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Biomedical subjects

L Raij

Publications and source records attributed to L Raij.

At least 37 records · Page 2Linked to original sources
PubMed1997

Induction of endothelial cell injury by cigarette smoke.

Cigarette smoke contains different populations of free radicals which may be responsible for endothelial cell (EC) injury of smokers. The purpose of this study was to examine the effects of gas-phase cigarette smoke on EC endothelium-derived relaxing factor (EDRF)/NO-guanylate cyclase (GC)-cGMP pathway and on EC detachment-type injury after incubation with smoke. Furthermore, we examined whether different kind of antioxidants can prevent smoke-caused EC injury. We measured cGMP pathway using direct (sodium nitroprusside, SNP) and indirect (A23187, the calcium ionophore and bradykinin, BK) activators of GC. Directly and indirectly stimulated EC cGMP production dose-dependently decreased and EC detachment increased after incubation with smoke. Externally added thiols (glutathione, GSH; D-Penicillamine, DP; N-acetylcysteine, NAC) protected EC from damage of cGMP production and cell detachment. Other antioxidants (catalase, deferoxamine and superoxide dismutase) were ineffective. These results suggest that the thiol containing GC in EC is destroyed or inactivated or thiol like species responsible for activation of GC is incomplete in EC after incubation with smoke. It is also possible that externally added thiols bind an unknown component of smoke and this way, EC is protected. EC injury may contribute to vascular diseases associated with cigarette smoking.

Animals↗
PubMed1996

Pathophysiology of the vascular wall: the role of nitric oxide in renal disease.

Nitric oxide (NO) is formed in the endothelium by the constitutive enzyme NO synthase from the substrate amino acid L-arginine. As an endogenous vasodilator it contributes to renal arteriolar tone and modulates relaxation of the mesangium, thus contributing to regulation of glomerular microcirculation. NO also plays a role in regulating renal sodium excretion and renin release. It has antiplatelet and antithrombogenic effects and thus helps prevent thrombosis within the glomerular capillaries. In sepsis and sepsis-related syndromes, NO has a renoprotective role in that it aids in maintaining renal vasodilation and inhibiting platelet adhesion and aggregation. More knowledge of these effects may lead to the design of therapeutic interventions for preventing glomerular injury.

Animals↗
PubMed1996

End-stage renal disease: why aren't improvements in hypertension treatment reducing the risk?

Although we have seen a decreased incidence of some of the complications of hypertension, such as myocardial infarction and stroke, the same cannot be said for end-stage renal disease (ESRD). The disparity brings up the question of why improvements in hypertension control apparently do not bring improvement in the incidence of ESRD. Some of the factors likely at play include variation in the mechanisms at work in hypertensive patients of different races and variation in the degree to which antihypertensive agents affect systemic blood pressure and glomerular capillary pressure. These and other factors relating to hypertension and ESRD are the focus of this review.

Antihypertensive Agents↗
PubMed1996

Salt intake and plasma atrial natriuretic peptide and nitric oxide in hypertension.

In response to a high salt intake, salt-sensitive hypertensive individuals retain more sodium and manifest a rise in blood pressure greater than that in salt-resistant individuals. In this study, we tested whether salt sensitivity might be related at least in part to reduced secretion of atrial natriuretic peptide (ANP) or to abnormal nitric oxide production. We measured plasma ANP and NO2+NO3 in 7 normotensive individuals and 13 salt-sensitive and 14 salt-resistant blacks with essential hypertension under conditions of low (10 mEq/d) and high (250 mEq/d) salt intake. To evaluate possible racial differences in ANP secretion, we also measured plasma ANP in 6 salt-sensitive and 8 salt-resistant hypertensive whites during low and high salt intakes. Under low salt conditions, plasma ANP levels were not different in normotensive control subjects and salt-sensitive and salt-resistant hypertensive blacks. During high salt intake, plasma ANP levels did not change in control subjects and salt-resistant patients but decreased in salt-sensitive patients. ANP levels after high salt diet were lower (P < .01) in salt-sensitive than salt-resistant blacks. In hypertensive whites, high salt intake caused no significant change in plasma ANP. Under low salt conditions, plasma NO2+NO3 levels were higher (P < .05) in salt-sensitive (189 +/- 7.9 mumol/L) and salt-resistant (195 +/- 13.5 mumol/L) black patients than in control subjects (108 +/- 9.7 mumol/L). During high salt intake, plasma NO2+NO3 decreased significantly (P < .01) in both salt-sensitive (150 +/- 7.0 mumol/L) and salt-resistant (142 +/- 9.0 mumol/L) patients. These studies show that under conditions of high salt intake, salt-sensitive hypertensive blacks manifest a paradoxical decrease in ANP secretion. This abnormality may play a role in the reduced ability of these individuals to excrete a sodium load and in the sodium-induced rise in blood pressure. This study does not support the hypothesis that salt sensitivity depends on a deficit of nitric oxide production, but it suggests that high salt intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.

