Search PubMed⌕ Search

Biomedical subjects

L Raij

Publications and source records attributed to L Raij.

At least 55 records · Page 3Linked to original sources
PubMed1993

Tertatolol: a beta-blocker with unique effects on human glomerular cell function.

Tertatolol is a beta-blocker with unique renal vasodilatatory effects, mainly at the level of the microcirculation. Since many vasodilatory agents inhibit human mesangial cell (HMC) proliferation, the effects of tertatolol on the incorporation of 3H-thymidine in HMC were studied. Tertatolol plus mitogens (either fetal calf serum, platelet-derived growth factor (PDGF) or bovine thrombin) were incubated with HMC for 28 h, and 3H-thymidine was added during the last 4 h. Trichloroacetic acid-precipitable counts per well were divided by the mean number of cells in representative wells from the same experiment. The effect of tertatolol on angiotensin II (10(-6) mmol/l)-induced HMC contraction was also assessed by measuring the planar surface area of individual cells. In serum-free media, tertatolol did not significantly alter the incorporation of 3H-thymidine after 28 h of incubation in HMC. When tertatolol was added in the presence of 1% serum, 3H-thymidine incorporation was significantly reduced, compared to 1% serum alone. Tertatolol also inhibited 3H incorporation when PDGF and thrombin were used as the stimulus. The increase in cell number normally seen after 7 days in serum was also reduced by tertatolol. Tertatolol inhibited the reduction in planar surface area of HMC induced by angiotensin II. The inhibitory effect of tertatolol on HMC proliferation was also potentiated by ritanserin and MDL 72222, 5HT2 and 5HT3 antagonists, respectively. Conversely, the 5HT1A agonist 8-OH-DPAT did not modify the 3H-thymidine incorporation in HMC in the presence of tertatolol. In conclusion, tertatolol inhibits HMC proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1993

Hypercholesterolemia promotes endothelial dysfunction in vitamin E- and selenium-deficient rats.

Abnormal regulation of local vascular tone occurs early in human and experimental atherosclerosis. Impaired endothelium-dependent vascular relaxations mediated by endothelium-derived relaxing factor are an important contributor to these abnormalities. Endothelium-derived relaxing factor is nitric oxide released as such or attached to a carrier molecule. Oxidized lipoproteins impede endothelium-derived relaxing factor-mediated responses in vitro. We designed in vivo experiments to determine whether hypercholesterolemia with and without deficiency of two endogenous lipid antioxidants, vitamin E and selenium, would result in endothelial dysfunction. Vitamin E and selenium deficiencies were induced in a group of hypertension-prone Dahl salt-sensitive rats fed a diet high in cholesterol (4%) but low in NaCl (0.5%) for 18 weeks. Two other groups of Dahl salt-sensitive rats received diets sufficient in vitamin E and selenium but containing either high or normal cholesterol levels (control group). Serum cholesterol levels increased approximately 10-fold in the two groups of rats fed high-cholesterol diets. Systolic blood pressure was 143 +/- 3 mm Hg in high-cholesterol/vitamin E- and selenium-sufficient rats and 142 +/- 5 mm Hg in high-cholesterol/vitamin E- and selenium-deficient rats (P = NS). Mild intimal thickening and occasional mononuclear cell infiltration were observed in both of these groups. Serum vitamin E levels were decreased, whereas serum thiobarbituric acid-reactive substances and exhaled pentane (two indicators of endogenous lipid oxidation) were significantly increased in high-cholesterol/vitamin E- and selenium-deficient rats compared with high-cholesterol/vitamin E- and selenium-sufficient rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Endothelium-derived relaxing factor, nitric oxide: effects on and production by mesangial cells and the glomerulus.

The endothelium-derived relaxing factor nitric oxide (EDRF/NO) is a labile, endogenous vasodilator that is important in the control of systemic vascular tone. This review focuses on the effects of EDRF/NO on glomerular mesangial cells in vitro and on the role of EDRF/NO in mesangial and glomerular physiology and pathophysiology in vivo. It was concluded that EDRF/NO can stimulate increases in cGMP, inhibit mesangial cell contraction, and inhibit growth factor-induced proliferation of mesangial cells in culture. Furthermore, incubation with endotoxin or cytokines stimulates mesangial cells to produce EDRF/NO, via an inducible NO synthase enzyme. Therefore, it is likely that NO could play a role in the inflammatory response within the glomerulus. Finally, recent studies providing evidence that EDRF/NO is functional within the glomerulus in vivo, especially during endotoxemia and inflammation are also reviewed.

