PubMed Health⌕ Search

Biomedical subjects

A Wennmalm

Publications and source records attributed to A Wennmalm.

At least 37 records · Page 2Linked to original sources
PubMed1996

Role of nitric oxide in induction of inflammatory fluid secretion by the mucosa of the feline gallbladder.

BACKGROUND & AIMS: Nitric oxide is synthesized from L-arginine and is metabolized to nitrate and nitrite. This study evaluates the effects of a pharmacological blockade of NO synthesis on fluid transport by the inflamed gallbladder mucosa. METHODS: Experiments were performed in cats with cholecystitis and in control animals. NO synthase activity was measured in gallbladder tissue; the enzyme was characterized by immunoblotting techniques and localized by immunofluorescence. Fluid transport and release of nitrate and nitrite by the gallbladder mucosa and bile and bile salt secretion from the liver were registered simultaneously in vivo. RESULTS: Fluid secretion in inflamed gallbladders was reversed to a net absorption in response to the NO synthase blockers N omega-nitro-L-arginine and aminoguanidine, and formation of nitrate was reduced. The effects were reversed by L-arginine. Increased levels of inducible NO synthase in inflamed gallbladders were shown by immunoblotting, by immunofluorescence (mainly in macrophages), and by Ca(2+)-independent [3H]citrulline formation from [3H]arginine. The NO synthase blockers had no effect on gallbladder fluid transport in normal gallbladders. CONCLUSIONS: Increased levels of inducible NO synthase activity are shown in inflamed gallbladders, and a pharmacological blockade of this enzyme blocks fluid secretion and decreases nitrate release from the mucosa.

Analysis of Variance↗
PubMed1996

Smoke-derived nitric oxide and vascular prostacyclin are unable to counteract the platelet effect of increased thromboxane formation in healthy female smokers.

The incidence of cigarette smoking tends to be higher in women, justifying directed studies on smoke-related mechanisms of cardiovascular disorder in females. Platelet activity plays an important etiological role in several settings of cardiovascular disease. Cigarette smoking facilitates platelet formation of proaggregatory thromboxane A2. However, cigarette smoke contains nitric oxide (NO), which has antiplatelet activity. Furthermore, the formation of anti-aggregatory prostacyclin (PGI2) may be higher in smokers than in non-smokers. Hence, the concerted action of NO and PGI2 on platelet activity in smoking females is important to elucidate. The metabolites of TxA2, NO, and PGI2, as well as cyclic guanosine 3':5'-monophosphate (cGMP; second messenger for NO in the platelets) and cyclic adenosine 3':5'-monophosphate (cAMP; second messenger for PGI2 in the platelets), were analysed in 23 healthy female smokers (daily consumption 11-20 cigarettes per day) and in 26 matched non-smokers. The urinary excretion of 2,3-dinor TxB2 (metabolite of TxA2) was considerably higher in smokers than in non-smokers (177 vs. 72 pg/mg creatinine, respectively; P<0.001). Plasma and urinary levels of nitrate (metabolite of inhaled NO) did not differ between the groups. Plasma and urinary cGMP were slightly increased (252 vs. 193 nmol/L; P<0.05 and 0.63 vs. 0.51 micromol/24 h; P<0.05, respectively) in smokers compared to non-smokers, while platelet cGMP was lower in smokers than in non-smokers (81 vs. 10.3 pmol/10(6) platelets, respectively; P<0.05). The urinary excretion of 2,3-dinor-6-keto-PGF1a (metabolite of PGI2) did not differ between the groups. Platelet or urinary cAMP did not differ between the groups either, while plasma cAMP was lower in smokers than in non-smokers (19.2 vs. 26.2 nmol/l, respectively; P<0.001). In healthy female smokers NO is not absorbed from the inhaled smoke, and endothelial PGI2 formation is not enhanced to counterbalance the increased platelet formation of proaggregatory TxA2.

Adult↗
PubMed1996

Thromboxane metabolite excretion in patients with hand-arm vibration syndrome.