Adult↗
PubMed1995

Glomerular actions of nitric oxide.

NO, a simple molecule synthesized from L-arginine by NO synthases, has been identified to play an important role in cell communication, cell defense and cell injury. The half life of NO is very short because NO either reacts with superoxide anion (O2-), and/or binds to heme molecules or Fe-S groups present in proteins. The biological effects of NO depend on both the concentration of NO at the site of action as well as upon the specific location where NO is generated. Small quantities of NO are generated by cNOS such as that present in the vascular endothelium, while large quantities of nitric oxide are synthesized by iNOS in response to cytokines or bacterial products. Within the kidney NO generated by endothelial cNOS participates in the regulation of the glomerular microcirculation by modifying the tone of the afferent arteriole and mesangial cells (Fig. 4). In addition, NO generated by macula densa and the afferent arteriole control glomerular hemodynamics via TGF and by modulating renin release. Therefore NO is important in the physiologic regulation of glomerular capillary blood pressure, glomerular plasma flow and the glomerular ultrafiltration coefficient. Through its actions on glomerular pressures and flows, NO may also regulate the macro- and micromolecular traffic through the mesangium. Chronic NO insufficiency causes hypertension and glomerular damage and may be causally involved in the genesis of salt dependent hypertension. Increased NO production may be involved in the early pathogenic hemodynamic changes in diabetes and in the physiologic hemodynamic responses to normal pregnancy. Maintenance of the antithrombogenic properties of the endothelium is another important action of NO which inhibits platelet aggregation and adhesion. Large quantities of NO such as that synthesized by either glomerular cells or macrophages during glomerular inflammation may lead to glomerular injury. A better understanding of the physiology and pathophysiology of NO in the kidney will lead to the development of new therapeutic avenues.

Animals↗
PubMed1995

The pressor effect of recombinant human erythropoietin is not due to decreased activity of the endogenous nitric oxide system.

In a subset of dialysis patients, erythropoietin (rHuEpo) treatment exacerbates hypertension. The mechanism of this pressor effect is unknown; however, it has been suggested that decreased endogenous nitric oxide (NO) activity may play a role. To explore this hypothesis, Sprague-Dawley rats were given rHuEpo (150 U/kg s.c. three times per week) or corresponding vehicle. Blood pressure, haematocrit, and urinary excretion of the stable NO metabolites, nitrite (NO2) and nitrate (NO3), were determined at baseline and 3 weeks. After 3 weeks of rHuEpo treatment there was a significant increase in blood pressure and haematocrit, while in vehicle-treated rats blood pressure and haematocrit remained at basal levels. Urinary excretion of NO2+NO3 increased compared to basal in rHuEpo, but not vehicle rats. Thus in normal rats rHuEpo does have a significant pressor effect, but this is not associated with decreased activity of the endogenous NO system. Thus decreased endogenous NO activity is not responsible for rHuEpo-associated hypertension. These data further suggest that endogenous NO activity is increased in rHuEpo-treated rats, perhaps as a counter-regulatory mechanism that limits the pressor effect. Whether this mechanism is active in the setting of rHuEpo-treated chronic renal failure in humans is unknown.

Animals↗
PubMed1995

Increased nitric oxide synthase activity despite lack of response to endothelium-dependent vasodilators in postischemic acute renal failure in rats.

