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B Fellström

Publications and source records attributed to B Fellström.

At least 37 records · Page 2Linked to original sources
PubMed1998

Eotaxin and capping protein in experimental vasculopathy.

Ischemia-induced tissue activation may contribute to the pathogenesis of graft vasculopathy, but the mediators implicated have only partially been characterized. To gain further insight into the molecular mechanisms involved, syngeneic rat aortic transplants with cold-storage-induced vasculopathy were studied for differentially expressed mRNA transcripts. Vessel segments were exposed to either 1 or 18 hours of cold ischemia, followed by transplantation into syngeneic recipients. After 3 days or 4 weeks, the grafts were removed and total mRNA was isolated and used for differential display to identify modulation of transcript expression related to prolonged storage. Using 15 sets of random primers, 17 polymerase chain reaction products were up-regulated and 2 were downregulated in grafts exposed to 18 hours of ischemia. Sequencing of these amplicons showed that 6 had a high degree of homology to known sequences whereas 13 had no homology to any of the genes in the database. Two of the differentially displayed amplicons (capping protein and eotaxin) were cloned, re-amplified, and used as probes for Northern blot analysis to confirm their differential expression. Immunohistochemistry using monoclonal antibodies against capping protein-alpha and eotaxin confirmed that both proteins are expressed in the media of normal aortas and that there was an increased expression in vessels exposed to prolonged ischemia albeit that the increase at the protein level seemed less compared with changes in transcript expression. Northern blots with RNA from aortic allografts exposed to prolonged ischemic storage also showed increased levels of capping protein and eotaxin mRNA whereas there was a decrease in the relative amount of these transcripts in vessels exposed to balloon denudation, suggesting that the increase after prolonged ischemic exposure is not the result of a nonspecific response to injury. Based on the biological characteristics of capping protein and eotaxin it is conceivable that they play a pathogenetic role in ischemia-induced vessel wall remodeling. It remains to be established whether these genes or their products serve as target molecules for therapeutic interventions to prevent or treat cold-storage-induced graft vasculopathy.

Actin Depolymerizing Factors↗
PubMed1998

Accelerated atherosclerosis in the transplant recipient: role of hypertension.

An accelerated atherosclerosis may occur in the native arteries of a transplant recipient as well as in arteries of transplanted kidneys or hearts. The dominating cause of patient mortality are cardiovascular diseases, where ischaemic heart disease is predominant. The accelerated form of arteriosclerosis which takes place in transplanted kidneys and hearts, has a complex pathogenesis, which includes both immunological and nonimmunological factors. Hypertension is one such factor which has been claimed to be an independent risk factor of chronic renal transplant dysfunction, usually characterised by transplant arteriosclerosis. Whether a more intense treatment of hypertension or a more selective use of antihypertensive drugs would have a beneficial effect upon the progression rate of chronic rejection is still an open question.

Arteriosclerosis↗
PubMed1998

Effects of endothelin receptor type A antagonism and nitric oxide synthase inhibition on cerebral blood flow in hypertensive rats.

Effects of the endothelin receptor type A antagonist BQ 123 and the NO synthase inhibitor L-NMMA on cerebral blood flow were studied in vivo in anaesthetized hypertensive (SHR) and normotensive (WKY) rats. The effects of acetylcholine following pre-treatment with these drugs were also studied with the microsphere method for blood flow determination in the cortex, thalamus, caudatus, pons, medulla, cerebellum and hypophysis. BQ 123 (1 mg kg-1) induced only minor effects on cerebral blood flow in both strains (n = 8), whereas L-NMMA (N = 8; 20 mg kg-1) reduced regional cerebral blood flow significantly in most regions (21-54%) in the hypertensive, but not in the normotensive rat. In normotensive rats pre-treated with BQ 123 intravenous administration of acetylcholine (2 micrograms kg-1 min-1) induced a widespread significant increase (20-50%) in cerebral blood flow despite a reduction of the mean arterial blood pressure, while no significant effects were seen in hypertensive animals. Intravenous infusion of acetylcholine in animals pre-treated with L-NMMA did not affect cerebral blood flow in most regions in either of the two rat strains. In conclusion, a vasodilatory response to acetylcholine was found following endothelin receptor A antagonism in the WKY rat only, suggesting a role for endothelin in the control of cerebral blood flow in this strain. Furthermore, a higher basal vasodilating nitric oxide-tone seems to be present in the hypertensive rat compared with the normotensive rat.