As chronic exposure to hand-held vibrating tools may cause endothelial injury, a subsequent sustained platelet activation with the increased release of vasoconstricting thromboxane A2 (TxA2) could be of pathophysiological importance in vibration-induced Raynaud's phenomenon. Therefore, the aim of this study was to elucidate whether or not hand-arm vibration syndrome is accompanied by increased endogenous TxA2 biosynthesis. The study involved 64 men, aged 23-61 years, stratified according to the exposure to vibrating tools, the presence of Raynaud's phenomenon, and smoking habit. Forty of them were car mechanics and 24 were age-matched healthy volunteers who served as controls. The assessment of platelet TxA2 formation in vivo was performed by quantification of the urinary excretion of its major metabolite, 2,3-dinorthromboxane B2 (2,3-dinor-TxB2), employing gas chromatography-mass spectrometry. The average urinary excretion rate of 2,3-dinor-TxB2 in patients with Raynaud's phenomenon was 296 +/- 42 pg/mg creatinine and did not differ significantly from the corresponding values in controls (328 +/- 62 pg/mg creatinine) or individuals exposed to vibrating tools, but without any signs of vasospastic disease (232 +/- 29 pg/mg creatinine). The only statistically significant difference was found between smokers and non-smokers (P < 0.001), a finding confirming the existence of chronic platelet dysfunction in cigarette smokers. The present data indicate that chronic exposure to vibrating tools, with or without Raynaud's phenomenon, is not associated with an enhanced platelet function as monitored by the urinary excretion of 2,3-dinor-TxB2. Hence, a possible vibration-induced vascular injury does not seem to provide a stimulus sufficient to induce a persistent platelet activation.

Adult↗
PubMed1996

Plasma nitrate as an index of nitric oxide formation in man: analyses of kinetics and confounding factors.

Nitric oxide (NO) is metabolized to nitrate in humans. Accordingly, plasma nitrate has been proposed as an index of the in vivo formation of NO. Such an application requires knowledge about the possible influence of nitrate from sources other than endogenous NO formation, as well as of the kinetics of nitrate in plasma. In the present study, plasma nitrate increased from 32 +/- 4 to 205 +/- 27 mumol/l (mean +/- SE) following intake of nitrate-rich food. It dropped during the intake of nitrate-restricted diet and stabilized at a level of 29 +/- 1 mumol/l. The urinary excretion of nitrate during nitrate restriction was 840 +/- 146 mumol/24 h. Plasma nitrate was not affected following the intake of a gastrointestinal antibiotic drug for a period of four days. Smoking three cigarettes in succession did not affect the plasma nitrate levels significantly. The oral intake of potassium nitrate (500 mg approximately 4950 mumol) elevated plasma nitrate from 29 +/- 3 to 313 +/- 12 mumol/l within 60 min. The subsequent drop in plasma nitrate, with a t1/2 of 451 +/- 42 min, was probably a reflection of the redistribution of nitrate within the body fluids and the renal excretion of nitrate. The plasma clearance of nitrate was 30 +/- 2 ml/min/1.73 m2 BSA. The distribution volume for nitrate was 28 +/- 1% of the bodyweight (BW). We conclude that plasma nitrate can be used as an index of the endogenous formation of NO, provided that the oral intake of nitrate is restricted for at least 48 h. Due to the large distribution volume and the low clearance of the ion wide-spread, marked, and chronic changes in NO formation are required to significantly affect the levels of nitrate in samples of mixed blood.

Administration, Oral↗
PubMed1996

Nitric oxide-donating properties of mesoionic 3-aryl substituted oxatriazole-5-imine derivatives.

