PubMed Health⌕ Search

Biomedical subjects

S M Bode-Böger

Publications and source records attributed to S M Bode-Böger.

At least 55 records · Page 3Linked to original sources
PubMed1997

[Endothelial dysfunction in peripheral arterial occlusive disease: from basic research to clinical use].

Nitric oxide (NO) exerts pleiotroptic anti-atherosclerotic effects in the vascular wall: vasodilation, inhibition of platelet aggregation, elukocyte adhesion, and smooth muscle cell proliferation. Experimental and clinical studies showed that the biological effects of NO are impaired in patients with peripheral arterial occlusive disease. In a cross over study with 77 PAOD patients, we could demonstrate impaired NO formation by measuring the index metabolites of NO, nitrate and cyclic GMP. One possible mechanism of these pathophysiological changes is accumulation of the endogenous inhibitor of NO synthesis, asymmetrical dimethylarginine (ADMA). The NO-mediated functions of the vascular endothelium will become increasingly important in the clinic: diagnostically, measuring endothelium-dependent vasodilation may become a risk indicator for the development or progression of cardiovascular disease and for assessing the effects of antiatherosclerotic therapy; therapeutically, treatment strategies will be developed aiming at improving endothelial function. In early clinical studies, administration of L-arginine, the amino acid precursor of endogenous NO, has resulted in increased NO formation rates, which may prove therapeutically effective in the future.

Arginine↗
PubMed1996

Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study.

We studied the effects of recombinant growth hormone on systemic nitric oxide (NO) formation and hemodynamics in a double-blind, placebo-controlled trial in adult patients with acquired growth hormone deficiency. 30 patients were randomly allocated to either recombinant human growth hormone (r-hGH; 2.0 IU/d) or placebo for 12 mo. In the subsequent 12 mo, the study was continued with both groups of patients receiving r-hGH. In months 1, 3, 6, 9, and 12 of each year, urine and plasma samples were collected for the determination of urinary nitrate and cyclic GMP as indices of systemic NO production, and of plasma IGF-1 levels. Cardiac output was measured in months 1, 12, and 24 by echocardiography. r-hGH induced a fourfold increase in plasma IGF-1 concentrations within the first month of treatment. Urinary nitrate and cyclic GMP excretion rates were low at baseline in growth hormone-deficient patients (nitrate, 96.8+/-7.4 micromol/mmol creatinine; cyclic GMP, 63.6+/-7.1 nmol/mmol creatinine) as compared with healthy controls (nitrate, 167.3+/-7.5 micromol/mmol creatinine; cyclic GMP, 155.2+/-6.9 nmol/mmol creatinine). These indices of NO production were significantly increased by r-hGH, within the first 12 mo in the GH group, and within the second 12 mo in the placebo group. While systolic and diastolic blood pressure were not significantly altered by r-hGH, cardiac output significantly increased by 30-40%, and total peripheral resistance decreased by approximately 30% in both groups when they were assigned to r-hGH treatment. In the second study year, when both groups were given r-hGH, there were no significant differences in plasma IGF-1, urinary nitrate, or cyclic GMP excretion, or hemodynamic parameters between both groups. In conclusion, systemic NO formation is decreased in untreated growth hormone-deficient patients. Treatment with recombinant human growth hormone normalizes urinary nitrate and cyclic GMP excretion, possibly via IGF-1 stimulation of endothelial NO formation, and concomitantly decreases peripheral arterial resistance. Increased NO formation may be one reason for improved cardiovascular performance of patients with acquired hypopituitarism during growth hormone therapy.

Adult↗
PubMed1996

Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits.

