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Biomedical subjects

A Edlund

Publications and source records attributed to A Edlund.

At least 37 records · Page 2Linked to original sources
PubMed1994

Turnover of extracellular-superoxide dismutase in tissues.

BACKGROUND: The secretory glycoprotein, extracellular-superoxide dismutase (EC-SOD) is in the body, primarily located to the tissue interstitial space, and in tissue is almost completely composed of homotetrameric high-heparin-affinity C-type. The aim of the present study was to determine the turnover rate of EC-SOD C in tissue and the importance of the heparin-affinity for the retention. EXPERIMENTAL DESIGN: EC-SOD C and two EC-SOD carboxyterminal truncation variants with reduced and absent heparin-affinities, respectively, were labeled with 125I and then subcutaneously and intramuscularly injected into rats. The retentions were followed with repeated determinations with a gamma camera. RESULTS: EC-SOD C displayed a tissue half-life of about 85 hours, whereas the EC-SOD variants with reduced and absent heparin-affinities displayed half-lives of about 20 and 7 hours, respectively. The half-lives were remarkably similar in the intramuscular and subcutaneous injection sites, suggesting rather small overall differences between tissues in EC-SOD C retention. CONCLUSIONS: The findings established that EC-SOD C in the tissue interstitium exists almost completely anchored to heparan sulfate proteoglycan via the carboxyterminal heparin-binding domains, and that this binding is the determinant of the long tissue retention of the enzyme. The findings further suggest that reductions in heparin-affinity, e.g., by proteolytic truncation of the highly susceptible heparin-binding domain, may be an important mechanism of elimination of EC-SOD from tissues, both physiologically and as enhanced under pathologic conditions.

Animals↗
PubMed1993

Proteolytic modification of the heparin-binding affinity of extracellular superoxide dismutase.

The heparin-binding affinity of the tetrameric extracellular superoxide dismutase (EC-SOD) is a result of the cooperative effect of the heparin-binding domains of the subunits, located in the hydrophilic, strongly positively charged C-terminal ends. EC-SOD C, the high-heparin-affinity type, exposed to immobilized trypsin and plasmin was found to rapidly lose its affinity for heparin, without any loss of enzymic activity or major change in molecular mass as judged by size-exclusion chromatography. Heparin and dextran sulphate 5000 inhibited the proteolysis, suggesting that EC-SOD C sequestered by heparan sulphate proteoglycan in vivo is partially protected against proteolysis. The loss of heparin-affinity occurred with the stepwise formation of intermediates, and the pattern upon chromatography on heparin-Sepharose and subsequent immunoblotting was compatible with the notion that the changes are due to sequential truncations of heparin-binding domains from subunits composing the EC-SOD tetramers. A similar pattern with intermediates and apparent truncations has previously been found with EC-SOD of human plasma. The findings show that the unique design of the heparin-binding domain of EC-SOD allows easy modification of the heparin-affinity by means of limited proteolysis, and suggest that such proteolysis is a major contributor to the heterogeneity in heparin-affinity of EC-SOD in mammalian plasma.

Animals↗
PubMed1993

Pharmacokinetics of extracellular-superoxide dismutase in the vascular system.

Extracellular-superoxide dismutase C (EC-SOD C) is a secretory tetrameric Cu- and Zn-containing glycoprotein which has high affinity for heparin and heparan sulfate. Upon intravenous injection into rabbits, recombinant human (rh) EC-SOD C was found to be rapidly 97-98% sequestered to the vascular wall, forming an equilibrium with the plasma phase. Recombinant EC-SOD truncation variants with reduced, T216, and without, T213, heparin affinity were found to be sequestered to a reduced extent and not at all, respectively, establishing the importance of the heparin affinity for this behaviour. The halflife of rhEC-SOD C in the vasculature was of the order of 20 h. Injection of large doses resulted in saturation of the binding of rhEC-SOD C to the vascular wall. Scatchard analysis revealed a heterogeneity in affinity of the ligands on the vascular wall. The maximal binding capacity was very high. The equilibration of rhEC-SOD C to the vascular wall of an organ, clamped during enzyme injection, and the primary equilibration phase was studied by comparing binding to a clamped and reperfused kidney with binding to the contralateral control kidney. rhEC-SOD C injected in a low dose was found to equilibrate very slowly to the reperfused kidney with a halftime of about 2 h. With higher rhEC-SOD C doses, at which evidence for saturation is seen, and with the variant rhEC-SOD with reduced heparin affinity. T216, very rapid equilibrations were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Renal effects of i.v. adenosine infusion in humans.