Lack of response to endothelium-dependent vasodilators generally has been considered to be evidence for decreased nitric oxide synthase (NOS) activity and NO generation after ischemic or hypoxic injury to vital organs including the kidney. In this study, renal blood flow (RBF) responses to endothelium-dependent vasodilators acetylcholine and bradykinin and the endothelium-independent vasodilator prostacyclin, the nonselective NOS inhibitor L-NAME (without and with L-arginine), the inducible NOS inhibitor aminoguanidine, and the NO-donor sodium nitroprusside were examined in 1-wk norepinephrine-induced (NE) and sham-induced acute renal failure (ARF) rats. Compared with sham-ARF, there was no increase in RBF to intrarenal acetylcholine and bradykinin, but a comparable RBF increase to prostacyclin in NE-ARF kidneys. However, there was a significantly greater decline in RBF to intravenous L-NAME in NE- than sham-ARF rats (-65 +/- 8 vs. -37 +/- 5%, P < 0.001) which was completely blocked by prior L-arginine infusion. There was no change in RBF to the inducible NOS specific inhibitor aminoguanidine. Unlike sham-ARF, there was no increase in RBF to intrarenal sodium nitroprusside in NE-ARF. Immunohistochemistry and immunofluorescence detection of constitutive (c) NOS using mouse monoclonal antibody were carried out to positively determine the presence of cNOS in NE-ARF. 90% of renal resistance vessels showed evidence of endothelial cNOS in both sham- and NE-ARF. Taken together, results of these experiments are consistent with the conclusion that NOS/NO activity is, in fact, maximal at baseline in 1-wk NE-ARF and cannot be increased further by exogenous stimuli of NOS activity. The increased NOS is likely of the constitutive form and of endothelial origin. It is suggested that the increased NOS activity is in response to ischemia-induced renal vasoconstrictor activity. Attenuated response to endothelium-dependent vasodilators cannot be interpreted only as evidence for decreased NOS activity.

Acetylcholine↗
PubMed1995

Renal hemodynamic effects of dietary protein in the rat: role of nitric oxide.

The biologic mediator(s) of the renal hemodynamic effects of a high dietary protein intake (hyperfiltration and renal vasodilation) are unknown. The endogenous nitrovasodilator nitric oxide (NO) derives from the amino acid L-arginine, and NO has been demonstrated to mediate the hyperfiltration and vasodilation observed during amino acid infusion in rats. We therefore hypothesized that NO may also mediate the long-term renal hemodynamic effects of variations in dietary protein intake. We studied rats maintained with low protein (6%) and high-protein (50%) diets for 2 weeks. An additional group of rats receiving a high-protein diet was also treated with the NO synthase inhibitor, L-nitro-arginine-methyl ester (NAME, 100 mg per liter of drinking water). After 2 weeks a high-protein diet was associated with a significant increase in glomerular filtration rate (GFR) (50% protein group vs 6% protein group, 1.01 +/- 0.03 vs 0.61 +/- 0.03 ml/min; p < 0.05) and renal vasodilation (renal vascular resistance: 50% protein group vs 6% protein group, 11.70 +/- 0.88 vs 17.65 +/- 1.55 mm Hg/min/ml; p < 0.05) compared with a low-protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

Lack of contribution of nitric oxide to basal vasomotor tone in heart failure.

Patients with heart failure have reduced forearm vasodilator responses when endothelial cell nitric oxide production is stimulated by muscarinic agonists. The aim of this study was to determine if activity of the nitric oxide pathway was also abnormal under basal conditions. Forearm blood flow (FBF) was measured with strain-gauge plethysmography in response to the intraarterial infusion of a subsystemic dose range of L-N-monomethylarginine (L-NMMA), a competitive inhibitor of nitric oxide synthase. In 18 normal subjects, the baseline FBF of 3.6 +/- 1.4 was decreased by 0.3 +/- 0.5 (p < 0.01), 1.0 +/- 0.7 (p < 0.01), 1.4 +/- 0.9 (p < 0.01), and 1.3 +/- 1.3 (p < 0.01) ml/min/100 ml forearm volume during infusions of 1, 4, 8, and 16 mumol/min of L-NMMA, respectively. In 10 patients with heart failure, the baseline FBF of 2.6 +/- 0.9 was decreased by 0.4 +/- 0.5 (p < 0.05), 0.4 +/- 0.5 (p < 0.05), 0.9 +/- 0.8 (p < 0.01), and 0.9 +/- 0.7 (p < 0.01) ml/min/100 ml forearm volume with the 4 doses of L-NMMA, respectively. There was no difference in the L-NMMA response between the 2 groups in terms of absolute flow, percent change, or with analysis of covariance to adjust for different baselines. The stable end products of nitric oxide (nitrite and nitrate) were measured in the forearm venous effluent. Nitrite and nitrate levels at baseline were not reduced in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Glomerular thrombosis in pregnancy: role of the L-arginine-nitric oxide pathway.