Acetylcholine↗
PubMed1998

Serum total homocysteine concentration before and after renal transplantation.

BACKGROUND: Hyperhomocysteinemia is by now an established risk factor for the development of atherosclerosis. Total homocysteine concentration (tHcy) correlates inversely with glomerular filtration rate, and it is roughly three times as high in hemodialysis patients as in healthy individuals. Therefore, tHcy would be expected to fall markedly after successful renal transplantation. The aim of the present study was to assess the changes in tHcy associated with renal transplantation. METHODS: tHcy was analyzed in samples collected before renal transplantation and at six months after transplantation in 55 stable patients, all of whom were treated with cyclosporine (CS). tHcy was also analyzed in samples from 55 controls characterized by markers of renal function that matched those of the post-transplant state. RESULTS: At six months after transplantation, tHcy was significantly decreased as compared with pretransplant tHcy (27.7 +/- 14.8 vs. 36.9 +/- 21.3 micromol/liter, P < 0.001). Post-transplant tHcy was markedly higher than the tHcy of the control group (27.7 +/- 14.8 vs. 16.0 +/- 5.3 micromol/liter, P < 0.0001). The post-transplant change in tHcy ranged widely, the average change being a reduction of 14%. Sixteen patients (29%) actually manifested an increase in post-transplant tHcy. The post-transplant changes in tHcy correlated inversely with pretransplant tHcy (r = -0.66, P < 0.0001) and directly with the changes in serum albumin concentrations (r = 0.35, P < 0.05) and CS trough concentrations (r = 0.29, P < 0.05). A multivariate analysis, including the post-transplant changes in serum concentrations of folate and albumin as well as creatinine clearances explained 21% of the change in tHcy (P < 0.05). After inclusion of the CS concentration, an independent predictor, the model accounted for 28% of the post-transplant change in tHcy (P < 0.01). CONCLUSION: The post-transplant reduction in tHcy was far smaller than expected with respect to renal function, and the post-transplant changes in the major biochemical determinants of tHcy contributed relatively little to explain the change in tHcy. Thus, the results suggest the post-transplant introduction of one or more factors that induce an increase in tHcy. Treatment with CS appears to be such a factor.

Adult↗
PubMed1998

Endothelium-dependent vasodilation in the uvea of hypertensive and normotensive rats.

PURPOSE: The effects of endothelium-related substances such as acetylcholine, a stimulator of endogenous NO-production, the NO-synthesis inhibitor L-NMMA, the exogenous NO-donor sodium nitroprusside and the endothelin (ET)A-receptor antagonist BQ123, on uveal blood flow were investigated in normotensive and hypertensive SHR rats. METHOD: The radioactively-labelled microsphere method was applied for the measurement of regional blood flow in the uvea. RESULTS: Under resting conditions, local blood flow was lower in the hypertensive animals. The increase in choroidal blood flow (145 +/- 50%; P < 0.01) and reduction in vascular resistance (-58 +/- 7%; P < 0.01) observed in the WKY after i.v. infusion of acetylcholine, 2 micrograms x kg bw-1 x min-1, were significantly less pronounced in animals pretreated with L-NMMA, indicating local formation of NO as a vasodilator mechanism. In contrast, acetylcholine did not induce significant vasodilation in the choroid of SHR rats. In the anterior uvea of both strains, acetylcholine did not affect local blood flow. L-NMMA, 20 mg x kg bw-1, alone reduced blood flow in the entire uvea of both strains. Intravenous injection of BQ123, 1 mg x kg bw-1, did not affect regional blood flow in the uvea of WKY or SHR animals. Infusion of acetylcholine following ETA-receptor blockade induced vasodilation in both the choroid and anterior uvea in the WKY but not in the SHR. CONCLUSIONS: Acetylcholine-stimulated NO-mediated vasodilation, but not basal NO-formation, was impaired in the choroid of the SHR. Furthermore, an interaction between vasoconstricting ET and acetylcholine was found in the anterior uvea of normotensive but not hypertensive rats.

