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T J Rabelink

Publications and source records attributed to T J Rabelink.

At least 73 records · Page 4Linked to original sources
PubMed1998

Nitric oxide availability in diabetes mellitus.

Diabetes mellitus is associated with early development of cardiovascular complications. Under physiological conditions the endothelium protects against the development of atherosclerosis. Endothelial cells produce, e.g., nitric oxide (NO), a substance which is capable of keeping vascular tone, coagulation and inflammation well balanced. However, in pathological conditions, such as in diabetes mellitus, impaired NO activity may be present. Decreased NO activity can be caused by impaired production of NO, due to uncoupling of receptor-mediated signal transduction, a deficiency of the NO synthase (NOS) substrate L-arginine, or a decreased availability of one or more cofactors essential for optimal functioning of NOS. However, hyperglycaemia also stimulates the production of advanced glycosylated end products, enhances the polyol pathway and activates protein kinase C. These conditions may lead to increased oxidative stress. Reactive oxygen species rapidly inactivate NO leading to the formation of peroxynitrite. Peroxynitrite is a toxic oxidant capable of damaging many biological molecules. Reduced NO availability may not only be of relevance to the development of atherosclerotic complications in diabetes but may also interfere with insulin-mediated postprandial glucose disposal and possibly contribute to the development of insulin resistance. Understanding of the complex metabolic disturbances interacting with the NO system may provide us with further therapeutic options to decrease cardiovascular morbidity and mortality in diabetes mellitus.

Animals↗
PubMed1998

Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension.

OBJECTIVE: Nitric oxide is a vasodilating and blood pressure lowering substance. To investigate whether calcium antagonists or angiotensin-converting enzyme (ACE) inhibitors increase vascular nitric oxide activity, we assessed systemic and renal vascular sensitivity to nitric oxide synthase inhibition in hypertensives on and off medication. METHODS: Ten essential hypertensive patients, aged 22-51 years, were studied 3 times: > or = 4 weeks off medication, after 3 weeks treatment with enalapril 20 mg twice a day and after 3 weeks nifedipine 60 mg/day. Each time, 24-h blood pressure registration was performed, followed by a clearance study to obtain a 3-h dose-response curve for intravenously infused NG-monomethyl-L-arginine (L-NMMA, respectively 0.75, 1.5 and 3.0 mg/kg/h). RESULTS: L-NMMA dose-dependently increased mean arterial pressure with 5 +/- 2 mmHg and systemic vascular resistance with 24 +/- 5% at maximum dose, whereas cardiac output decreased (all P < 0.001). Enalapril and nifedipine treatment decreased blood pressure, while the L-NMMA-induced increase in systemic vascular resistance was potentiated (enalapril: 45 +/- 7% and nifedipine: 46 +/- 8%; both P < 0.01). L-NMMA also dose-dependently decreased renal blood flow by 58 +/- 8% at maximum dose (P < 0.001), but neither drug potentiated these effects. CONCLUSION: These results indicate that, in essential hypertensives, antihypertensive therapy with enalapril or nifedipine increases nitric oxide dependency of systemic vascular tone, which may play a role in the blood pressure lowering effect of these drugs. However, this phenomenon cannot be observed in the renal circulation, suggesting a different regulation of endothelium-dependent vasomotion in the hypertensive kidney.

Adult↗
PubMed1998

Endothelin: new discoveries and rapid progress in the clinic.