Dietary supplementation of L-arginine, the precursor of endogenous NO, has been shown to enhance endothelial function in the cholesterol-fed rabbits. However, the mechanism by which dietary L-arginine accomplishes these effects has been unclear. In the present study we have assessed the plasma concentrations of L-arginine and of asymmetrical dimethylarginine (ADMA), a known endogenous inhibitor of NO synthase, in cholesterol-fed rabbits with or without dietary supplementation of L-arginine. Urinary nitrate excretion rates were assessed as an index of endogenous NO formation. Plasma L-arginine levels were not different between control and cholesterol-fed rabbits, but they were elevated nearly threefold in rabbits fed cholesterol + L-arginine. Plasma ADMA concentration increased about two-fold in hypercholesterolemia, but was unaffected by dietary L-arginine. Thus, dietary L-arginine elevated the plasma L-arginine/ADMA ratio above the normal level, and partly restored urinary nitrate excretion, which was decreased by hypercholesterolemia. We conclude that elevation of the L-arginine/ADMA ratio may at least partly explain the restored NO formation by exogenous L-arginine in hypercholesterolemia.

Arginine↗
PubMed1996

L-arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study.

BACKGROUND: L-Arginine is the precursor of endogenous nitric oxide (NO), which is a potent vasodilator acting via the intracellular second-messenger cGMP. In healthy humans, L-arginine induces peripheral vasodilation and inhibits platelet aggregation due to an increased NO production. Prostaglandin E1 (PGE1) induces peripheral vasodilation via stimulating prostacyclin receptors. METHODS AND RESULTS: We investigated the effects of one intravenous infusion of L-arginine (30 g, 60 minutes) or PGE1 (40 microgram, 60 minutes) versus those of placebo (150 mL 0.9% saline, 60 minutes) on blood pressure, peripheral hemodynamics, and urinary NO3- and cGMP excretion rates in patients with critical limb ischemia (peripheral arterial occlusive disease stages Fontaine III or IV). Blood flow in the femoral artery was significantly increased by L-arginine (+42.3 +/- 7.9%, P<.05) and by PGE1 (+31.0 +/- 10.2%, P<.05) but not by placebo (+4.3 +/- 13.0%, P=NS). Urinary NO3- excretion increased by 131.8 +/- 39.5% after L-arginine (P<.05) but only by 32.3 +/- 17.2% after PGE1 (P=NS). Urinary cGMP excretion increased by 198.7 +/- 84.9% after L-arginine (P<.05) and by 94.2 +/- 58.8% after PGE1 (P=NS). Both urinary index metabolites were unchanged by placebo. CONCLUSIONS: We conclude that intravenous L-arginine induces NO-dependent peripheral vasodilation in patients with critical limb ischemia. These effects are paralleled by increased urinary NO3- and cGMP excretion, indicating an enhanced systemic NO production. Increased urinary NO3- excretion may be a sum effect of NO synthase substrate provision (L-arginine) and increased shear stress (PGE1 and L-arginine).

Aged↗
PubMed1996

Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids.

Hypertension is the main side effect developing in patients suffering from renal anemia who are treated with recombinant human erythropoietin (rHuEPO). We investigated the effect of rHuEPO on the vascular tone of isolated rabbit aorta and carotid artery under isometric conditions. The production of prostacyclin and the vasoconstrictor prostanoids PGF2 alpha and TXB2 was investigated in arterial rings incubated with rHuEPO. Endothelial cells from human umbilical veins (HUVECs) were isolated and cultured in flasks (37 degrees C, 5% CO2). After incubation with rHuEPO, the formations of prostacyclin (as its stable metabolite 6-keto-PGF1 alpha), PGF2 alpha, PGE2, thromboxane (TX) B2 and of ET-1 were measured by radioimmunoassays. rHuEPO had no direct vasoconstrictor effect, but it enhanced noradrenalin-induced contractions. This effect was more prominent in rings with intact endothelium than in rings from which the endothelium had been mechanically removed, indicating that endothelial vasoactive factors might be involved. Relaxations to acetylcholine (ACh, 1 microM) were unaltered in the presence or absence of rHuEPO, suggesting that the endothelial NO-cGMP pathway was not impaired by rHuEPO. Incubation with rHuEPO (20 to 200 U/ml) increased the release of the vasoconstrictor mediators ET-1, PGF2 alpha and TXB2, and decreased prostacyclin formation in isolated rabbit arterial rings and in HUVECs, respectively. The cyclooxygenase inhibitor indomethacin abolished the rHuEPO-induced increase in vasoconstrictor prostanoid production. ET-1 formation by HUVECs was also increased by rHuEPO in a dose-dependent manner (maximal effect +90% by rHuEPO 200 U/ml, P < 0.05). Indomethacin and the selective ETA receptor antagonist BQ123 each partly inhibited the enhancement of vascular responsiveness to noradrenalin induced by rHuEPO in rabbit carotid artery, but simultaneous administration of rHuEPO with both antagonists completely abolished the force increment. In conclusion, these studies show that a dose-dependent shift in the balance of constrictor and relaxing prostanoids as well as an increased synthesis of ET-1 induced by rHuEPO lead to the enhanced vascular responsiveness to noradrenalin in isolated rabbit arteries. The increased vascular responsiveness to noradrenalin, which is in line with clinical observations, may contribute to the hypertensive side effect associated with rHuEPO therapy in patients with chronic renal failure.