Acetylcholine↗
PubMed1998

Effects of nitric oxide synthase inhibition and endothelin ETA receptor blockade on haemodynamics in hypertensive rats.

1. The objectives of the present study were to study regional differences in haemodynamics between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats induced by the nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) and the endothelin ETA receptor antagonist BQ 123 in vivo in tissues known to be important for blood pressure (BP) regulation (heart, kidney and skeletal muscle). Furthermore, the effect of acetylcholine (ACh) infusion (2 micrograms/kg per min) was examined after L-NMMA or BQ 123. The microsphere method was used for determinations of cardiac index (CI) and regional haemodynamics. 2. NG-Monomethyl-L-arginine (20 mg/kg) increased BP (26-48%; P < 0.01) and reduced CI in both rat strains. BQ 123 (1 mg/kg) reduced BP slightly (-4 to 11%; P < 0.05). 3. NG-Monomethyl-L-arginine significantly increased myocardial and skeletal muscle vascular resistance in SHR only; however, in the kidney, L-NMMA reduced blood flow and increased vascular resistance in both rat strains. 4. BQ 123 induced minor changes in regional haemodynamics that were not significantly different between the two strains. 5. Acetylcholine following BQ 123 induced an increase in myocardial blood flow in WKY rats, but decreased blood flow in SHR. Acetylcholine following L-NMMA reduced myocardial blood flow in both strains. 6. Acetylcholine following BQ 123 induced renal vasodilation in WKY rats but, following L-NMMA, ACh did not induce renal vasodilation in either rat strain. In contrast, L-NMMA did not abolish the vasodilation of acetylcholine in skeletal muscle in WKY rats. 7. In conclusion, the contribution of nitric oxide to basal vessel tone was not impaired in the heart, skeletal muscle and kidney in SHR. Antagonism of ETA receptors caused similar haemodynamic responses in both rat strains in these organs. Furthermore, NOS inhibition, but not ETA blockade, blunted the expected ACh-induced vasodilation in the heart and kidney in WKY rats, but not in skeletal muscle in both strains.

Acetylcholine↗
PubMed1998

Effects of acetylcholine and nitroprusside on systemic and regional hemodynamics in hypertensive rats.

This study was performed to investigate the in vivo effects of acetylcholine, a stimulator of endogenous NO production, and nitroprusside, an exogenous NO-donor, on hemodynamics in the normotensive (WKY) and the hypertensive (SHR) rat. Anesthetized rats were given microspheres for the measurement of cardiac index (CI), total vascular resistance (TPRI), regional blood flow and vascular resistance. Infusion of acetylcholine (2 microg/kg/min) caused a marked decrease in TPRI by (-35+/-5%, +/-SEM) in the WKY (n=8), whereas in the SHR (n=8) a less pronounced reduction was seen (-14+/-3%, p<0.01 between groups). CI increased by 27+/-9% in the WKY, but was unaltered in the SHR. Blood pressure decreased similarly (17-20%). Acetylcholine significantly increased blood flow by about 40% in the kidneys and the heart in the WKY, but had no significant effect in the SHR. Other tissues, such as skeletal muscle and cerebral tissues, showed no major changes. Infusion of nitroprusside (1 microg/kg/min) reduced blood pressure by 5 to 10% in the strains. The regional effects of nitroprusside did not differ between the strains. In conclusion, the acetylcholine-induced vasodilation in the kidney and the heart was attenuated in the SHR compared to the WKY. These findings might suggest a difference in the endothelial response between the SHR and the WKY in some, but not in all, tissues.

Acetylcholine↗
PubMed1998

Regional haemodynamic differences between normotensive and spontaneously hypertensive rats--a microsphere study.

