Endothelium-dependent and-independent relaxation of aortas from copper-deficient rats.
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Acetylcholine↗
Biomedical subjects
J T Saari
Publications and source records attributed to J T Saari.
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↗
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↗
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↗
Effect of dimethyl sulfoxide on enlarged hearts of copper-deficient rats.
The purpose of this study was to examine, by transmission electron microscopy (TEM), the nature of the protective effect of dimethyl sulfoxide (DMSO) on hearts of copper-deficient (CuD) rats. Male, weanling Sprague-Dawley rats were fed, in a two-way design, CuD (0.45 micrograms/g) or copper-sufficient (CuS, 5.4 micrograms/g) diets with or without 5% DMSO in their drinking water. After 28 d, CuD rats showed typical signs of copper deficiency, including reduced liver and heart Cu, enlarged hearts, and anemia. DMSO-treated, CuD rats had lower heart weights and higher hematocrits than CuD rats. DMSO enhanced organ Cu concentrations in CuS, but not in CuD rats. TEM of CuD hearts showed myofibrillar distortion and enlarged, vacuolated mitochondria with fragmented cristae; morphometric measurements indicated an enhanced mitochondrial/myofibrillar ratio (mito/myo), but an increase of both mitochondrial and myofibrillar mass relative to CuS hearts. Compared to CuD hearts, DMSO-treated CuD hearts showed better mitochondrial morphology and myofibrillar organization, as well as a greater mito/myo, but lower mitochondrial and myofibrillar masses. Its function as a hydroxyl radical scavenger indicates that DMSO could protect CuD hearts, in particular their mitochondria, against oxidative damage. However, because measurements of thiobarbituric acid reactive substances were not consistent with this theory, other metabolic mechanisms, direct and indirect, must be examined.
Animals↗
Progressive microcirculatory changes caused by hypercholesterolemia in rats.
The progressive microcirculatory changes caused by hypercholesterolemia were studied in the rat cremaster model by use of intravital microscopy. Male Sprague-Dawley rats were fed either a normal chow diet or a chow diet supplemented with 1% cholesterol and 0.5% cholic acid for 1, 3, or 5 wk before experimentation. After 3 wk on the diet, hypercholesterolemia produced a significantly decreased vasoconstrictor response to norepinephrine in both arterioles and venules. After 5 wk, there was also significantly reduced macromolecular leakage induced by exogenous histamine and compound 48/80 in the high-cholesterol group. However, there was no change in the degree of base-line macromolecular leakage. Platelet thrombi formation induced by light activation of intravascular fluorescein isothiocyanate tagged to bovine serum albumin was slightly increased by hypercholesterolemia. Despite these microcirculatory changes there was no microscopic evidence of atheromatous pathology after 5 wk on the cholesterol diet. These results suggest a progressive nonspecific receptor desensitization and decreased inflammatory response shortly after the initiation of elevated serum cholesterol but before any histological evidence of atherosclerosis.
Animals↗
Ethane production in copper-deficient rats.
Evidence is accumulating which indicates that copper-deficient animals are prone to oxidative damage. To investigate this possibility further, we measured the production of breath ethane, a hydrocarbon by-product of lipid peroxidation, in copper-deficient rats. Male, weanling Sprague-Dawley rats were fed either a purified diet which was deficient in copper (CuD) or the same diet made sufficient with 5 ppm of copper (CuS). After 33 to 34 days the rats were placed individually in gastight metabolic cages through which ethane-free air or 100% O2 was passed. Expired ethane was absorbed onto cold, activated charcoal, liberated by heating, and measured by gas chromatography. Ethane production rates (pmoles/min/100 g +/- SD) were 3.3 +/- 0.8 (CuS-air), 4.3 +/- 1.4 (CuD-air), 8.3 +/- 2.5 (CuS-O2), and 12.2 +/- 4.3 (CuD-O2). Repeated measures analysis of variance indicated that both copper deficiency (P less than 0.01) and breathing 100% O2 (P less than 0.0001) enhanced ethane production, with no interaction between treatments. This finding complements previous evidence that increased lipid peroxidation occurs in copper-deficient rats.
Animals↗
Effect of copper deficiency and cis-diamminedichloroplatinum (II) treatment on the activities of renal microvillar enzymes in rats.
