental intracranial aneurysms (IAs) in healthy individuals with a family history of IA. MATERIALS AND METHODS: Four hundred asymptomatic individuals in 68 families with a history of aneurysmal subarachnoid hemorrhage underwent MR angiography. Six families also had a history of polycystic kidney disease. A multislab, three-dimensional, time-of-flight sequence was used. Conventional angiography was performed to confirm positive MR angiographic findings. RESULTS: IAs were detected with MR angiography in 37 individuals, 32 of whom underwent conventional angiography. Intraobserver consistency was excellent (kappa = 0.96), and interobserver reproducibility was good to excellent (kappa = 0.59-0.82). Both techniques showed similar results in the evaluation of size, localization, and orientation of aneurysms and visibility of the aneurysm neck. CONCLUSION: MR angiography is an accurate and feasible method of noninvasive screening for IAs in individuals at high risk. Conventional angiography is still necessary before operative treatment.

Adult↗
PubMed1995

A role for dietary copper in nitric oxide-mediated vasodilation.

OBJECTIVE: This study was designed to investigate the role of dietary copper in nitric oxide-mediated arteriolar dilation. METHODS: Male weanling Sprague-Dawley rats were fed a purified diet that was either copper-adequate (6.0 micrograms Cu per g diet) or copper-deficient (0.3 microgram Cu per g diet) for a period of 4 weeks. Each rat was anesthetized with pentobarbital and its cremaster muscle was positioned in a Krebs'-filled bath to which graded concentrations of vasoactive agents were added. In the first series, responses to norepinephrine (NE 10(-9)-10(-6) M) and acetylcholine (ACH 10(-7)-10(-4) M) were compared in third-order arterioles. Second, the dilator response to 10(-5) M ACH in the absence and presence of 240 U/ml Cu, Zn-superoxide dismutase (SOD) was determined. Third, arteriolar dilation was determined in response to NO-independent stimulation of soluble guanylate cyclase with hydrogen peroxide (10(-7)-10(-5) M) and to dibutyryl cGMP (10(-6)-10(-4) M), dibutyryl cAMP (10(-6)-10(-4) M), and papaverine (10(-4) M). RESULTS: The arteriole constrictor response to NE and the dilator response to hydrogen peroxide, dibutyryl cGMP and cAMP, and papaverine were not different between the dietary groups. Copper deficiency attenuated the ACH-induced dilation, but the response was restored in the presence of SOD. CONCLUSIONS: The inactivation of cytosolic Cu, Zn-SOD by restriction of dietary copper results in the depression of NO-mediated vascular smooth-muscle relaxation probably by interaction of NO with superoxide.

Animals↗
PubMed1995

Expression of gamma-glutamylcysteine synthetase in the liver of copper-deficient rats.

Copper deficiency in rats increases hepatic glutathione concentration. The present study was undertaken to determine the biochemical and molecular basis for the glutathione elevation. Weanling Sprague-Dawley rats were fed a purified diet deficient in copper (0.4 micrograms/g diet) or one containing adequate copper (5.7 micrograms/g diet) for 4 weeks. Hepatic glutathione concentration, the activity of the rate-limiting enzyme in glutathione biosynthesis, gamma-glutamylcysteine synthetase (gamma-GCS) and the relative amount of mRNA for the enzyme were determined. Hepatic glutathione concentration in copper-deficient rats was significantly elevated (6.6 vs 5.6 mumol/g). The activity of hepatic gamma-GCS was 1.6 times higher in the copper-deficient than in the copper-adequate rats (58.0 vs 35.9 nmol NADH/min.mg protein). The steady-state amount of mRNA for gamma-GCS was increased 5-fold in the copper-deficient rat liver. The findings demonstrate that the elevated hepatic glutathione concentration in copper-deficient rats results from upregulation of gamma-GCS activity. This study provides further understanding of changes in hepatic glutathione metabolism induced by copper deficiency.

Analysis of Variance↗
PubMed1995

Hemostatic mechanisms in marginally copper-deficient rats.