The objective of the present study was to compare systemic and regional haemodynamics in a large series of spontaneously hypertensive rats (SHR, n=32) with normotensive Wistar-Kyoto rats (WKY, n=26) at the age of 12-16 weeks. All rats were anaesthetized with thiobutabarbital and the radioactively labelled microsphere method was used to evaluate regional blood flow with special emphasis on different cerebral areas. The high blood pressure in the SHR was mainly due to elevated total peripheral resistance, which was 90% higher in the SHR compared to the WKY. Furthermore, heart rate was 25% (p<0.001) higher, but the cardiac index was lower by 20% (p<0.01) in the SHR. Blood flow was significantly lower and vascular resistance higher in several organs such as the kidneys, other visceral organs, skeletal muscle and skin of the SHR compared to the WKY. On the contrary, blood flow in the myocardium was augmented by 40% (p<0.01) in the SHR. Blood flow was 20-50% higher in the cerebral cortex, thalamus and caudatus (p<0.05-0.001), but attenuated in the hypophysis of the SHR. In the pons, medulla and cerebellum, blood flow was similar in the two strains. In this large microsphere study, the basal cardiac index was lower in the SHR already at this relatively early stage of established hypertension. Despite this, increased blood flow in the above mentioned cerebral regions was found in the SHR compared to the WKY.

Animals↗
PubMed1998

Influences of carvedilol treatment on the effects of acetylcholine on regional haemodynamics in the spontaneously hypertensive rat.

1. In a previous report, we have shown that vasodilatation induced by acetylcholine is impaired in the kidney and the heart of the spontaneously hypertensive rat (SHR) in vivo. The present investigation was performed to study the influence of oral antihypertensive treatment with carvedilol for 6 to 10 weeks on acetylcholine-induced changes in regional haemodynamics in SHR in vivo. Cardiac output, regional blood flow and vascular resistance in organs of major importance in hypertensive disease, such as the kidney, heart, skeletal muscle, brain and eye, were measured with radioactively labelled microspheres in anaesthetized rats (aged 12-16 weeks).2. Mean arterial blood pressure was significantly lower in the carvedilol-treated SHR group (156+/-3 mmHg, n=17) than in an untreated SHR group (172+/-6 mmHg, n=13). Infusion of acetylcholine (2 microgram.min-1.kg-1) caused similar significant reductions in blood pressure in the two groups (-13+/-1% and -14+/-2%). However, acetylcholine induced a significant increase in total peripheral vascular resistance in the carvedilol group (29+/-10%, P<0.01), whereas no significant change was observed in the control group (0+/-11%).3. Acetylcholine significantly increased renal vascular resistance in the carvedilol group (+62+/-15%, P<0.01), but did not change vascular resistance in the control group (-6+/-6%). In the heart, acetylcholine did not affect vascular resistance in the carvedilol group, but reduced vascular resistance significantly in the control group (-17+/-8%, P<0.05). The circulatory changes induced by acetylcholine in the skeletal muscle, brain and ophthalmic circulation did not differ between the groups.4. In conclusion, the results demonstrate that long-term oral carvedilol treatment in the SHR did not enhance acetylcholine-induced vasodilatation, but instead pronounced renal vasoconstriction was induced by acetylcholine, which could partly be due to a decreased cardiac index.

Acetylcholine↗
PubMed1998

Serum total homocysteine concentration does not predict outcome in renal transplant recipients.

Established cardiovascular risk factors such as hypercholesterolemia have been claimed to adversely influence the outcome of renal transplants. The aim of the present study was to assess the effect of another risk factor, hyperhomocysteinemia, on graft outcome. This was relevant for two reasons; hyperhomocysteinemia is by now recognized as an independent risk factor for the development of atherosclerosis and it is highly prevalent in both dialysis patients and renal transplant recipients. The serum concentration of total homocysteine (tHcy) was analyzed in samples collected before transplantation in 81 patients and at 6 months after transplantation in 57 of these patients. Before transplantation, mean tHcy was 33.2 +/- 19.2 mumol/L and the prevalence of hyperhomocysteinemia was 94%. Six months after transplantation, mean tHcy was 27.7 +/- 14.6 mumol/L and the prevalence of hyperhomocysteinemia was 88%. The patients were followed up for 5 yr. Six months and 5 yr after transplantation, serum creatinine concentration and endogenous creatinine clearance were determined. After 6 months, allograft biopsy was evaluated. Neither pre- nor post-transplant tHcy was found to influence patient or graft survival, graft function or histopathology. Thus, tHcy does not seem to predict either short-term or long-term outcome of renal transplantation.