Recent studies have shown that some manifestations of cis-diamminedichloroplatinum (II) (cis-Pt) induced nephrotoxicity in animals may be exacerbated if the animals are nutritionally deprived of copper. The objective of the present study was to determine the effects of cis-Pt induced toxicity on enzyme activities in the kidney microvilli of rats with different copper statuses. Weanling male rats were fed copper-deficient (CuD) (less than 1 mg/kg Cu of diet) or copper-adequate (CuA) (5 mg/L of Cu in drinking water) regimens. After 24 days, rats were given i.v. injections of either cis-Pt (5 mg/kg BW) or saline in a 2 x 2 factorial design. At days 2 and 4 post-injection rats were killed and tubular microvilli isolated from the kidney cortex. Each preparation was assayed for the activities of 5 membrane-bound enzymes. Angiotensin-I converting enzyme (ACE) activity was 20 to 30% higher in the microvilli of CuD rats than in controls. Cis-Pt treatment enhanced ACE activity as well, and activity in treated rats was 60 to 110% higher than in controls. At day 2 there was a 20% greater increase in ACE activity in cis-Pt-treated CuD rats than in CuA rats. Aminopeptidase N activity was 35% lower in CuD rats than controls, but activity was not affected by cis-Pt. Gamma-glutamyltransferase activity was lowered by as much as 30% in cis-Pt-treated rats when compared to controls, but there was no effect of copper deficiency. Alkaline phosphatase and neutral endopeptidase 24.11 activities were significantly lower in microvilli of cis-Pt-treated rats than in those not treated.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkaline Phosphatase↗
Microvascular responses in copper-deficient rats.
In this study on copper deficiency, the rat crewmaster microcirculation was used as a model for endogenous histamine release and platelet thrombi formation. Male Sprague-Dawley rats were fed either a copper-supplemented diet (CuS, 5 ppm) or a copper-deficient diet (CuD, 0 ppm) for 5 wk before experimentation. The crewmasters of anesthetized rats were spread in a Krebs-filed tissue bath. In venules of CuS animals, photoactivation of intravascular fluorescein isothiocyanate tagged to bovine serum albumin caused significant platelet aggregation and reduction of red blood cell column diameter (RBCCD) by 40 min and stasis of flow by 60 min. In CuD animals there was only minor platelet aggregation and no reduction in RBCCD. Platelet aggregometry studies did not demonstrate reduced platelet aggregation in the CuD group, suggesting that copper deficiency alters the endothelium to inhibit adhesion. Compound 48/80 (1.0 and 10.0 microgram/ml) induced macromolecular leakage in both CuS and CuD groups, with the response in the CuD animals being significantly greater. The results demonstrate that copper deficiency results in alterations of the regulatory mechanisms governing inflammation and thrombosis.
Animals↗
Histamine-mediated vasoconstriction and cAMP levels in coronary arteries of the isolated rabbit heart.
The role of adenosine 3',5'-monophosphate (cAMP) in histamine-mediated vasomotion of coronary vascular smooth muscle was studied in the isolated perfused rabbit heart. In paired physiological studies, histamine-mediated vasoconstriction, as indicated by change in perfusion pressure, was inhibited by the presence of either theophylline, a phosphodiesterase inhibitor, or forskolin, an adenylate cyclase activator. The inhibitory effect of theophylline, but not of forskolin, was removed with cimetidine (H2-receptor antagonist). In biochemical studies, coronary vessel cAMP was measured immediately after, and compared to, the vasomotor response to histamine alone and to histamine in the presence of forskolin, theophylline, diphenhydramine (H1-receptor antagonist) or cimetidine. These studies showed that cAMP levels correlate inversely with the vasoconstrictor response to histamine, indicating that stimulation of H1-receptors is associated with a reduction of cAMP and that H2-receptors modify this reduction.
Animals↗
Chronic treatment with dimethyl sulfoxide protects against cardiovascular defects of copper deficiency.
Published reports indicate that Cu deficiency reduces antioxidant defenses and may result in tissue peroxidation. Dimethyl sulfoxide (DMSO), a highly penetrant antiinflammatory agent and purported hydroxyl radical scavenger, was chronically fed to male, weanling Sprague-Dawley rats which were either supplemented with or deficient in Cu. DMSO was found to inhibit the cardiac hypertrophy, anemia and depression of heart Cu concentration which occurs with Cu deficiency. This suggests that the hydroxyl free radical may contribute to the cardiovascular defects caused by dietary Cu deficiency.
Anemia↗
Effect of histamine on cardiac sarcolemmal calcium binding as indicated by use of ionic lanthanum.