Acetylcholine↗
PubMed1996

Effect of captopril on prostacyclin and nitric oxide formation in healthy human subjects: interaction with low dose acetylsalicylic acid.

1. Angiotensin converting enzyme inhibitors have been suggested to act in part by potentiating the stimulatory effect of bradykinin on endothelial prostacyclin and/or nitric oxide (NO) formation. This may give rise to interaction with cyclo-oxygenase inhibiting drugs like acetylsalicylic acid, which is most often used in low doses in patients with cardiovascular diseases. 2. We investigated the effects of captopril (2 x 25 mg day-1), or ASA (1 x 100 mg day-1), or the combination of both drugs for 7 days, on blood pressure, prostanoid and NO formation rates in a double-blind, double dummy, randomized crossover study in 13 healthy female subjects. The urinary metabolites of thromboxane A2 (2,3-dinor-TXB2) and prostacyclin (2,3-dinor-6-keto-PGF1 alpha), and PGE2 were measured by gas chromatography/tandem mass spectrometry in urine on days 1, 6 and 7 of each medication. NO formation was assessed using urinary NO3- and cyclic GMP as indicators. 3. Urinary 2,3-dinor-6-keto-PGF1 alpha excretion was not significantly changed by either captopril, ASA, or their combination. Urinary 2,3-dinor-TXB2 excretion was inhibited by > 80% by ASA alone or in combination with captopril (each P < 0.05), but was not affected by captopril alone. Urinary PGE2 excretion was not significantly changed by either of the treatments. Urinary NO3- and cyclic GMP excretion rates were not significantly changed by captopril, ASA, or their combination. 4. Blood pressure was slightly reduced by captopril. ASA had no effect on blood pressure when given alone, nor did it modulate the effect of captopril on blood pressure during co-administration. Angiotensin II/angiotensin I ratio (index of ACE activity) was significantly decreased by captopril alone or in combination with ASA, but was unaffected by ASA alone. 5. Captopril does not stimulate prostacyclin formation in healthy human subjects in a dose sufficient to substantially inhibit ACE activity. Co-administration of ASA significantly inhibits 2,3-dinor-TXB2 excretion, but does not interfere with the blood pressure lowering effect of captopril in healthy human subjects.

Adult↗
PubMed1996

Urinary nitrate excretion is increased in cardiac transplanted patients with acute graft rejection.