Severe dietary copper restriction has been shown to alter platelet structure and function and to significantly delay thrombogenesis and hemostasis in rats. In the present study, the relationship between dietary copper status and hemostasis were determined in the rat cremaster muscle microcirculation. Male, weanling Sprague-Dawley rats were fed a purified diet that was made copper-adequate by addition of 6.0 micrograms copper/gm of diet (CuA) or was marginally deficient by adding 1.5 micrograms (CuM1.5) or 3.0 micrograms (CuM3.0) copper/gm of diet for 1, 3, or 5 weeks. The rats were anesthetized with sodium pentobarbital, and the cremaster was spread in a Krebs'-filled tissue bath. Hemostasis was quantified after two methods of thrombus induction: (1) micropuncture of a 60 to 80 microns venule, which exposes subendothelial structures, and (2) intravascular light-dye photochemistry, which does not expose the subendothelial collagen. The CuM1.5 and CuM3.0 diets significantly decreased hepatic copper after 3 weeks as compared with the CuA diet. Bleeding time after micropuncture was significantly longer at all times in the CuM1.5 group and after 5 weeks in the CuM3.0 group. Platelet thrombus formation and time to vessel occlusion in the light dye-treated vessels were not different between any of the dietary groups at any times tested. There was also no difference in prothrombin time (PT), in the activity of copper-related plasma coagulation factors V and VIII, or in the hematocrit between the CuA and CuM1.5 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The role of the mast cell in acute inflammatory responses of copper-deficient rats.

Macromolecular leakage associated with mast cell degranulation was studied in the cremaster muscle microcirculation of copper-deficient rats. Male Sprague-Dawley rats were fed a purified diet either adequate for copper (6 micrograms copper/gram diet) or deficient (no added copper) 4 weeks prior to experimentation. The rats were anesthetized and the cremasters (with nerve and blood supply intact) were spread in a tissue bath filled with Kreb's solution. In vivo television microscopy was used to observe the microcirculation. Intravascular fluorescein isothiocyanate conjugated to bovine serum albumin was injected and interstitial fluorescent emission intensity was used as an index of macromolecular leakage. Topical administration of the mast cell degranulator compound 48/80 (1.0 and 10.0 micrograms/ml) induced a significantly greater macromolecular leakage in the copper-deficient animals. The compound 48/80 leakage was blocked in both groups of rats by pretreatment with diphenhydramine which is a histamine H1 receptor blocker. Topical administration of the inflammatory mediators histamine, serotonin, and bradykinin all induced macromolecular leakage which was not significantly different between groups. These results suggest that copper deficiency increases macromolecular leakage associated with mast cell degranulation by a primary effect on the mast cell rather than on the endothelium.

Animals↗
PubMed1994

Weak antioxidant defenses make the heart a target for damage in copper-deficient rats.

Copper deficiency causes more salient pathologic changes in the heart than in the liver of rats. Although oxidative stress has been implicated in copper deficiency-induced pathogenesis, little is known about the selective toxicity to the heart. Therefore, we examined the relationship between the severity of copper deficiency-induced oxidative damage and the capacity of antioxidant defense in heart and liver to investigate a possible mechanism for the selective cardiotoxicity. Weanling rats were fed a purified diet deficient in copper (0.4 microgram/g diet) or one containing adequate copper (6.0 microgram/g diet) for 4 weeks. Copper deficiency induced a 2-fold increase in lipid peroxidation in the heart (thiobarbituric assay) but did not alter peroxidation in the liver. The antioxidant enzymatic activities of superoxide dismutase, catalase, and glutathione peroxidase were, respectively, 3-, 50- and 1.5-fold lower in the heart than in the liver, although these enzymatic activities were depressed in both organs by copper deficiency. In addition, the activity of glutathione reductase was 4 times lower in the heart than in the liver. The data suggest that a weak antioxidant defense system in the heart is responsible for the relatively high degree of oxidative damage in copper-deficient hearts.

Animals↗
PubMed1994

Platelet thrombus formation and hemostasis are delayed in the microcirculation of copper-deficient rats.