E. coli endotoxin (LPS) and certain cytokines induce synthesis of nitric oxide (NO) from L-arginine, but also promote endothelial injury and intravascular coagulation. NO has vasodilator and antithrombogenic properties. We investigated the relationship between the L-arginine-NO pathway and the susceptibility to LPS-induced glomerular thrombosis in pregnancy. Pregnant rats were given either 0.15 or 0.75 mg/kg/body wt of LPS intraperitoneally. In rats given 0.15 mg/kg/body wt of LPS urinary NO2-/NO3- (end products of NO) increased 200% (P < 0.05), plasma L-arginine did not change, and glomerular thrombosis was minimal. Pregnant rats given 0.75 mg/kg/body wt of LPS developed glomerular thrombosis in 75% of glomeruli (P < 0.05). In these rats plasma L-arginine fell 98%, from 53 +/- 4 to 1.4 +/- 0.9 mmol/liter (P < 0.05) but the urinary NO2-/NO3- did not increase. Oral administration of L-arginine but not D-arginine increased urinary NO2-/NO3- by 250% and averted glomerular thrombosis in these rats (P < 0.05). Virgin rats given 0.75 mg/kg/body wt of LPS did not contract glomerular thrombosis. In these rats plasma L-arginine decreased only 40% while urinary NO2-/-NO3- concomitantly increased over 200% (P < 0.05). Plasma endothelin-1 increased only in rats exhibiting glomerular thrombosis. Thus, limited maternal reserve capability for NO synthesis may underlie, at least in part, the susceptibility for glomerular thrombosis in pregnancy.

Animals↗
PubMed1994

Exogenous nitric oxide prevents endotoxin-induced glomerular thrombosis in rats.

Nitric oxide (NO) synthesized from L-arginine is an endogenous vasodilator and inhibitor of platelet adhesion and aggregation. Gram-negative lipopolysaccharide (LPS) can induce NO synthesis, which may mediate the pathophysiologic effects of endotoxemia. In addition, our previous studies suggested that LPS-induced NO may protect against thrombosis in rats. In the present study, male Sprague-Dawley rats given LPS (0.1 mg/kg) i.p. increased their urinary excretion of NO2 + NO3 (stable end-products of NO) by 4.3-fold. Rats given 10 micrograms/kg/hr i.v. of nitroglycerin (GTN), an exogenous NO donor, showed a similar increase. L-NAME, an inhibitor of NO synthesis, abrogated the increase in urinary NO2 + NO3 in LPS-treated rats but not in rats given GTN. Glomerular thrombosis developed in rats given LPS + L-NAME (thrombosis score = 3.02 +/- 0.4), while those given LPS + L-NAME + GTN were largely protected (thrombosis score = 1.37 +/- 0.5, P < 0.05). Atrial natriuretic peptide (ANP), an NO-independent vasodilator, neither increased urinary NO2 + NO3 nor prevented glomerular thrombosis (thrombosis score = 2.68 +/- 0.5, NS). Hydralazine, another vasodilator without effects on NO or platelets, also failed to prevent glomerular thrombosis in rats given LPS + L-NAME. We conclude that in endotoxemia, the antithrombogenic properties of endogenously synthesized NO are important in preventing alomerular thrombosis. The exogenously NO donor, GTN, can substitute for the antithrombogenic effect of endogenous NO. Clinically, administration of NO synthesis inhibitors to treat endotoxic shock may need to be combined with concomitant administration of exogenous NO donors to prevent microvascular thrombosis.

Animals↗
PubMed1993

Angiotensin-converting enzyme inhibition and renal protection. An assessment of implications for therapy.

The role of hypertension in the pathogenesis of renal damage is a subject of both historical interest and current investigation. Because of the difficulty associated with studying the pathophysiologic role of glomerular injury in systemic hypertension, experimental models have provided much of the data in this field. The mechanisms leading to glomerular injury are complex and not fully elucidated. Mesangial and endothelial cell injury are thought to be important pathophysiologic mechanisms in the renal injury associated with hypertension. One hypothesis suggests that glomerular hypertension (ie, a hemodynamic event) is the primary pathogenetic mechanism, but another supports the notion that glomerular hypertrophy (ie, abnormal growth-related events) contributes to injury. The intrarenal renin-angiotensin system may play an important pathogenetic role in end-stage renal disease. Angiotensin-converting enzyme (ACE) inhibition has been shown to arrest the progression of renal injury in animal models. Although the clinical database is incomplete, the findings of anecdotal reports and short-term studies suggest that ACE inhibition may preserve renal function in patients with scleroderma renal crisis, reduce proteinuria in patients with diabetic nephropathy, and normalize renal hemodynamics in patients with a variety of renal diseases. The beneficial effects of ACE inhibition may be due to both hemodynamic (eg, reduction in glomerular capillary and intraglomerular pressures) and nonhemodynamic (eg, potassium-sparing and reduction in mesangial proliferation) mechanisms. The precise role of ACE inhibitors in the prevention of renal damage awaits the results of ongoing long-term, double-blind clinical studies. Nevertheless, ACE inhibition may be an appropriate therapeutic alternative in the hypertensive patient whose renal injury is progressing despite aggressive antihypertensive therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Effects of cardiac transplantation on endothelium-dependent dilation of the peripheral vasculature in congestive heart failure.