This fifth international conference on ET serves to underline the rapid pace of development of our understanding of the very versatile ET system. On the one hand, the body uses ETs at several stages in embryonic development, in normal postnatal growth, and in cardiovascular homeostasis under healthy conditions. On the other hand, overwhelming evidence now exists that ET-1 plays important pathophysiological roles in conditions of decompensated vascular homeostasis. Indeed, in CHF this evidence is sufficient to justify the large-scale studies of morbidity and mortality needed to market ET antagonists as medicines. Other potentially important cardiovascular indications for ET antagonists are still emerging--including hypertension, stroke, subarachnoid haemorrhage and renal failure--and all are likely to be the subject of clinical trials over the next few years. As yet, there has been little work outside the cardiovascular and renal fields, but other areas, such as cancer treatment, may also prove promising. New molecules with increasing selectivity (ETA and ETB) continue to emerge and may be valuable. Inhibition of ECE-1 remains as an alternative approach and nonpeptide ECE inhibitors now exist. There appears to be a consensus that ETA blockade is beneficial in cardiovascular and renal disease. However, several strands of work presented at the meeting--the hypertensive salt-sensitive phenotype of rescued ETB knockout mice, the sustained and progressive hypertensive effects of ETB-selective antagonism in rats, ETB-mediated vasodilatation and natriuresis in dogs, and nitric oxide-dependent ETB-mediated vasodilatation in humans--all suggest that ETB-mediated vascular and renal responses may be protective. The development of selective ETA antagonists, therefore, now seems fully justified. In the future, direct comparisons in animal models, and patients, of ETA and ETA/B antagonists will be important in determining the value of additional ETB receptor blockade in individual diseases.

Animals↗
PubMed1998

Endothelial function: strategies for early intervention.

Assessment of endothelial function appears to be a valuable additional tool for diagnosing and therapeutic monitoring of coronary artery disease. The first part of this review discusses the biosynthesis, degradation, and antiatherosclerotic properties of nitric oxide, a major determinant of endothelial function. In the second part methods for assessing endothelial function and strategies for reversal of endothelial dysfunction are reviewed. Improvement of endothelial function may be obtained by lifestyle modifications, such as cessation of smoking, better blood glucose regulation, exercise, dietary measures, and pharmacological interventions, such as lipid lowering, antioxidant therapy, angiotensin-converting enzyme inhibition, and calcium channel blockers.

Animals↗
PubMed1998

Plasma alpha 2 macroglobulin is increased in nephrotic patients as a result of increased synthesis alone.

BACKGROUND: alpha 2 Macroglobulin (alpha 2M), a protease inhibitor, is often increased in plasma of patients with the nephrotic syndrome. Although it has been speculated that synthesis is increased, no direct measurements have been performed. METHODS: alpha 2M synthesis in both normal subjects (N = 4) and nephrotic patients (N = 7) were measured using endogenous labeling with 13C valine in order to establish the mechanism of increased plasma level in the nephrotic syndrome and the relationship between alpha 2M synthesis rate and plasma concentration over a wide range of plasma concentration values. A primed (15 mumol/kg)/continuous (15 mumol/kg/hr) infusion was administered for six hours. Blood samples were collected at different intervals and at each time point alpha 2M was isolated from EDTA plasma using immunoprecipitation and SDS-polyacrylamide gel electrophoresis (PAGE). Care was taken to ensure that the alpha 2M used for combustion had not been subjected to proteolysis. The rate of appearance of 13C valine derived from the isolated alpha 2M was measured by gas chromatography combustion isotope ratio mass spectrometry. RESULTS: Plasma alpha 2M was significantly elevated in nephrotic subjects (3.13 +/- 0.33 g/liter) versus controls (1.64 +/- 0.15 g/liter; P = 0.012). The alpha 2M fractional synthesis rate [(FSR), which is equal to fractional catabolic rate (FCR) in steady state] was the same in the two groups: 2.70 +/- 0.18%/day for the nephrotic patients versus controls 2.74 +/- 0.21%/day. However, the alpha 2M absolute synthesis rate (ASR) was significantly (P = 0.012) increased in the patients (3.69 +/- 0.33 mg/kg/day) versus controls (2.06 +/- 0.35 mg/kg/day). Plasma alpha 2M concentration correlated directly to its ASR (r2 = 0.821; P = 0.0001; N = 11). CONCLUSIONS: Increased plasma alpha 2M concentration in nephrotic patients is therefore a result of increased synthesis alone.

Adult↗
PubMed1998

Proportionate increase of fibrinogen and albumin synthesis in nephrotic patients: measurements with stable isotopes.