The role of dietary copper in platelet thrombus formation and hemostasis was studied in the cremaster muscle microcirculation. Male weanling Sprague-Dawley rats were fed purified diets that were either copper-adequate (94 mumol Cu/kg diet) or copper-deficient (0 mumol Cu/kg diet) for 1, 3 or 5 wk. The rats were anesthetized with pentobarbital, and the cremaster was spread in a Krebs-filled tissue bath. Fluorescein isothiocyanate tagged to bovine serum albumin (FITC-BSA) was injected intra-arterially. After a 20-min equilibration, blue light (1.8 W/cm2, 450-490 nm) was used to activate the FITC-BSA and induced platelet thrombus formation within the vasculature. In vivo television microscopy was used to quantify the thrombus formation. In rats fed the copper-deficient diet for 3 or 5 wk, platelet thrombus formation induced by photoactivation was significantly (P < 0.05) delayed and prothrombin time was significantly longer but the number of circulating platelets was significantly greater than in age-matched rats fed the copper-adequate diet. Bleeding time, measured after micropuncture of a second-order venule, was significantly longer but hematocrit was significantly lower in rats fed the copper-deficient diet than in those fed the copper-adequate diet. The results demonstrate that platelet-mediated hemostasis is depressed in dietary copper deficiency and that this may be due to a decrease in hematocrit, a decrease in the activity of a coagulation factor and/or an alteration of platelet function.

Animals↗
PubMed1994

Dietary copper deficiency increases the mast cell population of the rat.

Mast cell-released histamine has been implicated in the enhanced acute inflammatory response of copper-deficient rats. The present study examined possible changes in the copper-deficient mast cell which may account for increased macromolecular leakage and edema formation. Mast cell populations were determined in the cremaster muscle of copper-adequate and copper-deficient rats. Total histamine content, unstimulated histamine release and concentration-dependent histamine release with the mast cell secretagogue compound 48/80 were also determined in isolated peritoneal mast cells. A significantly higher number of mast cells were found in the cremaster muscle of the copper-deficient rats (78 +/- 7 cells/5 microns section) than in the copper-adequate controls (51 +/- 4). Total histamine content per cell as well as unstimulated and stimulated release of the inflammatory mediator per cell were not different between the groups. The results suggest that dietary copper deficiency increases the mast cell population but does not alter the mast cell histamine content or sensitivity to degranulation in the rat. This increase in the number of mast cells may be a mechanism by which acute inflammation is enhanced in copper deficiency.

Animals↗
PubMed1994

Dietary copper deficiency reduces heat shock protein expression in cardiovascular tissues.

Dietary copper deficiency impairs cardiovascular function by depression of catecholamine metabolism, and alteration of the structure and function of cardiac mitochondria. Heat shock proteins (HSPs) are a group of cellular homeostatic proteins that are induced in vascular tissue by catecholaminergic transmission after exposure to stress. We investigated the effects of dietary copper deficiency on the induction and accumulation of HSPs in several cardiovascular tissues. Stress-induced levels of aortic HSP70 mRNA were reduced in copper-deficient (CuD) rats when compared with copper-adequate (CuA) controls. Cocaine-induced HSP70 mRNA accumulation was not different between CuA and CuD rats, suggesting that reduced HSP70 levels in restrained CuD animals may result from altered catecholaminergic neurotransmission. The level of HSP60 mRNA was specifically reduced in the atria of CuD rats, which may be associated with altered mitochondrial structure and function. These results describe a novel relationship between dietary copper deficiency and the expression of highly conserved cellular stress response proteins. Loss of these essential homeostatic proteins in vascular tissue may contribute to the impairment of cardiovascular function known to accompany copper deficiency.

Adrenal Glands↗
PubMed1993

Hyperbaric hyperoxia exaggerates respiratory membrane defects in the copper-deficient rat lung.

Scanning (SEM) and transmission electron microscopy (TEM) were used to examine the effect of dietary copper deficiency and hyperbaric hyperoxia, alone and in combination, on lung structure. Male, weanling Sprague-Dawley rats were fed a copper-deficient (CuD, 0.2 microgram/g) or copper-adequate diet (CuA, 5.1 micrograms/g). After 35-41 d on their respective diets, rats from each group were placed inside a pressure vessel kept at 27 degrees C under one of two pressure protocols. Air controls were maintained at 1 atm for 75 min. Rats exposed to oxygen were maintained at 1 atm of air plus 3 atm of oxygen for 1 h and then decompressed for 15 min. Under SEM, none of the treated lungs (CuD, CuA-O2 exposed, or CuD-O2 exposed) showed abnormal lung morphology from the conducting bronchioles down to the alveoli. Copper-deficient red blood cells were abnormally shaped. Under TEM, CuA-O2-exposed lungs showed thicker respiratory membranes, especially basement membranes and endothelial cells, and alveolar Type II cells having more than the usual number of surfactant vacuoles. CuD lungs also showed thicker endothelial and basement membrane components of the respiratory membrane, but normal looking Type II cells. CuD-O2-exposed lungs showed greatly thickened respiratory membranes and severe disruption of both endothelium and basement membrane and, judging by the increased number of nuclei per field, an increase in the number of both Type I and Type II cells. We conclude that copper deficiency enhances the damage caused by O2 toxicity, an effect that may be caused by reduced antioxidant status.