Acute allograft rejection in patients after cardiac transplantation is associated with intense infiltration of inflammatory cells. It has been shown in animal studies that this inflammatory process is accompanied by an induction of nitric oxide syndrome (NOS) enzyme within the grafted organ. We sought to test the hypothesis that acute rejection in cardiac transplanted patients is associated with an increased production of nitric oxide. The radical nitric oxide is unstable in blood and oxidized to nitrite and nitrate; nitrate is secreted by the kidneys. Therefore, nitric oxide production was indirectly assessed by measuring urinary nitrate excretion. During a period of 1 yr, 86 consecutive patients after cardiac transplantation underwent one or more right heart biopsies (total 194) in order to assess for acute graft rejection. At the time of biopsies, urine was collected under sterile conditions. Urinary nitrate excretion was expressed as the ratio of nitrate to creatinine concentration in the urine (mumol/ mmol). Urinary nitrate excretion was 99.7 +/- 9.2 (mean +/- SEM) for patients without evidence of rejection, and tended to increase for patients with moderate/severe rejection (128 +/- 15.1). In a subgroup of patients who underwent several biopsies and showed different degrees of rejection (7 patients, 48 biopsies), urinary nitrate excretion significantly increased by about 99% during episodes of acute rejection. It is concluded that urinary nitrate excretion appears to be elevated in a subgroup of cardiac transplanted patients during episodes of acute rejection. Results are consistent with the hypothesis that acute graft rejection stimulates the production/release of nitric oxide. Because of a large inter- and intraindividual variation in urinary nitrate excretion, this parameter appears not to be suitable for diagnosis of acute rejection in cardiac transplanted patients.

Acute Disease↗
PubMed1996

[Restenosis after percutaneous transluminal angioplasty: II. Possibilities for pharmacologic intervention].

Reocclusion after percutaneous transluminal angioplasty is a major mechanism contributing to morbidity of patients after catheterization. Until now, pharmacological approaches to the prevention of restenosis were mostly disappointing, as only the early phase of thrombotic reocclusion, in which platelet activation is a major patho-physiological mechanism, could be treated with inhibitors of platelet aggregation and coagulation. Recently, several new approaches to the pharmacotherapy of restenosis have been introduced, for example thromboxane receptor antagonists or synthase inhibitors, GPIIb/IIa antagonists and hirudin as new inhibitors of platelet aggregation and coagulation, PDGF antagonists as inhibitors of intimal proliferation, and modulators of endothelial cell function, some of which may be effective in the late phase of myointimal proliferation. However, many substances that had been promising in experimental restenosis have proven ineffective in the first clinical trials. More recently, molecular biological techniques are increasingly used in experimental angioplasty. The role of these different approaches for the prevention of restenosis still has to be proven in clinical trials.

Angioplasty, Balloon↗
PubMed1996

Differential systemic and pulmonary hemodynamic effects of L-arginine in patients with coronary artery disease or primary pulmonary hypertension.

The endothelial EDRF/NO-mediated relaxing mechanism is impaired in atherosclerotic and in hypertensive arteries. Recently, it was suggested that primary pulmonary hypertension might be another disease in which the endothelial EDRF/NO pathway is disturbed. We tested the hypothesis that intravenous administration of L-arginine (L-ARG), the physiological precursor of EDRF/NO, stimulates the production of NO, subsequently increasing plasma cGMP levels and reducing systemic and/or pulmonary blood pressure, in patients with coronary artery disease (CAD, n = 16) or with primary pulmonary hypertension (PPH, n = 5). L-ARG (30 g, 150 ml, 15 min) or placebo (150 ml NaCl) was infused in CAD patients, and L-ARG was infused in PPH patients during cardiac catheterization. Mean aortic (Pao) and pulmonary (PAPmean) arterial pressures were continuously monitored. Cardiac output (CO, by thermodilution), total peripheral resistance (TPR), and pulmonary vascular resistance (PVR) were measured before and during the infusions. In CAD patients Pao decreased from 87.2 +/- 4.9 to 81.8 +/- 5.1 mmHg during L-ARG (p < 0.05), whereas PAPmean and PVR were unchanged. TPR decreased from 1008.9 +/- 87.9 to 845.0 +/- 81.7 dyne x sec x cm-5 during L-ARG administration (p < 0.01). CO significantly increased during L-ARG (from 7.3 +/- 2.8 to 8.1 +/- 0.9 l/min, p < 0.05). Placebo did not significantly influence any of the hemodynamic parameters. Plasma cGMP (determined by RIA) slightly increased by 12.2 +/- 9.6% during L-ARG, but slightly decreased during placebo (-12.3 +/- 9.2%) (p < 0.05 for L-ARG vs. placebo). In PPH patients, L-ARG induced no significant change in Pao, TPR, and CO, PAPmean was 59.4 +/- 8.5 mmHg at the beginning of the study and was not significantly reduced by L-ARG nor was PVR (basal: 1042.4 +/- 211.4 dyne x sec x cm-5) changed by L-ARG. Plasma cGMP was not significantly affected by L-ARG in these patients. We conclude that L-ARG stimulates NO production and induces vasorelaxation in CAD patients but not in patients with primary pulmonary hypertension.