1. The nitric oxide (NO)-releasing properties of two new mesoionic 3-aryl substituted oxatriazole-5-imine derivatives (GEA 3162 and GEA 3175) were characterized and compared with the known NO-donors 3-morpholino-sydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). 2. GEA 3162, GEA 3175, SIN-1 and SNAP inhibited adenosine 5'-diphosphate-induced platelet aggregation (IC50 values 0.18, 0.39, 3.73 and 2.12 microM, respectively). All four compounds induced a dose-dependent and more than 4 fold increase in cyclic GMP in platelets. The increase in cyclic GMP concentration was potentiated more than 1.5 fold by a phosphodiesterase inhibitor, zaprinast (10 microM) and inhibited 38-97% by oxyhaemoglobin (10-45 microM). 3. All of the four compounds studied converted oxyhaemoglobin to methaemoglobin and formed a paramagnetic NO-haemoglobin complex. All but GEA 3175 formed nitrite and nitrate in phosphate buffer. During a 40 min incubation, GEA 3162, SIN-1 and SNAP (100 microM) produced 50-70 microM NO2- + NO3- as determined by high performance liquid chromatography. The release of NO and NO2 by GEA 3175 was increased 140 fold in the presence of human plasma (0.14 and 19.7 ppb in the absence and presence of 1% human plasma, respectively) as analyzed by ozone chemiluminescence. 4. The results suggest that the mesoionic 3-aryl substituted oxatriazole-5-imine derivatives GEA 3162 and GEA 3175 as well as SIN-1 and SNAP release nitric oxide.

Blood Platelets↗
PubMed1996

Magnesium inhibits platelet activity--an infusion study in healthy volunteers.

Magnesium (Mg) has shown the ability to inhibit arterial thrombus formation in some experimental animal studies. This effect may be due to an inhibition of platelet reactivity as in vitro studies have demonstrated that Mg inhibits platelet aggregation. In order to evaluate the in vivo effect of Mg in humans measurements of platelet activity, fibrinolytic activity, as well as measurements of prostacyclin (PGI2), and nitric oxide (NO) release were performed after infusion of magnesium sulphate (MgSO4) in healthy volunteers. In a placebo controlled, cross-over study in 14 healthy male subjects, 8 mmol MgSO4 was given as an intravenous bolus over 15 min followed by 3 mmol MgSO4/h. The mean S-Mg concentration increased from 0.85 to 1.50 mM during the Mg infusion period. A transient decrease in blood pressure was observed during the initial bolus infusion of Mg. Haemodynamic parameters were otherwise unstable. The bleeding time increased by 48% during the Mg infusion (p < 0.005), and in accordance with this, ex vivo platelet aggregation in platelet rich plasma was significantly inhibited, both following collagen (p = 0.02) and ADP (p = 0.04) stimulation. There were no significant changes in plasma beta-thromboglobulin concentration or the excretion of 2,3-dinor-thromboxane B2 in the urine. Neither tissue plasminogen activator (t-PA)activity, tissue plasminogen activator (t-PA)antigen nor plasminogen activator inhibitor (PAI)antigen changed during the Mg infusion period. There was no sign of increased release of PGI2 from the vessel wall as judged by urinary concentration of 2,3-dinor-6-keto-prostaglandin F1 alpha. Nor was there any sustained increase in the release of NO, measured as nitrate concentration in urine. However, a transient increase in NO release was observed during one sample period. In conclusion a reduced platelet activity and increased bleeding time, was found during Mg infusion in healthy volunteers. Fibrinolytic activity showed no changes. An anti-platelet effect may in part be responsible for the beneficial effect of Mg, described in patients with acute myocardial infarction (MI) and preeclampsia.

Adult↗
PubMed1995

Acute supplementation with the nitric oxide precursor L-arginine does not improve cardiovascular performance in patients with hypercholesterolemia.

Endothelial dysfunction based on lack of nitric oxide (NO) may contribute to several settings of cardiovascular disorder. Chronic oral supplementation with the NO precursor L-arginine counteracts the development of aortic atherosclerosis in cholesterol-fed rabbits, and i.v. infusion of L-arginine may acutely improve endothelium-dependent coronary epicardial vasodilation in patients with hypercholesterolemia (HC). To clarify whether excess NO precursor may also improve general cardiovascular performance in HC, we measured working capacity indices of myocardial ischemia, and basal and post-occlusive forearm and skin blood flow in nine patients with elevated plasma cholesterol (9.1 +/- 0.2 mumol/l) following random double-blinded administration of L-arginine (16 g i.v.) or placebo. Infusion of L-arginine raised the plasma concentration of this amino acid from 85 +/- 12 to 2460 +/- 230 mumol/l but did not change the plasma level of the major NO metabolite nitrate. Maximal working capacity, indices of myocardial ischemia, and basal and post-occlusive blood flow in the skin or forearm did not differ between the treatments. The lack of positive effect of L-arginine compared to placebo indicates that excess NO precursor did not improve microvascular endothelial function in the patients, or alternatively, that the indices measured in the present study were not dependent on endothelial microvessel function. Thus, in patients with HC, deficiency of precursor for NO formation does not seem to impair either maximal exercise capacity myocardial perfusion during maximal exercise, or maximal vasodilator capacity in skeletal muscle or skin.