Animals↗
PubMed1993

Amelioration of effects of severe dietary copper deficiency by food restriction in rats.

To test the effect of food restriction on responses to dietary copper deficiency, male weanling rats were fed two amounts of dietary copper via five dietary-intake regimens ranging from ad libitum to 70% of ad libitum intake. Copper-deficient rats exhibited characteristic signs, including depressed organ copper content, reduced activity of copper-dependent enzymes, enlarged hearts, and anemia. Food restriction attenuated the cardiac enlargement, red blood cell defects, and reduction of superoxide dismutase activity in copper-deficient rats. Mineral and enzyme assays suggested that possible mechanisms for this amelioration are the correction of copper status and/or the improvement of antioxidant status. Also, food restriction depressed serum cholesterol and enhanced cytochrome c oxidase activity in both copper-adequate and copper-deficient rats, which compensated for effects of copper deficiency. A second experiment illustrated that the mortality associated with severe copper deficiency was also inhibited by food restriction.

Animals↗
PubMed1993

Isolated hearts from copper-deficient rats exhibit improved postischemic contractile performance.

Dietary copper deficiency affects a number of enzymes, the function of which may influence the outcome of myocardial ischemia-reperfusion injury. Male weanling rats were fed diets that were adequate (> 5 mg/kg) or deficient (< 1 mg/kg) in copper. After 4 wk, the rats' hearts were isolated and used to study the effects of ischemia-reperfusion on intraventricular developed pressure (DevP), positive and negative rates of intraventricular pressure change (+dp/dt and -dp/dt) and release of lactate dehydrogenase and creatine kinase from the heart. The ischemia-perfusion protocol included a 15-min equilibration period, 30 min of warm, total ischemia and reperfusion for 30 min. Preischemic hearts from copper-deficient rats produced lower DevP than hearts from copper-adequate rats at all levels of preload. However, postischemic recovery of DevP was significantly greater in the hearts of the copper-deficient group. Furthermore, the postischemic patterns of lactate dehydrogenase and creatine kinase release in the two groups were significantly different. These findings indicate that, although dietary copper deficiency adversely affects a number of enzymatic systems, the functional recovery of hearts subjected to ischemia-reperfusion injury is improved when the diet is restricted in copper.

Animals↗
PubMed1993

Comparative responses of rats to different copper intakes and modes of supplementation.

Purified diets deficient in copper and based on either sucrose, egg white, and corn oil or sucrose, casein, corn starch, and safflower oil were fed to young rats. Graded amounts of copper were supplied in drinking solutions with the former diet and by addition to the latter diet; anatomical, chemical, and physiologic responses were compared. Three micrograms Cu/ml and 5 micrograms Cu/g were sufficient to maximize the direct assessments of copper nutriture (copper in blood plasma, heart, and liver). Nutritional adequacy by indirect criteria (heart iron, plasma ceruloplasmin, heart weight divided by body weight, plasma cholesterol, and body weight) generally was found with 3 micrograms/ml and 4 micrograms/g. Anemia was an insensitive characteristic of deficiency. Liver iron was minimized by 4 micrograms Cu/ml and 5 micrograms Cu/g. Most of the differences in response to copper added to water in comparison to copper added to diet probably were explained by the lower amount of copper in the casein diet. Responses to the two dietary regimens were similar when variables were plotted against liver copper. Correlation coefficients with liver copper ranged from 0.52 for liver zinc to 0.96 for heart iron. Liver copper probably is the best index of copper nutriture.

Animals↗
PubMed1992

Short-term dietary copper deficiency does not inhibit angiogenesis in tumours implanted in striated muscle.