The effects of systemic intravenous (i.v.) infusion of adenosine on renal blood flow and glomerular filtration in eight healthy, awake females have been examined. Renal blood flow and glomerular filtration rate were measured as the clearance of para-aminohippuric acid (PAH) and inulin, respectively. Following basal sampling adenosine was infused i.v. at successive rates of 60 and 80 micrograms kg-1 min-1 for 30 min at each rate. Plasma clearance of PAH showed a minor, but non-significant, increase from 697 +/- 41 to 775 +/- 97 ml min-1. However, the arterial plasma concentration of PAH decreased by 17 +/- 4% (P < 0.001), indicating that there was a small increase in renal blood flow. Inulin clearance was reduced from 123 +/- 14 to 88 +/- 11 ml min-1 1.73 m-2 (P < 0.01). The resulting filtration fraction was reduced from 18 +/- 1 to 11 +/- 1 (P < 0.001). The K+/Na+ excretion ratio increased from a basal value of 10 +/- 1 to 42 +/- 11 (P < 0.01) at the highest dose of adenosine, and renal oxygen consumption decreased from 17 +/- 2 to 9 +/- 1 ml min-1 (P < 0.001). In conclusion, i.v. infusion of adenosine in healthy, awake subjects causes a minor increase in total renal blood flow and a marked reduction in glomerular filtration. This shows that adenosine also exerts a vasodilatory effect in the renal circulation, primarily on postglomerular arterioles. In addition, adenosine may produce an aldosterone-like effect on salt excretion, and a reduction in renal oxygen consumption.

Adenosine↗
PubMed1993

Metabolism and excretion of nitric oxide in humans. An experimental and clinical study.

Despite the increasing insight in the clinical importance of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), there is limited information about the metabolism and elimination of this mediator in humans. We studied the degradation of NO in healthy subjects inhaling 25 ppm for 60 minutes and in patients with severe heart failure inhaling 20, 40, and 80 ppm in consecutive 10-minute periods. In other healthy subjects, the renal clearance of NO metabolite was measured. The metabolism ex vivo was evaluated by direct incubation of nitrite, the NO oxidation product, in blood from healthy humans. During inhalation of NO, the plasma levels of nitrate increased progressively, both in the healthy subjects (from 26 to 38 mumol/L, P < .001) and in the patients (from 72 to 90 mumol/L, P < .001). Methemoglobin (MetHb) also increased in the healthy subjects (from 7 to 13 mumol/L, P < .001) as well as in the patients (from 19 to 42 mumol/L, P < .01). No change in nitrosohemoglobin (HbNO) was detected, either in the healthy subjects or in the patients. In arterialized blood (O2 saturation, 94% to 99%), incubated nitrite was semiquantitatively converted to nitrate and MetHb. In venous blood (O2 saturation, 36% to 85%) moderate amounts of HbNO were also formed. Plasma and urinary clearance of nitrate in healthy subjects averaged 20 mL/min. We conclude that uptake into the red blood cells with subsequent conversion to nitrate and MetHb is a major metabolic pathway for endogenously formed NO. Nitrate may then enter the plasma to be eliminated via the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Plasma nitrate as an index of immune system activation in animals and man.