Arginine↗
PubMed1995

Conversion of inhaled nitric oxide to nitrate in man.

1. Nitric oxide (NO) is potentially useful as a selective vasodilator drug in infants and adults with pulmonary hypertension. In vitro and in vivo observations demonstrate that NO may be converted to nitrate in the blood, to be further excreted into the urine. The aim of the present study was to assess quantitatively the importance of this pathway for inhaled NO in human subjects. 2. Healthy subjects inhaled 15NO (25 p.p.m.) for 1 h. The plasma and urine levels of 15NO3- were followed for 2 and 48 h, respectively. 3. The measured retention of 15NO in the lungs was 224 +/- 13 mumol, corresponding to 90 +/- 2% of the inhaled amount. Plasma 15NO3- increased during the inhalation of 15NO, to about 15 mumol l-1, and fell when inhalation of 15NO was terminated. 4. Urinary excretion of 15NO3- during the first 24 h after inhalation was 154 +/- 12 mumol. During the following 24 h another 8 +/- 2 mumol of 15NO3- appeared in the urine. 5. We conclude that conversion of inhaled NO to nitrate is a major metabolic pathway in man, covering more than 70% of its inactivation. The metabolic fate of the remaining NO inhaled requires further study.

Administration, Inhalation↗
PubMed1995

The insulin secretory response to intravenous glucose in the rat is independent of NO formation.

In isolated pancreative beta cells from rats the insulin secretory response to glucose is amplified by L-arginine. Since this effect is inhibited by NO synthesis inhibitors, and since L-arginine is precursor of NO, the observation indicates a role for NO in insulin secretion from beta cells. We recently reported that i.v. L-arginine elicited insulin secretion in anaesthetized rats by a mechanism that was partly NO dependent. The aim of the present study was to assess if the insulin secretory response to an intravenous infusion of glucose also requires an intact NO formation. Anaesthetized rats were given D-glucose (100 mg kg-1 min-1 i.v. for 30 min). Plasma insulin (PI), blood glucose (BG) levels and mean arterial blood pressure (MAP) were assessed from before and until 15 min after the end of the infusion. One group of rats were untreated and served as controls. The two other groups were pretreated with either of the NO synthase inhibitors NW-nitro-L-arginine methyl ester (L-NAME, 50 mg kg-1 i.v.), or NG-monomethyl-L-arginine (L-NMMA, 100 mg kg-1 i.v.). In controls infusion of glucose elevated PI by up to 25 +/- 3 U L-1, and BG by up to 27 +/- 1 mmol L-1. Pretreatment with L-NAME elevated MAP from 74 +/- 6 to 132 +/- 4 mmHg, indicating that NO synthase was inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Arterial smooth muscle cells express nitric oxide synthase in response to endothelial injury.

Endothelial cells regulate vascular tone by secreting paracrine mediators that control the contractility of arterial smooth muscle cells. Nitric oxide (NO) is an important vasodilating agent that is generated from L-arginine by the enzyme nitric oxide synthase (NOS), which is expressed constitutively by the endothelium. NO also inhibits platelet aggregation, contributing to the antithrombotic properties of the endothelial surface. It would therefore be expected that loss of the endothelium during arterial injury would lead to vasospasm and thrombosis but instead, the neointima formed after injury has a nonthrombogenic surface and a maintained vascular patency. We report here that arterial smooth muscle cells in the neointima formed after a deendothelializing balloon injury to the rat carotid artery express the cytokine-inducible isoform of NOS. Expression was detectable by reverse transcription-polymerase chain reaction from day 1-14 after injury and in situ hybridization showed expression of NOS mRNA by neointimal smooth muscle cells, particularly at the surface of the lesion. This was associated with systemically detectable NO production as revealed by electron paramagnetic resonance spectroscopic analysis of nitrosylated red cell hemoglobin. Local NO production by intimal smooth muscle cells after endothelial injury could represent an important mechanism for the maintenance of arterial patency and nonthrombogenicity in the injured artery.