The effect of dietary copper deficiency on tumour growth, neovascularisation and microvascular integrity was studied in the rat cremaster muscle. Male, weanling Sprague-Dawley rats were fed purified diets which were copper deficient (< 0.5 micrograms g-1 of diet) or copper adequate (5 micrograms g-1 of diet). Seven days after initiation of diets, a chondrosarcoma was implanted in the cremaster muscle of each rat. Five, 10 or 20 days after tumour implantation, rats were anesthetised and their cremasters prepared for observation by intravital microscopy. Intraarterial injection of fluorescein isothiocyanate-conjugated albumin and subsequent observation of fluorescence in the perivascular space indicated no difference in microvascular albumin leakage between the tumour vasculature of copper deficient and copper adequate rats. Neither tumour growth (assessed by wet weight), vascular density (assessed by light microscopy), nor any ultrastructural characteristics of the tumour or its vasculature (assessed by electron microscopy) were affected by copper deficiency. In view of findings by others which indicate changes in tumour characteristics with copper deficiency, we conclude that the copper dependency of tumour growth and vascularisation is a function of the type of tumour, the host tissue, or the conditions of copper depletion.

Animals↗
PubMed1992

Copper deficiency alters vasodilation in the rat cremaster muscle microcirculation.

The effects of copper deficiency on smooth muscle relaxation were studied in the cremaster muscle microcirculation. Male Sprague-Dawley rats were fed either a copper-adequate diet (CuA, 5 micrograms copper/g diet) or copper-deficient diet (CuD, no added copper) for 17-27 d before experimentation. In vivo television microscopy was used to quantify agonist-induced diameter changes in third-order arterioles. Endothelium-dependent relaxation, which is hypothesized to be mediated by nitric oxide, was attenuated by copper deficiency. Both receptor (acetylcholine, 10(-7) to 10(-4) mol/L) and nonreceptor (calcium ionophore A23187, 10(-8) to 10(-7) mol/L) relaxation was decreased. Nitric oxide-mediated dilation, which was endothelium-independent (10(-7) to 10(-5) mol/L sodium nitroprusside), was also attenuated by copper deficiency. Maximal responses were as follows: for acetylcholine, 136 +/- 16% CuA vs. 45 +/- 15% CuD; for A23187, 104 +/- 16% CuA vs. 21 +/- 11% CuD; and for nitroprusside, 125 +/- 12% CuA vs. 46 +/- 13% CuD. There was no difference in microvascular dilation between groups treated with 10(-6) to 10(-4) mol/L of the phosphodiesterase inhibitor papaverine (e.g., CuA 109 +/- 11% vs. CuD 133 +/- 21% with 10(-4) mol/L). These results suggest that copper deficiency inhibits the nitric oxide-mediated mechanism of vascular smooth muscle relaxation without altering the capacity of the smooth muscle to relax. We suggest that copper deficiency either decreases nitric oxide radical availability or disrupts the nitric oxide-guanylate cyclase interaction.

Acetylcholine↗
PubMed1992

Dietary copper deficiency and endothelium-dependent relaxation of rat aorta.

Endothelium-dependent relaxation of aortas was studied in dietary copper (Cu) deficiency. Male, weanling Sprague-Dawley rats were fed diets deficient (CuD, less than 0.5 ppm) or adequate (CuA, 5.0-5.5 ppm) in Cu for 4 weeks. Aortic rings from paired Cu-deficient and Cu-adequate rats were isolated from the descending thoracic aorta, placed in tandem tissue baths, and attached to force transducers. Aortas were contracted with phenylephrine (3 x 10(-7) M) and the degree of force reduction was measured after successively increasing the dose of acetylcholine (10(-8)-10(-5) M), histamine 10(-6)-10(-3) M), or sodium nitroprusside (10(-9)-10(-6) M). Cu deficiency was found to significantly reduce the relaxation responses of each relaxing agent at the highest three of the four doses tested. The ability of Cu-adequate and Cu-deficient aortas to relax was not different, as indicated by their complete relaxation in response to 10(-4) or 10(-5) M papaverine. Because the relaxation responses to both acetylcholine and histamine in rat aorta are dependent on the presence of endothelium, the reduction of these responses suggests that endothelium, or its interaction with smooth muscle, was disrupted in dietary Cu deficiency. The reduction in response to sodium nitroprusside, an endothelium-independent analog of endothelium-derived relaxing factor, indicates that the interaction of endothelium-derived relaxing factor with smooth muscle was disrupted. These findings have implications regarding blood pressure regulation in Cu deficiency.

Animals↗