Animals↗
PubMed1992

Cardiovascular risk factors in chronic renal failure and hemodialysis populations.

Cardiovascular disease is the leading cause of death in patients with end-stage renal disease (ESRD). Risk factors for cardiovascular disease, including hypertension, lipid abnormalities, left ventricular hypertrophy (LVH), and glucose intolerance, are present more frequently in patients with chronic renal failure than in the general population, even before the onset of replacement therapy. The prevalence, pathogenesis, and significance of these factors in the uremic population are examined, and the potential roles of intervention are reviewed. Evidence suggests, but is not conclusive, that these factors are of predictive value for cardiovascular complications in patients with chronic renal failure. The effect of modification of these factors on cardiovascular morbidity and mortality in this population, especially in the early stages of renal failure, is an important area for further study.

Cardiomegaly↗
PubMed1992

Interactions of hypercholesterolemia and hypertension in initiation of glomerular injury.

In the Dahl S rat (DS), salt induces systemic and glomerular capillary hypertension associated with progressive glomerulosclerosis, while Dahl R rats (DR) remain normotensive, without glomerular abnormalities. Studies in experimental models have suggested that hypercholesterolemia may play a role in the development of glomerulosclerosis; however, it is unclear whether hypercholesterolemia alone, in the absence of hypertension, can initiate injury. To answer this question we induced hypercholesterolemia in salt-supplemented DS (DSC) and DR (DRC) by feeding a high cholesterol (4%) chow. Control rats (DS, DR) received high-salt, normal cholesterol chow. After eight weeks, DS and DSC developed equivalent hypertension (161 +/- 3 vs. 153 +/- 3 mm Hg, respectively, P = NS), while DR and DRC remained normotensive (138 +/- 5 vs. 131 +/- 5 mm Hg, P = NS; P less than 0.05 vs. DS and DSC). Cholesterol fed rats developed marked and equivalent hypercholesterolemia compared to controls (DS vs. DSC, 71 +/- 3 vs. 289 +/- 91 mg/dl, P less than 0.05; DR vs. DRC, 52 +/- 2 vs. 327 +/- 54 mg/dl, P less than 0.05). Hypertensive rats (DS, DSC) developed worse proteinuria and glomerular injury than normotensive rats (DR, DRC), but hypercholesterolemia exacerbated proteinuria and glomerulosclerosis only in DSC and not in DRC. Proteinuria significantly correlated with serum cholesterol in hypertensive rats (DS, DSC, P less than 0.05), but not normotensive rats (DR, DRC, P = NS). Furthermore, DSC had increased renal vascular resistance compared to DS, while no differences were found between DRC and DR. Thus, in the Dahl rat, hypercholesterolemia alone does not initiate glomerular injury. In this model, hypercholesterolemia is a pathogenetic factor in glomerular injury only when it coexists with systemic hypertension.

Animals↗
PubMed1992

Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis.

Escherichia coli endotoxin (LPS) can induce the clinical syndrome of septic shock and renal cortical necrosis and can stimulate nitric oxide (NO) production from macrophages, vascular smooth muscle, and glomerular mesangial cells in vitro. NO is an endogenous vasodilator, which also inhibits platelet aggregation and adhesion. We therefore sought to determine whether LPS would stimulate NO production in vivo and, if so, whether this NO would modulate endotoxin-induced glomerular thrombosis. The stable NO end-products, NO2 and NO3, were measured in serum and urine collections from rats during baseline and after injection of LPS, with or without substances that modulate NO synthesis. The urinary excretion of NO2/NO3 was 1,964 +/- 311 nm/8 h during the baseline and increased to 6,833 +/- 776 nm/8 h after a single intraperitoneal injection of 0.1 mg/kg LPS (P < 0.05). The serum concentration of NO2/NO3 also significantly increased after LPS injection. Both the urine and serum stimulation was significantly prevented by the NO synthesis inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME). L-Arginine, given with LPS+L-NAME significantly restored the NO2/NO3 levels in the urine. Ex vivo incubation of tissues from rats treated with LPS demonstrated NO production by the aorta, whole kidney, and glomeruli, but not cortical tubules. Histological examination of kidneys from rats given either LPS or L-NAME alone revealed that 2 and 4.5% of the glomeruli contained capillary thrombosis, respectively. In contrast, rats given LPS+L-NAME developed thrombosis in 55% of glomeruli (P < 0.001), which was significantly prevented when L-arginine was given concomitantly. We conclude that LPS stimulates endogenous production of NO in vivo and that this NO is critical in preventing LPS-induced renal thrombosis.