Adult↗
PubMed1996

[Pathogenetic aspects of the L-arginine-NO metabolic pathway in arteriosclerosis and possible therapeutic aspects].

L-arginine is the physiological precursor of nitric oxide (NO) which is formed in endothelial cells by the activity of the constitutive NO synthase isoenzyme. NO is tonically released from the endothelium, thus maintaining an active vasodilator tone and inhibiting platelet aggregation, leukocyte adhesion, and vascular smooth muscle cell proliferation. In experimental hypercholesterolemia and atherosclerosis as well as in hypercholesterolemic patients, NO-mediated responses have been shown to be impaired. Whether decreased formation and/or enhanced oxidative inactivation are involved in this process, is still unclear. Chronic dietary administration of L-arginine has been shown to exert anti-atherosclerotic effects in hypercholesterolemic rabbits. Intravenous infusion of L-arginine induces NO-dependent peripheral vasodilatation and inhibits platelet aggregation in healthy humans as well as in patients with severe limb ischemia and generalized atherosclerosis. Whether L-arginine may induce therapeutic effects in peripheral vascular disease, still remains unclear.

Animals↗
PubMed1995

Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production.

L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce intimal plaque area in cholesterol (Chol)-fed rabbits. We have studied endogenous NO production in such animals in vitro (endothelium-dependent relaxations) and in vivo (assessed by urinary NO3- excretion) before and during chronic oral administration of L-arginine and inhibitor of NO synthesis, L-NAME. Vascular superoxide anion (O2-) production of aortic rings was measured under basal conditions and following exposure to phorbol-myristate-acetate (PMA). Cholesterol feeding reduced endothelium-dependent relaxations and decreased urinary NO3- excretion. These effects were potentiated by administration of L-NAME. L-arginine partly restored endothelium-dependent relaxations and increased NO3- excretion. PMA-stimulated O2- production was increased in aortic rings from rabbits given cholesterol ( +159 +/- 28%; mean +/- S.E.M.) or cholesterol + L-NAME ( +149 +/- 37%) as compared with controls ( -22 +/- 7%). In rabbits given cholesterol + L-arginine, O2- production was decreased to control levels ( +14 +/- 17%; P < 0.05). We conclude that the systemic synthesis of NO is impaired in cholesterol-fed rabbits, as indicated by the decreased urinary excretion of NO3-. Enhanced O2- production may further contribute to the decreased biological activity of NO in hypercholesterolaemia. L-arginine restores endothelial function in hypercholesterolaemia by enhancing NO production and by protecting NO from early breakdown by O2-.

Acetylcholine↗
PubMed1995

Increased prostacyclin production during exercise in untrained and trained men: effect of low-dose aspirin.