To determine whether the inotropic effect of histamine might be associated with enhanced calcium binding to the sarcolemmal-glycocalyx complex, the effect of histamine on lanthanum binding to the cell membrane in the presence of verapamil was assessed. Rabbit hearts were perfused firstly with histamine, secondly with histamine and verapamil, and subsequently with histamine in the presence of lanthanum and verapamil. Subsequent transmission electron microscopy showed the presence of bound lanthanum on both the cellular surface and cytoplasmic vesicles of most cardiac myocytes, which is in contrast to the absence of lanthanum binding that occurs in the presence of verapamil alone. Furthermore, this histamine mediated enhancement of lanthanum binding is not affected by the H1 antagonist diphenhydramine but is reduced by the H2 antagonist cimetidine. This visual evidence of an apparent enhancement of lanthanum binding under histamine and subsequent attenuation with cimetidine supports the hypothesis that histamine may exert its positive inotropic effect by causing increased calcium binding to the sarcolemmal-glycocalyx complex of cardiac muscle and that the effect is mediated at least in part by H2 receptors.
Animals↗
Histamine induced alteration of calcium binding to microvascular endothelium as indicated by use of ionic lanthanum.
To determine whether histamine's effect on microvascular permeability might be associated with altered calcium binding, the influence of histamine on lanthanum binding to vascular endothelium was assessed in the presence of verapamil. Isolated rabbit hearts were perfused firstly with histamine, secondly with histamine and verapamil, and subsequently with histamine in the presence of lanthanum and verapamil. Examination by transmission electron microscopy showed that 92% of microvessels examined contained bound lanthanum on plasma membranes, plasmalemmal vesicles, or endothelial clefts of vascular endothelium, or all three, in both atria and ventricles, which is in contrast to the low proportion (4%) of microvessels containing bound lanthanum found in the presence of verapamil alone. The enhancement of lanthanum binding was reduced by both H1 and H2 receptor antagonists. This evidence supports the hypothesis that the increase in vascular permeability with histamine may be associated with increased calcium binding to vascular endothelial membranes and that both H1 and H2 receptors play a part in this activity.
Animals↗
Characterization of the coronary vascular response to histamine in rabbit hearts using cimetidine.
Successive applications of histamine in the isolated, perfused rabbit heart revealed a transient constriction of coronary vasculature. The mechanism of this vasoconstriction, in particular its tachyphylactic nature, was the subject of this study. Diphenhydramine, perfused during one of the applications of histamine, blocked the vasoconstriction, indicating an H1-receptor-mediated response. Cimetidine, perfused during one of the applications of histamine, enhanced the vasoconstriction, indicating that H2-receptors mediate an inhibition of vasoconstriction. Cimetidine perfused during all applications of histamine reduced, and in some cases eliminated, the apparent tachyphylaxis, implying that the waning vasoconstrictor response normally seen with histamine was due to a gradually increasing H2-receptor-mediated inhibition.
Animals↗
The effect of coronary perfusion pressure on contractile force in the isolated rabbit heart.
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Animals↗
Permeability coefficients by the hemolytic method: a correction.
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Cell Membrane Permeability↗
A comparison of tooth accumulated materials from quadrants treated surgically or nonsurgically.
The objective of this study was to test the validity of the clinical concept that periodontal surgery is beneficial in aiding the patient to reduce the amount of tooth accumulated materials in moderate to advanced cases of periodontal disease. Twelve arches in eight patients with moderate to severe bone loss were selected for this investigation. Using a split-mouth technique, 12 quadrants were subjected to pocket elimination by the use of osseous and soft tissue recontouring, and 12 quadrants received thorough deep scaling, root planing, and polishing. These patients were seen at 1,2, and 4 weeks after surgery for root planing and more oral hygiene instructions. At 6 weeks they received a prophylaxis, including root planing if indicated, throughout the mouth. The patients returned in 2 weeks, at which time plaque accumulations were then removed and collected by quadrant to be subjected to analysis using wet weights, dry weights and ash weights. The quantity of tooth accumulated debris on the surgically-treated quadrants was significantly greater than on those treated nonsurgically, as determined by the wet weight (P less than 0.01) and dry weight (P less than 0.05). There was, however, no significant difference with ash weight comparisons. The dry weight was the more accurate indicator of tooth accumulated materials. The mean ash weight on the surgically-treated mandibular quadrants (2.21 mg) was significantly greater (P less than 0.05) than from those treated nonsurgically (1.35 mg). The investigators' hypothesis that there would be more accretions on the side not involved in osseous surgery and pocket eradication was not supported in this study. Several possible reasons for this were elucidated and discussed.
Dental Deposits↗
Statistical synthesis of osmotic fragility curves.
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Cell Membrane Permeability↗