Patients with congestive heart failure demonstrate attenuated endothelium-dependent vasodilation of the peripheral vasculature, but there are no data regarding the effect of therapies on this abnormality or whether this abnormality is reversible. This study was performed to address the hypothesis that abnormalities in endothelium-dependent vasodilation in heart failure are improved by heart transplantation. Forearm blood flow responses to the intraarterial administration of a dose range of methacholine, an endothelium-dependent vasodilator, and nitroprusside, an endothelium-independent vasodilator, were examined in 2 separate protocols. In protocol 1, forearm blood flow responses to methacholine in 14 heart transplant recipients were 5.02 +/- 3.11, 11.55 +/- 7.20 and 11.61 +/- 10.24 ml/min/100 ml forearm volume. These responses were significantly greater than those in 10 patients with heart failure (2.23 +/- 1.22, 4.60 +/- 3.43 and 6.70 +/- 4.91 ml/min/100 ml forearm volume; p < 0.05). In contrast, the responses to nitroprusside were nearly identical in the 2 groups. In protocol 2, six patients were studied before and 4 months (range 1 to 11) after transplantation. Methacholine responses before transplantation were 2.5 +/- 1.3, 5.2 +/- 1.5 and 7.3 +/- 1.5 ml/min/100 ml forearm volume and were significantly improved after transplantation to 5.7 +/- 1.2, 12.1 +/- 3.0 and 14.2 +/- 2.2 ml/min/100 ml forearm volume (p < 0.05). Peak reactive hyperemia responses increased significantly from 19.0 +/- 3.7 to 44.8 +/- 6.4 ml/min/100 ml forearm volume (p < 0.01) after transplantation. These data demonstrate that heart transplantation was associated with a significant improvement in the forearm blood flow responses to methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The effects of various antihypertensive agents on cardiovascular risk factors in patients with renal failure.

Systemic cardiovascular diseases are the most important cause of morbidity and mortality among patients with chronic renal failure. Hypertension, lipid-profile abnormalities, glucose intolerance, and left ventricular hypertrophy are found in most patients with chronic renal failure and are responsible for the increased incidence of atherosclerosis. Hypertension is the risk factor most susceptible to treatment, but consideration must be given in selecting an antihypertensive agent not only to its effect on blood pressure but to its effects on the other risk factors. Improper selection could impair the long-term benefit of good blood pressure control by increasing the severity of the other cardiovascular risk factors and eventually worsening the prognosis of the chronic renal failure. The remaining renal function in patients not yet in end-stage renal failure deserves special consideration; an adequate antihypertensive regimen could potentially delay the need for dialysis.

Antihypertensive Agents↗
PubMed1993

Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO.

Diabetic rats manifest abnormal renal hemodynamic responses, with persistent renal vasodilation at reduced renal perfusion pressures. We hypothesized that in diabetes, renal hemodynamics are modulated by increased activity of the endogenous vasodilator, NO. In anesthetized Munich-Wistar rats, after 6 wk of streptozotocin-induced, insulin-treated diabetes, and in age-matched, nondiabetic littermates (n = 7-8), basal renal hemodynamics and responses to graded reductions in renal perfusion pressure were determined before and after intrarenal arterial infusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). An identical protocol was followed in a second cohort of rats pretreated with indomethacin (4 mg/kg iv). Diabetic rats demonstrated hyperglycemia, renal enlargement, hyperfiltration, and increased urinary excretion of the stable NO metabolites, NO2 and NO3. L-NAME eliminated basal hyperfiltration in diabetic rats, and L-NAME, but not indomethacin, also eliminated persistent renal vasodilation at reduced renal perfusion pressure. We conclude that in a rat model of diabetes, increased endogenous NO activity may play a role in basal hyperfiltration and in the persistent renal vasodilatation manifested at reduced renal perfusion pressures.

Amino Acid Oxidoreductases↗