Hyperfibrinogenemia is a common feature of the nephrotic syndrome, and contributes to increased tendency for thrombosis and atherosclerosis. Its genesis is not certain, but the increase in liver fibrinogen mRNA in nephrotic rats indicates increased synthesis. Data in humans are scarce. We presently compared synthesis rates of fibrinogen and albumin in nephrotic adults (N = 7; plasma albumin 22.3 +/- 0.7 g/liter, proteinuria 12 g/day) and healthy control subjects (N = 8) using a primed/continuous infusion of the stable isotope L-[1-13C]valine for six hours. Absolute synthesis rate (ASR) of fibrinogen was 31 +/- 3 mg/kg/day in nephrotic subjects and 21 +/- 1 mg/kg/day in control subjects (P < 0.05), and positively correlated with plasma fibrinogen (P = 0.0317). The plasma fibrinogen pool was disproportionately increased in the nephrotic patients (271 +/- 30 mg/kg) compared to the controls (126 +/- 8 mg/kg), suggesting decreased fractional catabolic rate as well. The ASR of albumin was increased from 71 +/- 4 mg/kg/day in the controls to 160 +/- 19 mg/kg/day in the patients (P < 0.0001), and strongly correlated with the ASR of fibrinogen (P = 0.0046). Plasma alpha 2-macroglobulin was also elevated and correlated with the albumin synthesis rate, whereas plasma serum amyloid A and C-reactive protein were not elevated. These data suggest that in nephrotic patients the increased albumin synthesis is associated with an increase in synthesis of a specific and coordinated group of proteins, among which is fibrinogen.

Adult↗
PubMed1998

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Aortic Dissection↗
PubMed1998

Progressive vascular damage in hypertension is associated with increased levels of circulating P-selectin.

OBJECTIVE: To assess whether increased shedding of adhesion molecules in plasma provides an index for endothelial damage in hypertension. DESIGN AND METHODS: Three groups of hypertensive patients with increasing severity of vascular damage were studied: 20 essential hypertensives, 21 atherosclerotic, renovascular hypertensives and four malignant hypertensives. Twenty healthy subjects were included as a control group. Levels of P-selectin, E-selectin, intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor in venous blood were measured, using sandwich-type enzyme-linked immunosorbent assay. RESULTS: For essential hypertensives a trend for increased P-selectin and E-selectin values compared with those in controls was observed (159+/-44 versus 132+/-40 ng/ml, P = 0.062 and 40+/-13 versus 34+/-17 ng/ml, P = 0.055, respectively). P-selectin (210+/-84 ng/ml, P = 0.0021) and E-selectin (42+/-12 ng/ml, P = 0.012) levels in renovascular hypertensives were significantly higher than those in healthy controls. There were no significant increases in circulating levels of intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor either in essential hypertensives or in renovascular hypertensives. Marked increases in circulating levels of adhesion molecules and von Willebrand factor relative to those in controls were observed in malignant hypertensives (P-selectin 634+/-332 versus 132+/-40 ng/ml, P = 0.0004; vascular cell adhesion molecule 968+/-187 versus 493+/-139 ng/ml, P = 0.0004; and von Willebrand factor 259+/-75 versus 130+/-72 U/dl, P = 0.016). CONCLUSIONS: Progression of vascular damage in essential, renovascular and malignant hypertension is associated with a rise in circulating levels of P-selectins and, to a lesser extent, E-selectins, whereas levels of intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor are elevated only in diseases associated with acute severe vascular damage, including malignant hypertension. Our data suggest that selectins may be useful as indicators of vascular damage in hypertension.

Adult↗
PubMed1998

Expression of connective tissue growth factor in human renal fibrosis.