Animals↗
PubMed1992

Effect of amlodipine on mesangial cell proliferation and protein synthesis.

Mesangial cells in the glomerulus have several important physiological functions, as has been demonstrated by past research. Platelet derived growth factor, thrombin, endothelin, and angiotensin II have all been shown to affect mesangial cell growth and protein synthesis. First generation Ca channel blockers also have a definite effect on mesangial cell proliferation. We investigated whether the effects of a second generation Ca channel blocker, amlodipine, were similar. Amlodipine was found to inhibit hyperplasia and hypertrophy in mesangial cells.

Amlodipine↗
PubMed1991

Hypertension, endothelium, and cardiovascular risk factors.

The functions of the endothelium and the effects of hypertension, atherosclerosis, and diabetes on the endothelium are reviewed. The endothelium affects vascular tone by releasing vasodilators and modulating the effects of vasoactive substances such as catecholamines, bradykinin, serotonin, and angiotensin II. Relaxation of vascular smooth muscle depends upon a functionally intact endothelium and the release of the endothelium-derived relaxing factor nitric oxide. Endothelial cells also appear to release a hyperpolarizing factor that relaxes smooth muscle through activation of the sodium-potassium pump, and of the endothelium-dependent contracting factors. Similarities are found in the vascular injury resulting from hypertension, atherosclerosis, and diabetes. When these risk factors coexist, they can act synergistically and magnify the vascular injury. The endothelium appears to be one of the major targets for these forms of injury. Future therapeutic strategies will focus on ways to prevent, arrest, or reverse endothelial injury.

Animals↗
PubMed1991

Synthesis and action of nitric oxide in rat glomerular mesangial cells.

Macrophages and certain tumor cell lines can be induced to synthesize nitric oxide (NO) from L-arginine after stimulation with lipopolysaccharide (LPS) or cytokines. In the present study, we have found that culture medium collected after 24 h from unstimulated rat mesangial cells (MC) contains 6.3 +/- 1.2 microM of NO3-/NO2- (the degradation products of NO). These levels were significantly increased when MC were incubated with LPS (10 micrograms/ml) for 24 h (23.9 +/- 4.1, P less than 0.05). The specific inhibitor of NO synthesis, NG-monomethyl-L-arginine (L-NMMA) completely inhibited LPS-stimulated production of NO3-/NO2-, confirming that the NO3-/NO2- was derived from NO within the MC. Recent studies suggest that endothelium-derived relaxing factor (EDRF) produced by vascular endothelium is also NO, and we have previously shown that both EDRF and NO stimulate increases in MC guanosine 3',5'-cyclic monophosphate (cGMP). Thus we sought to determine whether NO synthesized by the MC could affect cGMP levels within the same cells. After 24-h incubation with LPS (10 micrograms/ml), intracellular cGMP level within the MC was 706.3 +/- 197 (SE) compared with 40.5 +/- 7 fmol/micrograms protein in control MC incubated in media alone (P less than 0.01). The changes in cGMP in response to LPS were inhibited by greater than 90% by L-NMMA. Similar to LPS, incubation of MC with the cytokine gamma-interferon also increased NO3-/NO2- in the culture media and increased cGMP levels within MC. The induction of NO synthesis within MC and the concomitant stimulation of MC cGMP may be important in the modulation of the effects of endotoxemia, as well as inflammation, within the glomerulus.

Animals↗
PubMed1991

Effects of amino acid infusion on renal hemodynamics. Role of endothelium-derived relaxing factor.