The cytotoxic activity of activated macrophages is based upon their formation and release of nitric oxide (NO). In blood NO is rapidly metabolised to nitrate. We analysed plasma nitrate in rats given zymosan, an activator of the immune system, and found 20-fold increases above the basal level. Furthermore, in two human subjects with acute gastro-enteritis plasma nitrate increased from about 30 to 200 microM two days after onset of symptoms. These increased plasma levels of nitrate may reflect macrophage formation of NO. We propose that plasma nitrate may be a useful index for quantitative assessment of cytotoxic activity during immunological challenge.

Acute Disease↗
PubMed1992

A non-glycosylated extracellular superoxide dismutase variant.

The secretory tetrameric extracellular superoxide dismutase (EC-SOD) is the only glycosylated SOD isoenzyme. The importance of the carbohydrate moiety for the properties of the enzyme is unknown. An expression vector defining nonglycosylated EC-SOD (ngEC-SOD) was constructed by mutagenesis of the codon for Asn-89 into a codon for Gln. The vector was transfected into Chinese hamster ovary DXB-11 cells and ngEC-SOD was isolated to 70% purity from the culture media of selected clones. The absence of glycosylation was established by the lack of affinity for various lectins, the absence of staining with the periodic acid-Schiff reagent, the change in mobility and composition of the tryptic peptide containing the mutated glycosylation site, and the reduction in apparent molecular mass upon SDS/PAGE and size-exclusion chromatography. The tetrameric state was retained. The heparin affinity, a fundamental and distinguishing property of EC-SOD, was found to be slightly increased. The enzymic activity was essentially retained. The major difference from native glycosylated enzyme in physical properties was a marked reduction in solubility. Like glycosylated EC-SOD, ngEC-SOD was, after intravenous injection into rabbits, rapidly sequestered by the vessel endothelium, and was promptly released into plasma after injection of heparin. The only difference from glycosylated EC-SOD in this behaviour, was a slightly more rapid elimination of the mutant enzyme from the vasculature. It is concluded that no specific biological role for the EC-SOD carbohydrate moiety could be revealed.

Animals↗
PubMed1992

Improved working capacity in patients with ischaemic heart disease during a 10-day treatment with oral theophylline.

The objective of this study was to assess whether a 10-d treatment with oral theophylline improves the working capacity in patients with ischaemic heart disease, and to compare theophylline with conventional anti-anginal therapy. Twenty-four patients with stable effort-induced angina were included in the study. The patients received double-blind treatment in randomized order during 4 consecutive 10-d periods, separated by a 4-d wash-out period, with (a) metoprolol durules 200 mg once daily + theophylline durules 300 mg b.i.d., (b) theophylline + placebo, (c) metoprolol + placebo, and (d) placebo alone. At the end of each period a supine exercise stress test was performed. Maximal workload increased to 111 +/- 6 W during treatment with theophylline, compared to 106 +/- 6 W during placebo treatment (P = 0.01). Metoprolol increased the maximal workload to 117 +/- 6 W (P less than 0.001). The effects of metoprolol and theophylline were additive, and the working capacity increased to 123 +/- 7 W during combined therapy. Neither the degree of ST-depression nor the scoring of chest pain at maximal workload differed between the four treatment regimens. An improved working capacity was shown in patients with stable effort-induced angina pectoris during long-term theophylline treatment. The effect was additive to that of beta-blockade.

Administration, Oral↗
PubMed1991

Adenosine provokes myocardial ischaemia in patients with ischaemic heart disease without increasing cardiac work.