Chronic renal failure may occur in etiologically diverse renal diseases and can be caused by hemodynamic, immunologic and metabolic factors. Initial damage may evoke irreversible scarring, which involves production of a number of proinflammatory and fibrogenic cytokines, including platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Connective tissue growth factor (CTGF), a cytokine of the family of growth regulators comprising sef10, cyr61, CTGF and nov, has recently been described in association with scleroderma and other scarring conditions. We investigated CTGF mRNA expression in 65 human renal biopsy specimens of various renal diseases by in situ hybridization. In control human kidney CTFG mRNA was mainly expressed in visceral epithelial cells, parietal epithelial cells, and some interstitial cells. Connective tissue growth factor was strongly up-regulated in the extracapillary and severe mesangial proliferative lesions of crescentic glomerulonephritis, IgA nephropathy, focal and segmental glomerulosclerosis and diabetic nephropathy. An increase in the number of cells expressing CTGF mRNA was observed at sites of chronic tubulointerstitial damage, which correlated with the degree of damage. in the tubulointerstitial area the majority of the CTGF mRNA positive cells coexpressed alpha-smooth muscle actin, and were negative for macrophage markers. Our results indicate that CTGF may be a common growth factor involved in renal fibrosis.

Biopsy↗
PubMed1998

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis.

Increased very low density lipoprotein (VLDL) in nephrotic patients results from a decreased catabolism while increased low density lipoprotein (LDL) results from increased synthesis. Hyperlipidemia is a hallmark of nephrotic syndrome that has been associated with increased risk for ischemic heart disease as well as a loss of renal function in these patients. The hyperlipidemia usually is characterized by increased cholesterol levels, although hypertriglyceridemia may be present as well. The factors that determine the phenotype of nephrotic dyslipidemia are not understood, nor has the primary stimulus for nephrotic hyperlipidemia been identified. One hypothesis is that nephrotic hyperlipidemia is the result of a coordinate increase in synthesis of proteins by the liver. To address these issues we simultaneously measured the in vivo rate of VLDL apolipoprotein B100 (apo B100) secretion, LDL apo B100 synthesis and albumin synthesis in patients with a nephrotic syndrome (N = 8) and compared them with a control group (N = 7) using a primed/continuous infusion of the stable isotope L-[1-13C] valine for six hours. Kinetic data were analyzed by multicompartmental analysis. Patients studied had combined hyperlipidemia as reflected by an significant increase in both VLDL and LDL apo B100 pool sizes. In contrast, the albumin pool size was significantly decreased. VLDL apo B100 levels were primarily increased as a consequence of a decrease in fractional catabolic rate (FCR) rather than from an increase in the absolute synthesis rate (ASR). Both VLDL apo B100 and triglycerides were inversely related to the fractional catabolism (FCR) of VLDL apo B100 (r2 = 0.708; P = 0.0088) while neither had any relationship to the ASR of VLDL apo B100. In contrast to VLDL, increased LDL apo B100 was not a consequence of decreased catabolism. The LDL apo B100 ASR was significantly increased (P = 0.001) in the nephrotic patients compared to controls. Low density lipoprotein apo B100 ASR was greater than that of VLDL apo B100 in some patients, suggesting that LDL in these patients was not only derived from VLDL delipidation, but also by an alternative secretory pathway. There was no clear relationship between the ASR of VLDL apo B100 and the ASR of albumin within the current study population. Our data indicate that increased VLDL in nephrotic patients results from a decreased catabolism, while increased LDL results from increased synthesis.

Adult↗
PubMed1998

The renin-angiotensin system in diabetic nephropathy: the endothelial connection.

In recent years endothelial function has been forwarded a modulator in the pathogenesis of diabetic nephropathy. This review summarizes how an imbalance between endothelium-derived reactive nitrogen species and reactive oxygen species as well as increased expression of the endothelium-derived peptide endothelin-1 may contribute to loss of renal function in diabetes. In addition, the potentially beneficial effects of blockade of the renin-angiotensin system on this endothelial dysbalance is discussed.

Animals↗
PubMed1998

Endothelin A receptor blockade alleviates hypertension and renal lesions associated with chronic nitric oxide synthase inhibition.