Ingestion of protein or intravenous infusion of amino acids acutely elevates glomerular filtration rate (GFR) and renal plasma flow (RPF) by unknown mechanisms. Endothelium-derived relaxing factor (EDRF), now known to be nitric oxide derived from metabolism of L-arginine, participates in local regulation of vascular tone. To investigate the hypothesis that EDRF may participate in the renal vasodilatation and increased GFR after amino acid infusion, we characterized the effect of inhibition of EDRF synthesis with NG-monomethyl L-arginine (LNMMA) on basal renal hemodynamics and the response to infusion of a 10% mixed amino acid solution (1 ml/hr i.v.) in the rat. Renal arterial infusion of LNMMA (500 micrograms/kg/min) resulted in a significant increase in mean arterial pressure, decreases in GFR (20%) and RPF (44%), and a significant increase in filtration fraction. Pretreatment with the angiotensin II receptor antagonist Sar-Gly-angiotensin II did not prevent the increase in blood pressure but blunted the decreases in GFR (11%) and RPF (27%) after LNMMA infusion. Amino acid infusion in the untreated, fasted rat resulted in no change in blood pressure but significant increases in GFR and RPF; these effects were completely inhibited by intrarenal LNMMA but not an equihypertensive intravenous infusion of phenylephrine. In summary, EDRF participates in regulation of basal renal hemodynamics. Furthermore, amino acid-induced hyperfiltration and renal vasodilatation are completely prevented by inhibition of EDRF synthesis. We conclude that EDRF may participate in the renal hemodynamic response to amino acid infusion.

Amino Acids↗
PubMed1991

Role of endothelium-derived relaxing factor in regulation of vascular tone and remodeling. Update on humoral regulation of vascular tone.

In addition to preserving the permselectivity of the vascular wall and providing an antithrombogenic surface, the vascular endothelium contributes importantly to the regulation of vasomotor tone. Indeed, the endothelium participates in the conversion of angiotensin I to angiotensin II; the enzymatic inactivation of several plasma constituents such as bradykinin, norepinephrine, serotonin, and ADP; and the synthesis and release of vasodilator substances such as prostacyclin and the recently discovered endothelium-derived relaxing factor (EDRF). The diffusible EDRF released from the endothelium is nitric oxide or a substance closely related to it such as nitrosothiol. The endothelium also synthesizes and releases vasoconstrictive factors, including products derived from arachidonic acid metabolism and the recently discovered peptide endothelin. An increasing body of evidence from experimental and clinical studies indicates that EDRF and endothelium-derived contracting factors play an important role in vascular physiology and pathology. It has become apparent that the balance of these factors may be a major determinant of systemic and regional hemodynamics. Moreover, through generally opposite effects on growth-related vascular changes, contracting factors such as endothelin and relaxing factors such as EDRF also may be important determinants of the vascular response to injury in various disease states such as atherosclerosis and hypertension. It is clear that the vascular endothelium is a complex and dynamic organ. Understanding endothelium function in normal physiology and disease states is of potential clinical importance and should be the focus of future investigation.

Animals↗
PubMed1991

Chronic amphotericin B nephrotoxicity in the rat: protective effect of calcium channel blockade.

Amphotericin B is used despite predictable nephrotoxicity because it remains the most efficacious agent currently available for systemic fungal infections. It has been previously shown that calcium channel blockade prevents renal vasoconstriction and blunts the fall in glomerular filtration rate during acute amphotericin B infusion in the rat. Therefore, the effect of cotreatment with diltiazem on nephrotoxicity during chronic daily amphotericin therapy in rats was studied. Rats were given diltiazem (45 mg/kg, 1 h before and 1 h after amphotericin) or vehicle by gastric tube; and amphotericin B (5 mg/kg/day i.p.) for 10 days. Control rats received corresponding vehicles by gastric tube and daily i.p. infection. Renal function was determined 24 h after the last dose of amphotericin or vehicle. Serum creatinine rose significantly in rats receiving amphotericin alone (initial versus final, 0.50 +/- 0.07 versus 1.09 +/- 0.20 mg/dL; P less than 0.05) but not with amphotericin plus diltiazem (0.54 +/- 0.11 versus 0.84 +/- 0.23 mg/dL; P was not significant). Amphotericin rats had a marked decrease in glomerular filtration rate (amphotericin versus control, 0.28 +/- 0.04 versus 1.23 +/- 0.08 mL/min/g kidney wt; P less than 0.05) and renal plasma flow (1.63 +/- 0.19 versus 3.50 +/- 0.40 mL/min/g kidney wt; P less than 0.05). These adverse renal hemodynamic effects were prevented by cotreatment with diltiazem (amphotericin plus diltiazem; glomerular filtration rate, 0.82 +/- 0.18 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control; renal plasma flow, 3.24 +/- 0.63 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control).(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗
PubMed1991

Mechanisms of vascular injury: the emerging role of the endothelium.