Amino Acid Oxidoreductases↗
PubMed1994

Cytokine-induced expression of nitric oxide synthase results in nitrosylation of heme and nonheme iron proteins in vascular smooth muscle cells.

Nitric oxide synthase (NOS) catalyzes the synthesis of the biomediator, nitric oxide (NO), from L-arginine. We have analyzed NOS induction and activity in cultured rat vascular smooth muscle cells (SMC), which respond to NO by relaxation and inhibition of mitochondrial respiration. Both interferon-gamma and tumor necrosis factor-alpha induced the expression of NOS mRNA and a combination of the two cytokines had a synergistic effect. An internal oligonucleotide complementary to murine macrophage NOS mRNA hybridized to polymerase chain reaction (PCR) products derived from SMC NOS but not brain NOS. Direct sequencing of the PCR products showed a high degree of homology between inducible NOS from SMC and macrophages. Analysis of NOS-dependent nitrite production demonstrated that the enzyme requires NADPH as a cofactor but not calcium for its activity. Cytokine treatment resulted in the development of electron paramagnetic resonance (EPR) signals characteristic for nitrosyl complexes, indicating nitrosylation of SMC molecules by enzymatically synthesized NO. De novo NOS gene transcription and protein synthesis are required for the cytokine-induced protein nitrosylation since addition of actinomycin D and cycloheximide abolished the cytokine effect. At an early stage of cytokine treatment and when low doses of cytokines were used, the EPR signal was dominated by a triplet hyperfine structure typical for hemenitrosyl complexes. With increasing incubation time and/or cytokine dose, the EPR spectra were gradually converted into a pattern resembling that of nonheme iron(II)-nitrosyl thiol complexes. Thereafter, the EPR signal shape no longer changed while the signal intensity increased quantitatively with NO synthesis, suggesting that considerable amounts of NO synthesized could be trapped in the cells by formation of nitrosyl complexes with intracellular molecules. Together, these results provide direct biochemical evidence for cytokine induction of NO synthesis and protein nitrosylation in SMC. This may represent an important second messenger system for cytokine effects on cellular metabolism in blood vessels.

Amino Acid Oxidoreductases↗
PubMed1994

Epidural anaesthesia prolonged into the postoperative period prevents stress response and platelet hyperaggregability after peripheral vascular surgery.

The occlusion rate of peripheral vascular grafts depends on technical as well as endogenous factors. Platelets play an integral part in graft failure and it has been suggested that anaesthesia may influence platelet function. In order to evaluate the influence of anaesthesia on stress response and platelet function in peripheral vascular surgery, patients (n = 18) were allocated to either general anaesthesia (GA; n = 9) followed by alleviation of postoperative pain with intramuscular analgesics or to lumbar epidural anaesthesia (EPI; n = 9) which was continued for 24 hours postoperatively. Before, during, as well as after vascular surgery of the lower extremity plasma levels of cortisol, glucose, serotonin (p-5HT), and urinary 5-hydroxyindole-3-acetic acid (5-HIAA) were analysed and platelet aggregability was determined. In the GA group surgery was accompanied by a significant stress response while in the EPI group this stress response was almost completely abolished. Platelet aggregability was reduced intraoperatively in both groups but in the postoperative period there was a marked hyperaggregability only in the GA group. P-5HT was increased preoperatively in both groups but was not affected by surgery. It is concluded that epidural anaesthesia, due to its effects on platelet aggregability, may be advantageous for peripheral vascular surgery.

Aged↗
PubMed1994

Endothelial nitric oxide and cardiovascular disease.