Unopposed actions of vasoconstrictors, such as angiotensin, play an important role in the effects of chronic nitric oxide synthase (NOS) inhibition. In this study, it is hypothesized that endothelin (ET), another important vasoconstrictor, may also play a role in the development of hypertension and renal lesions during chronic NOS inhibition. The ET(A) receptor was blocked with A-127722 during chronic NOS inhibition with Nomega-nitro-L-arginine (L-NNA), a potent NOS inhibitor without antimuscarinic action. Male Sprague Dawley rats were treated for 3 wk with L-NNA (40 mg/kg per d), L-NNA (40 mg/kg per d) + A-127722 (30 mg/kg per d), or remained untreated (control). In preliminary experiments, L-NNA (40 mg/kg per d) had been found to cause the maximum increase of systolic BP and a 35% decrease in renal NOS activity. Three weeks of L-NNA treatment resulted in a marked rise in systolic BP (240+/-4 versus control 151+/-7 mmHg; P < 0.01), proteinuria (209+/-46 versus control 27+/-3 mg/d; P < 0.01), and a fall in GFR (1.41+/-0.16 versus control 2.23+/-0.19 ml/min; P < 0.05). Renal morphology showed severe vascular injury, characterized by focal adhesion and infiltration of mononuclear cells into the intima and media of preglomerular arteries and arterioles. This was sometimes associated with necrosis of the media and partial or total obstruction of the lumen with thrombotic material. Ischemic glomeruli were also present. Tubulointerstitial damage was moderate and accompanied by an influx of monocytes and macrophages. A-127722 administered simultaneously with L-NNA completely prevented the increase in proteinuria (39+/-8 mg/d) and glomerular ischemia. Vascular injury, tubulointerstitial damage, and the increase in systolic BP (191+/-6 mmHg) were partially prevented. The protective effects of ET(A) receptor blockade suggest that ET has hemodynamic as well as nonhemodynamic effects in the cascade of events following chronic NOS inhibition.

Animals↗
PubMed1998

Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome.

In patients with the nephrotic syndrome, markedly increased levels of lipoprotein(a) (Lp(a)) concentration have been frequently reported, and it has been suggested that this may contribute to the increased cardiovascular risk in these patients. The mechanism, however, is not clear. In the present study, in vivo fractional synthesis rate of Lp(a) was measured using incorporation of the stable isotope 13C valine. Under steady-state conditions, fractional synthesis rate equals fractional catabolic rate (FCR). FCR of Lp(a) was estimated in five patients with the nephrotic syndrome and compared with five control subjects. The mean plasma Lp(a) concentration in the patients (1749+/-612 mg/L) was higher than in control subjects (553+/-96 mg/L). Two patients were heterozygous for apolipoprotein(a) (range, 19 to 30 kringle IV domains), whereas all control subjects were each homozygous with regard to apolipoprotein(a) phenotype (range, 18 to 28 kringle IV domains). The FCR of Lp(a) was comparable between control subjects (0.072+/-0.032 pools/d) and patients (0.064+/-0.029 pools/d) despite the wide variance in plasma concentration. This suggests that differences in Lp(a) levels are caused by differences in synthesis rate. Indeed, the absolute synthetic rate of Lp(a) correlated directly with plasma Lp(a) concentration (P < 0.0001) in all subjects. The present results demonstrate that increased synthesis, rather than decreased catabolism, causes elevated plasma Lp(a) concentrations in the nephrotic syndrome.

Adult↗
PubMed1998

Oxygen radical stress in vascular disease: the role of endothelial nitric oxide synthase.

Impaired nitric oxide (NO) activity in proatherosclerotic states has been suggested to be caused mainly by increased degradation of NO by oxygen radicals. In recent years, endothelial NO synthase has been identified as a system that contributes to oxygen radical stress under pathophysiologic conditions. We discuss the origin of NO synthase-derived superoxide production, as well as possibilities to modulate (pathologic) shifts in NO/superoxide production by endothelial NO synthase.

Animals↗