Arteriosclerosis↗
PubMed1997

Metabolic abnormalities in renal transplant recipients. Risk factors and predictors of chronic graft dysfunction?

In summary, abnormalities in lipid and carbohydrate metabolism, including features of the metabolic risk factor syndrome, are frequently present in patients both before and after renal transplantation. Risk factors of atherosclerosis may not only contribute to increased cardiovascular morbidity and mortality in this patient population, but can also be assumed to contribute to the development and progression of CVR and chronic graft dysfunction. For preventing both early graft losses and the development of graft damage leading to late graft dysfunction and graft loss, it appears to be essential to identify patients at risk early, prior to transplantation. Intervention aiming to reduce overweight, diet and exercise may be of benefit. The role of omega-3 unsaturated fatty acid supplementation remains controversial. Pharmacological intervention by antioxidants or agents to reduce lipids and/or decrease PAI-1 synthesis may prove to be beneficial. Early identification of patients at risk and intervention in due time may improve the results of renal transplantation.

Fibrinolysis↗
PubMed1997

Elevation of cyclosporin A blood levels during carvedilol treatment in renal transplant patients.

In a consecutive study of 21 renal transplant patients suffering from chronic vascular rejection (CVR) we added the beta-receptor-blocking drug carvedilol to their regular medication. The purpose was to investigate possible pharmacokinetic interactions between carvedilol and cyclosporine (CsA), since carvedilol will soon be used in clinical trials in renal transplant patients with CVR. On the first day of the study the patients received 6.25 mg of carvedilol added to their daily medication. The dose was increased stepwise to 50 mg while the doses of other beta-blocking drugs were decreased. The goal was to exchange atenolol with carvedilol at a ratio of 2:1 when substituting atenolol with carvedilol. The patients' blood pressure was the final determinant of the dose of carvedilol. The trough levels of CsA were measured on days 1, 14, 30, 90 and 180. It was found that the blood levels of CsA increased when carvedilol was introduced. Thus, the doses of CsA had to be reduced in order to keep the blood levels within the therapeutic range. At 90 d, the daily doses of CsA had been reduced from 3.7 +/- 0.3 to 3.0 +/- 0.2 mg/kg BW (p < 0.001). The present results suggest an interaction between carvedilol and CsA that demands a 20% average reduction of CsA doses to maintain the CsA blood levels within the therapeutic range. However, the interaction shows a great interindividual variation, calling for careful monitoring of the CsA blood levels.

Adrenergic beta-Antagonists↗
PubMed1996

Increased immunoreactivity of transforming growth factor-beta in human kidney transplants.

Transforming growth factor-beta (TGF-beta) has been known to be involved in the pathogenesis of various kidney diseases. TGF-beta is also a potent immunosuppressor that has been shown to be induced after allogeneic transplantation. We have studied the distribution of immunoreactive TGF-beta proteins in different compartments of 21 allogeneic transplanted kidneys that had been rejected through acute (eight interstitial or six vascular) and chronic (seven vascular) processes. This distribution was compared with that in seven non-rejected transplanted and five non-transplanted kidneys with intact morphology. There were no obvious differences between the three groups of rejected grafts and the transplanted non-rejected group for the expression of TGF-beta s. A major difference was seen between transplanted kidneys, which exhibited clearly positive TGF-beta and LTBP1 (latent TGF-beta binding protein) immunoreactivities, and the non-transplanted kidneys. The non-transplanted kidneys showed only very weak or no immunoreactivity for these proteins. The morphologically intact non-rejected grafts showed a significantly increased immunoreactivity compared with the non-transplanted kidneys. When the transplanted kidneys were classified into two groups (i.e. with or without diabetes mellitus) and compared with regard to the expression of all TGF-beta s, no difference was found. Thus, transplantation was the most important predictor for expression of TGF-beta s and LTBP1, and the largest expression increase in the allografts occurred in the interstitium, followed by the glomeruli and blood vessels. Tubuli and lymphocyte aggregates stained only faintly. The results imply that TGF-beta is induced rapidly after kidney transplantation. This induction can suppress immunoreactivation, but concomitantly promotes changes such as arteriosclerosis and fibrosis associated with rejection.

Humans↗