Intravenous infusion of adenosine in patients with ischaemic heart disease (IHD) has been shown to induce chest pain and ST-depression. The aim of this study was to determine whether such myocardial ischaemia could be due to an increase in myocardial work. Thus patients with stable angina pectoris (n = 8) were randomly allocated to exercise or adenosine infusion, with a 1-h rest period before the second test. The maximal tolerable work load was 120 +/- 13 W, where all patients but one experienced typical angina pectoris. ECG revealed ST-depressions in all patients. The maximal tolerable dose of adenosine was 108 +/- 6 micrograms kg-1 min-1. All patients experienced chest pain typical of habitual angina pectoris, and all but one developed ST-depressions. During exercise there was a gradual and marked increase in the rate pressure product (RPP), in parallel with the development of ST-depression. By contrast, during infusion of adenosine there was only a minor increase in RPP (P = 0.0001). In conclusion, infusion of adenosine provokes signs and symptoms of myocardial ischaemia in patients with IHD with only a minor increase in cardiac work compared to exercise. These results are consistent with the hypothesis of a myocardial steal.

Adenosine↗
PubMed1991

Adenosine infusion to patients with ischaemic heart disease may provoke left ventricular dysfunction detected by echocardiography.

Infusion of the endogenous vasodilator adenosine to patients with ischaemic heart disease (IHD) frequently provokes myocardial ischaemia, possibly caused by a coronary steal. The aim of this study was to detect the occurrence and incidence of disturbances in left ventricular (LV) wall motion and Doppler indices of altered LV function during infusion of adenosine. Thirty-seven patients (six female) aged 37-74 years with IHD, verified by coronary angiography, were given up to 200 micrograms kg-1 min-1 (mean 155 +/- 5) adenosine i.v. for 18 +/- 1 min. LV wall motion was monitored by two-dimensional echocardiography (2D-echo). Doppler spectral signal was obtained from the mitral blood flow. All but six of the patients experienced angina pectoris of habitual character in connection with the adenosine infusion. Heart rate increased by 22 +/- 1 beats min-1, systolic blood pressure was unchanged, but diastolic blood pressure decreased slightly. 2D-echo revealed severe regional LV wall motion disturbances already in the basal state in 17 patients. During infusion of adenosine, these abnormalities were aggravated and disturbances also occurred in another 15 patients. Thus, adenosine increased the sensitivity for IHD in this selected material from 49 to 89%. In all, the mean index of wall motion abnormalities increased from 5.1 +/- 1.1 to 10.1 +/- 1.4 (P less than 0.001). The diastolic LV filling characteristics, as evaluated by the Doppler A/E ratios, were of limited value for determination of IHD grade. It is concluded that infusion of adenosine to patients with IHD frequently elicits myocardial ischaemia with disturbances in LV function, and offers an alternative to exercise for stress echocardiography.

Adenosine↗
PubMed1990

Acipimox stimulates skin blood flow by a cyclo-oxygenase-dependent mechanism.

The blood flow in the skin and the urinary excretion of the PGI2 metabolite 2,3-dinor-6-keto-PGF1a (PGI-M) were determined in the nine healthy subjects randomly assigned to double-blind oral treatment with a) placebo and acipimox (AC) 500 mg, b) acetylsalicylic acid 1500 mg and AC 500 mg, or c) placebo and nicotinic acid (NIC) 500 mg, on three different occasions. After treatment with placebo and AC there was a transient increase in the skin blood flow, up to about four-times the basal level, and a concomitant increase in skin temperature. After acetylsalicylic acid and AC no increase in skin flow rate or temperature was found. Urinary excretion of PGI-M was insignificantly increased by AC, but fell after acetylsalicylic acid pretreatment. NIC elicited a more marked increase in skin blood flow than AC, and in parallel the urinary excretion of PGI-M was more than doubled. It is concluded that cutaneous flushing induced by AC is cyclo-oxygenase dependent. In comparison to NIC, however, AC appears as a weak stimulant of vascular prostacyclin formation.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Haemodynamic and metabolic effects of infused adenosine in man.