The influence of a submaximal exercise on urinary 2,3-dinor-6-ketoprostaglandin F1 alpha (2,3-dinor-6-keto-PGF1 alpha), 2,3-dinor-thromboxane B2 (2,3-dinor-TxB2), and prostaglandin E2 excretion and on platelet aggregation was compared in untrained and trained subjects before and after low-dose aspirin administration (50 mg/day, 7 days). 2,3-Dinor-TxB2 excretion was significantly higher in the athletes at rest (P < 0.05). Submaximal exercise selectively increased 2,3-dinor-6-keto-PGF1 alpha excretion without affecting 2,3-dinor-TxB2 or prostaglandin E2 excretion rates or platelet aggregation. Low-dose aspirin inhibited platelet aggregation and 2,3-dinor-TxB2 excretion but reduced 2,3-dinor-6-keto-PGF1 alpha by only 24% in the untrained and by 51% in the trained subjects (P < 0.05). After low-dose aspirin administration, the selective stimulatory effect of submaximal exercise on urinary 2,3-dinor-6-keto-PGF1 alpha excretion was even more pronounced than before. The ratio of 2,3-dinor-6-keto-PGF1 alpha to 2,3-dinor-TxB2 was increased by exercise; this effect was significantly enhanced by low-dose aspirin (P < 0.05). Our results suggest that the stimulatory effect of submaximal exercise on prostacyclin production is mostly due to an activation of prostacyclin synthesis from endogenous precursors rather than the result of an enhanced endoperoxide shift from activated platelets to the endothelium. This effect is potentiated by low-dose aspirin pretreatment, indicating that 50 mg/day of aspirin do not impair exercise-induced endothelial prostacyclin production.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Quantification of nitrite and nitrate in human urine and plasma as pentafluorobenzyl derivatives by gas chromatography-mass spectrometry using their 15N-labelled analogs.

For the quantification of nitrite and nitrate, the stable metabolites of L-arginine-derived nitric oxide (NO) in human urine and plasma, we developed a gas chromatographic-mass spectrometric (GC-MS) method in which [15N]nitrite and [15N]nitrate were used as internal standards. Endogenous nitrite and [15N]nitrite added to acetone-treated plasma and urine samples were converted into their pentafluorobenzyl (PFB) derivatives using PFB bromide as the alkylating agent. For the analysis of endogenous nitrate and [15N]nitrate they were reduced to nitrite and [15N]nitrite, respectively, by cadmium in acidified plasma and urine samples prior to PFB alkylation. Reaction products were extracted with toluene and 1-microliter aliquots were analyzed by selected-ion monitoring at m/z 46 for endogenous nitrite (nitrate) and m/z 47 for [15N]nitrite ([15N]nitrate). The intra- and inter-assay relative standard deviations for the determination of nitrite and nitrate in urine and plasma were below 3.8%. The detection limit of the method was 22 fmol of nitrite. Healthy subjects (n = 12) excreted into urine 0.49 +/- 0.25 of nitrite and 109.5 +/- 61.7 of nitrate (mean +/- S.D., mumol/mmol creatinine) with a mean 24-h output of 5.7 mumol for nitrite and 1226 mumol for nitrate. The concentrations of nitrite and nitrate in the plasma of these volunteers were determined to be (mean +/- S.D., mumol/l) 3.6 +/- 0.8 and 68 +/- 17, respectively.

Female↗
PubMed1994

L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects.

1. L-Arginine is the physiological precursor of nitric oxide which induces vasodilatation and inhibits platelet aggregation by the formation of cyclic GMP. 2. In the present study we investigated the effects of an intravenous infusion of L-arginine (30 g, 30 min) compared with placebo on blood pressure, heart rate and peripheral haemodynamics in ten healthy male subjects. Cyclic GMP, NO2- and NO3- were determined in plasma and urine to assess NO production in vivo by a new, highly specific and sensitive gas chromatography-mass spectrometry method. 3. L-Arginine significantly decreased mean arterial blood pressure and increased heart rate. The effect was more pronounced on diastolic than on systolic blood pressure. This was due to a decreased peripheral arteriolar resistance, as in femoral artery Doppler sonography the arterial diameter was unchanged but blood flow was increased. These haemodynamic effects were not observed after placebo administration. 4. Urinary excretion of cyclic GMP increased by 65.4% after L-arginine and by 25.1 after placebo. Urinary NO2- excretion was near the threshold of detection. Urinary NO3- excretion increased by 79.7% after L-arginine. Plasma arginine levels increased nearly ten-fold after the L-arginine infusion, and plasma cyclic GMP increased by a similar rate as in urine. However, plasma NO2- and NO3- remained unchanged after both treatments, as did plasma alpha-atrial natriuretic peptide levels. 5. Platelet aggregation was inhibited by 32.7% after L-arginine (P < 0.05), but was unchanged after placebo. Platelet intracellular cyclic GMP was increased by 43.0% after L-arginine, but not after placebo (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