Evidence is increasing that vascular tone is highly dependent on the health of the endothelium and on the delicate balancing act between endothelium-derived relaxing and endothelium-derived contracting factors. Moreover, there is also evidence supporting the notion that the same factors which affect vascular tone also regulate, either in an autocrine or paracrine fashion, changes in vascular architecture. Synthesis and release of both endothelium-derived relaxing and contracting factors are affected by a number of physiologic and therapeutic agents as well as by other factors, among them vascular injury in disease states such as atherosclerosis, hypertension, diabetes, and acute renal failure. A number of trials indicate that therapeutic intervention may be capable of modulating the synthesis and release of these substances and the balance between the two as well as influencing the processes which control vascular remodeling.

Acute Kidney Injury↗
PubMed1991

Antihypertensive therapy and the progression of chronic renal disease. Are there renoprotective drugs?

The pathogenesis of hypertensive glomerular injury is complex, involving both hemodynamic and nonhemodynamic factors. One can therefore confidently predict that a wide variety of disparate therapeutic interventions, pharmacologic and nonpharmacologic, may be effective in arresting or slowing progressive glomerular injury. Based on the experimental and clinical literature available to date, it is clear that glomerular capillary hypertension is an important pathogenetic factor in this disease and that lowering of Pgc with antihypertensive drugs is associated with prevention of glomerular injury. Furthermore, the CEI may have a special renoprotective effect compared to other antihypertensive agents, most likely due to their unique renal hemodynamic actions. Pending the results of well-designed clinical trials, converting enzyme inhibitors represent the antihypertensive agents most likely to arrest the progressive decline in renal function observed in patients with hypertension and chronic renal failure. The calcium channel blockers are effective antihypertensive agents in patients with chronic renal failure, but whether they confer specific renoprotective effects remains uncertain. Since a large number of patients with chronic renal failure require more than one antihypertensive drug for adequate blood pressure control it may be of interest to evaluate the benefits of drug combinations. In this regard, it is possible that a combination of a CEI and a CCB may have complimentary effects in protecting the kidney. The development of these new classes of antihypertensive agents has had a major impact on the treatment of patients with chronic progressive renal failure. Future studies will hopefully clarify the optimal antihypertensive therapeutic regimen and allow us to move closer to the goal of eliminating end-stage renal failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Influence of nitric oxide on agonist-mediated calcium mobilization in platelets.

Recent studies have characterized endothelium-derived relaxing factor as nitric oxide. It appears to exert its effect by elevating intracellular levels of cyclic GMP. In this study we confirm that nitric oxide is a potent inhibitor of agonist-induced irreversible aggregation. At the concentrations tested nitric oxide effectively blocked thrombin-stimulated mobilization of cytosolic-free calcium in Fura 2-loaded platelets. In addition, nitric oxide prevented the inositol 1,4,5-trisphosphate-stimulated calcium rise in cytosolic calcium in saponin-permeabilized Fura 2-loaded platelets. Similar to the action of adenylate cyclase stimulators, nitric oxide facilitated lowering of calcium levels raised by the action of agonists. The specific mechanism by which it exerts its effect on intracellular levels of calcium is not clear.

Adult↗
PubMed1990

Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses.

An endothelium-derived relaxing factor (EDRF) has recently been identified as nitric oxide (NO), originating from endothelial cell metabolism of L-arginine. In vitro studies suggest that EDRF/NO stimulates soluble guanylate cyclase and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels in vascular smooth muscle cells, resulting in the vasorelaxant effects of endothelium-dependent vasodilators such as acetylcholine (ACh). The importance of EDRF/NO in normal physiology or disease states remains uncertain. We therefore investigated the relationship between ACh-induced hemodynamic responses, synthesis of EDRF/NO, and changes in the rate of urinary cGMP excretion in the anesthetized rat in vivo. Intravenous infusion of ACh resulted in hypotension, maintenance of glomerular filtration rate, and renal vasodilatation. ACh induced a dose-dependent increase in urinary cGMP excretion, an effect that was not observed with equihypotensive doses of the endothelium-independent vasodilator, prostacyclin. Rates of cGMP excretion were significantly correlated with the fall in systemic blood pressure induced by ACh. Treatment with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of enzymatic synthesis of nitric oxide from L-arginine, prevented the ACh-induced increase in urinary cGMP excretion as well as the systemic and renal hemodynamic effects of ACh. Plasma levels of atrial natriuretic peptide were unchanged by ACh infusion. Intravenous infusion of L-NMMA was associated with increased blood pressure and decreased basal rates of urinary cGMP excretion. This hypertensive effect was reversed by administration of L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