1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodilator, were studied in healthy humans. 2. Catheters were inserted into pulmonary and brachial arteries and into the hepatic and subclavian veins. Cardiac output was determined according to the Fick principle, and splanchnic blood flow was measured by using extraction of Indocyanine Green. Skin blood flow was estimated by a laser Doppler technique, calf blood flow by venous occlusion plethysmography and skeletal muscle and adipose tissue blood flow by a local isotope clearance technique. 3. Adenosine (infused in steps from 40 to 80 micrograms min-1 kg-1 into a central vein) elicited a gradual reduction in the peripheral vascular resistance to less than 50% of the basal level. There was a slight increase in the systemic blood pressure, but the pulmonary arterial and the ventricular filling pressures were unchanged. Cardiac output was doubled, accomplished by a combination of a positive chronotropic effect and an increase in stroke volume, which may be secondary to diminished peripheral resistance. 4. Skin blood flow increased by 100% at 50 micrograms of adenosine min-1 kg-1, whereas splanchnic blood flow rose significantly at 60 micrograms of adenosine min-1 kg-1. Blood flow in the calf, gastrocnemius muscle and adipose tissue did not change significantly. 5. Arterial concentrations of noradrenaline and adrenaline increased by 62 and 43%, respectively, during infusion of adenosine. Arterial levels of glycerol were depressed by more than 50%, but those of glucose and pyruvate were unchanged. 6. In conclusion, exogenous adenosine caused a marked systemic vasodilatation, with different responsiveness in the investigated vascular beds.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1990

Endothelin does not affect aggregation of human platelets.

Endothelin (ET-1) is a recently discovered endothelial-derived peptide with pronounced vasoconstrictor activity. The present study addressed whether ET-1, in analogy with several other vasoactive agents, can induce or modulate aggregation of human platelets in vitro. Venous blood from healthy donors was collected in citrate or heparin and platelet-rich plasma (PRP) was prepared. Portions of the PRP were added to drugs, and platelet aggregation was recorded according to Born & Cross (1963). ET-1 added to the PRP (final concentrations 1-100 nM) did not induce aggregation of platelets, either in citrate- or heparin-containing plasma. Adenosine-diphosphate (0.5-2 microM) or thrombin (0.1-0.4 NIH units ml-1) induced dose-dependent aggregation of platelets in citrate- or heparin-containing PRP; such aggregation was, however, not affected by ET-1 (1-100 microM) either. We conclude that ET-1, in contrast to other endothelial-derived vasoactive agents, lacks direct effect on platelet aggregation in vitro.

Adenosine Diphosphate↗
PubMed1989

Angina pectoris-like pain provoked by i.v. bolus of adenosine: relationship to coronary sinus blood flow, heart rate and blood pressure in healthy volunteers.

After finding the maximum tolerated i.v. bolus dose of adenosine, three fractions of this dose were given randomly to five volunteers in a double-blind manner. Pain, estimated by a 10-graded category-ratio scale, ECG and coronary sinus blood flow (CSBF), measured by thermodilution and intra-arterial blood pressure, were continuously recorded. At the highest tolerated dose (10.3 +/- 2.3 mg), the ECG showed short lasting (less than 5 s) AV-block but no ischaemic signs. Following the maximum dose, pain started 15 +/- 2 s after injection, reached a maximum (median 6 of 10 grades) after 25 +/- 4 s and disappeared after 62 +/- 7 s. Basal CSBF was 84 +/- 14 ml/min-1, and increased to 297 +/- 48 ml/min. The rise in CSBF started 2.4 +/- 0.8 s before pain appeared (P less than 0.05), but reached its peak 18 +/- 2 s after maximum pain (P less than 0.005). Although maximum coronary vasodilation was induced at the lowest dose of adenosine given--1/3 of the maximum dose--chest pain increased in a dose-dependent manner. When AV-block did not occur, diastolic pressure did not change from baseline, while systolic blood pressure increased by 5 +/- 2% (ANOVA, P less than 0.0001) and heart rate increased by 40 +/- 7% (ANOVA, P less than 0.0001). Following AV-block, except for a decrease of short duration in heart rate and systolic and diastolic blood pressures, the responses were similar. In conclusion, the vasodilator adenosine given as an i.v. bolus to human volunteers who were awake increased heart rate and systolic blood pressure with unchanged diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1989

The role of adenosine and prostacyclin in coronary flow regulation in healthy man.