The vascular endothelium is the site of formation of several powerful mediators. One of these is NO, a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen. NO elicits relaxation of VSMC by activating cytosolic guanylate cyclase. NO also counteracts platelet adhesion and aggregation. The biological actions of NO make it a key substance in the endogenous defense against vascular occlusion and thrombosis. The basal formation of NO maintains a moderate but significant vasodilation in the systemic resistance vessels and counteracts platelet activity. When blood flow in conduit arteries is increased there is an augmented endothelial formation of NO, eliciting flow-dependent vasodilation. Beside this, several vasodilators (acetylcholine, bradykinin, histamine, substance P) operate by stimulating endothelial NO formation. On the other hand, drugs like nitroglycerin and papaverine operate independently of the vascular endothelium. Vasodilator mechanisms, physiological as well as pharmacological, may therefore be characterized as endothelium-dependent (i.e. NO-mediated), or endothelium-independent (i.e. not mediated by NO). Physiologically, mixed mechanisms occur. Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation, increased degradation, decreased sensitivity to the NO formed, or a mixture of these factors. Irrespective of the mechanism behind, this is referred to as endothelial dysfunction. Endothelial dysfunction occurs in several cardiovascular settings, like atherosclerosis, hypercholesterolaemia, diabetes, and essential hypertension. Endothelial dysfunction leads to an impaired tissue perfusion, increased local vascular resistance, decreased defense against thrombus formation, and possibly also decreased defense against hypertrophy of the VSMC in the vessel wall media. In patients with CHD, endothelial dysfunction leads to an impaired coronary flow response to physical and mental stress, and to promotion of platelet adherence and aggregability. Endothelial dysfunction is thereby a probable aggravating factor in the atherosclerotic process, adding a functional component on top of the structural lesions characterizing this disease. A particular form of endothelial dysfunction, limited to the arterial resistance vessels, may explain the symptoms and clinical characteristics of microvascular angina. In patients with essential hypertension, endothelial dysfunction prevails, adding a functional component to the structural factors also in this disease. Hitherto, the only therapeutic tools available to restore endothelial dysfunction appear to be restriction of the dietary intake of lipids, possibly reinforced with intake of antioxidants like fish oil and vitamin E. However, large clinical trials to confirm the efficacy of such therapy in reversing endothelial dysfunction have not been conducted. In the future, more directly acting therapeutic regimens, aimed at supporting or substituting the endogenous formation of NO, are likely to appear as well.

Cardiovascular Diseases↗
PubMed1994

NO-dependent and -independent elevation of plasma levels of insulin and glucose in rats by L-arginine.

1. L-Arginine elevates plasma insulin in man. Recent in vitro data indicate that this is based on stimulation of endogenous nitric oxide (NO) with subsequent pancreatic release of insulin by L-arginine. L-Arginine also raises plasma glucose. 2. We studied plasma levels of insulin, glucose and NO metabolites, as well as systemic blood pressure, in anaesthetized rats during i.v. infusion of L-arginine (25-200 mg kg-1 min-1) or glucose (55 mg kg-1 min-1), before and after administration of the NO synthesis inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 50 mg kg-1). 3. Before L-NAME, L-arginine elevated plasma insulin from about 15 to 65 ul-1 and glucose from 5.2 to 6.7 mmol l-1. These effects of L-arginine were not dose-related. 4. L-NAME alone had no effect on plasma insulin and glucose levels, but diminished the effects of a low dose (25 mg kg-1 min-1) of L-arginine on plasma insulin by about 40%, and that on plasma glucose by more than 90%. In contrast, the effects of a high dose (200 mg kg-1 min-1) of L-arginine on plasma insulin and glucose levels were not affected by L-NAME. 5. L-NAME elevated systemic blood pressure by about 35 mmHg. L-Arginine (25-100 mg kg-1 min-1) had no effect on systemic blood pressure, either before or after L-NAME. L-Arginine (200 mg kg-1 min-1) lowered systemic blood pressure, both before and after L-NAME. 6. Glucose infusion elevated plasma glucose from about 5.5 to 6.8 mmol l-1, and plasma insulin from about 18 to 26 ul-1. 7. The basal plasma levels of the NO metabolite nitrate (18 +/- 4 mumol l-1) were not affected by L-arginine (200 mg kg-1 min-1). Plasma nitrosohaemoglobin was likewise unaffected by L-arginine (200 mg kg-1 min-1). 8. We conclude that L-arginine separately elevates plasma insulin and glucose levels, both by NO-dependent and -independent mechanisms.

Amino Acid Oxidoreductases↗