Coronary flow regulation in man is incompletely understood. We addressed the hypothesis that endogenous adenosine and prostacyclin (PGI2) affect basal coronary tone and/or the coronary flow response to increased myocardial work. In healthy volunteers coronary sinus flow and cardiac oxygen extraction were measured at rest and during leg exercise (40-50 W), before and after i.v. administration of theophylline (to block adenosine receptors) and oral administration of ibuprofen (to inhibit prostaglandin synthesis). Before drug, the basal coronary flow was 118 +/- 23 ml min-1 and the cardiac extraction of oxygen 122 +/- 3 ml l-1. Leg exercise elevated coronary flow by 89 +/- 16 ml min-1. Theophylline, at a dose blocking the coronary flow response to dipyridamole (an adenosine-dependent mechanism), induced a moderate increase in myocardial oxygen extraction (by 11%, P less than 0.05), but failed to affect either the basal coronary flow (105 +/- 16 ml min-1) or the increase during exercise (88 +/- 25 ml min-1). Ibuprofen inhibited the urinary excretion of PGI2 metabolite by about 90%, but did not affect basal coronary tone or the coronary response to exercise. These data indicate that endogenous adenosine is of limited importance for normal coronary regulation in man, and that PGI2 has no effect.

Adenosine↗
PubMed1988

Provocation of chest pain in patients with coronary insufficiency using the vasodilator adenosine.

Chest pain provoked by intravenous injection of adenosine was compared with natural angina pectoris in five patients with ischaemic heart disease. In seven healthy subjects a possible myocardial site for provocation of the chest pain was evaluated by analysis of time delays from injection to symptoms. The healthy volunteers were given the maximum tolerable dose of adenosine intravenously, together with 99Technetium-diethylentriaminpentaacetate (99Tcm-DTPA). Chest pain started after 4.1 +/- 2.4 s and reached its maximum 8.4 +/- 4.1 s after maximum left ventricular radioactivity. The patients with a history of typical angina pectoris were given similar doses of intravenous adenosine and the provoked chest pain did not differ in quality from the patients' habitual angina pectoris. The patients did not develop electrocardiographic signs suggesting myocardial ischaemia. Heart rate and blood pressure did not indicate increased myocardial work. In conclusion, the results concur with the hypothesis that adenosine elicits angina pectoris by stimulation of intracardiac adenosine receptors.

Adenosine↗
PubMed1988

Improved working capacity following theophylline infusion in patients with ischaemic heart disease.

The effect of theophylline on the working capacity of patients with ischaemic heart disease was evaluated in a double-blind, randomized cross-over study. Eight patients, receiving no medication, with stable effort-provoked angina pectoris and typical exercise-induced ST depressions were studied. Following intravenous administration of theophylline or placebo, the patients did a supine leg exercise limited by intolerable chest pain. The workload was continuously increased by 10 W/min. Following theophylline treatment the workload at the onset of chest pain increased from 71 +/- 9 to 114 +/- 14 W (P less than 0.002). The ST depression was less pronounced following theophylline at submaximal exercise (-0.01 +/- 0.00 vs. -0.09 +/- 0.02 mV, P less than 0.005, at 70 W). The maximum tolerable workload increased from 129 +/- 15 after placebo infusion to 153 +/- 12 W after theophylline infusion P less than 0.01). It is speculated that this beneficial effect of the adenosine receptor antagonist theophylline may possibly be due to inhibition of a pathophysiological coronary steal induced by elevated levels of adenosine during ischaemia.

Aged↗