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Biomedical subjects

A Wennmalm

Publications and source records attributed to A Wennmalm.

At least 55 records · Page 3Linked to original sources
PubMed1994

L-arginine-induced hypotension in the rat: evidence that NO synthesis is not involved.

L-Arginine is the biological precursor for nitric oxide (NO). NO is formed continuously in endothelial cells and maintains a certain degree of vasodilator tone under physiological conditions. Although the formation of NO is not primarily controlled by precursor availability, the extent to which extra supplementation with L-arginine may affect endothelial NO formation, and hence, vasodilator tone and systemic blood pressure, is not entirely clear. To address this issue, we infused L-arginine i.v. in anaesthetized normotensive rats pretreated with NG-nitro-L-arginine methyl ester (L-NAME, 50 or 200 mg-1) and in untreated controls, under continued recording of mean arterial pressure (MAP). In control animals L-arginine (25 or 100 mg kg-1 min-1) had no effect on systemic MAP (111 +/- 3 mm Hg), while L-arginine (200 mg kg-1 min-1) lowered MAP (to 70 +/- 6 mm Hg). D-Arginine (200 mg kg-1 min-1) also induced hypotension; during infusion of D-arginine MAP fell from 106 +/- 4 to 64 +/- 4 mm Hg. Pretreatment with L-NAME (50 and 200 mg kg-1) elevated MAP to 140 +/- 2 and 147 +/- 3 mm Hg, respectively, but failed to affect the hypotensive response to L-arginine; during infusion of L-arginine (200 mg kg-1 min-1) in rats pretreated with L-NAME (50 and 200 mg kg-1) MAP fell to 86 +/- 9 and 104 +/- 6 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Nitric oxide (NO) in the cardiovascular system: role in atherosclerosis and hypercholesterolemia.

Atherosclerosis is characterized by hypertrophy of the vascular media, intimal thickening and lipid-containing plaques. Atherosclerosis is a progressive systemic vascular disease which leads to impaired tissue perfusion due to vascular obstruction. In advanced stages it is often complicated by thrombosis. Recent research demonstrates that atherosclerosis is also a functional disease. In atherosclerosis and hypercholesterolemia, normal vasodilatation is impaired due to endothelial dysfunction. In addition, the ability of the vessel wall to reject adhering and aggregating platelets is deteriorated. Endothelial dysfunction in atherosclerosis is characterized by impaired formation of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF). NO is continuously formed in the vascular endothelium and promotes tissue perfusion by relaxation of vascular smooth muscle. Endogenously formed NO may also protect against foam cell formation and media hypertrophy, i.e. against the structural component of atherosclerosis. In patients with ischaemic heart disease, the endothelial dysfunction leads to decreased ability to dilate the coronary vessels in response to several forms of physiological stimuli. Endothelial dysfunction in atherosclerosis is reversed by lipid-lowering therapeutic interventions.

Animals↗
PubMed1993

Maintained hyperexcretion of thromboxane A2 metabolite in healthy young cigarette smokers: results from a prospective study in randomly sampled males with stable smoking habits.

Although several studies have identified cigarette smoking as a factor increasing platelet formation of thromboxane A2 (TxA2), no prospective data on this issue have been presented in a defined population with stable smoking habits. Therefore, we analysed the relation between smoking habits and urinary excretion of the 2,3-dinor metabolites of thromboxane A2 (Tx-M) and prostacyclin (PGI-M) in 87 males, randomly sampled from a population of 18-19-year-old men, at two different occasions separated by 31-49 months. The daily cigarette consumption among the smokers was unchanged between the study occasions (11 vs. 11 cigarettes day-1), but 9 of 43 initial smokers had quit. None of the initial non-smokers had begun smoking. Tx-M was higher in the smokers than in the non-smokers and correlated with the daily cigarette consumption both at the initial (176 vs. 123 pg mg-1 creatinine; P = 0.01) and the second (214 vs. 164 pg mg-1; P = 0.002) study occasion. Those who had quit smoking since the initial study did not differ in Tx-M from the non-smokers at the second study occasion. Urinary PGI-M did not differ between cigarette smokers, non-smokers and quitters at either of the study occasions. We conclude that cigarette smoking elicits an increased formation of thromboxane A2, indicating platelet activation, that is stable during an observation period of up to 4 years. The increased platelet activity is reversible upon quitting.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Excretion of thromboxane metabolites in healthy women after cessation of smoking.

Cigarette smokers, but not former smokers, excrete more thromboxane A2 (TxA2) metabolites in the urine than do lifelong nonsmokers, which suggests chronic activation of their platelets. To further characterize the effect elicited by smoking on platelet function, we followed the change in urinary excretion of the 2,3-dinor (Tx-M) and 11-dehydro (dTx) metabolites of TxA2, analyzed by gas chromatography/mass spectrometry and radioimmunoassay, respectively, in eight healthy women who quit habitual smoking and compared it with the recovery of these metabolites after a single dose of acetylsalicylic acid (ASA). Tx-M and dTx before cessation of smoking were approximately 550 and 600 pg/mg creatinine, respectively. Within 3 days after quitting smoking, Tx-M and dTx had dropped to stable levels of approximately 300 and 350 pg/mg, respectively. The rates of change in excretion of Tx-M and dTx after smoking cessation were more rapid (p < 0.02 and 0.02, respectively) than those observed during the recovery of platelet function after a single dose of ASA. The excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha, a metabolite of prostacyclin, was not affected by smoking cessation. We conclude that cigarette smoking elicits an increase in platelet activity in the absence of vascular injury. This increase is reversible within the life span of the platelets.

Administration, Oral↗
PubMed1993

Metabolism and excretion of nitric oxide in humans. An experimental and clinical study.

Despite the increasing insight in the clinical importance of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), there is limited information about the metabolism and elimination of this mediator in humans. We studied the degradation of NO in healthy subjects inhaling 25 ppm for 60 minutes and in patients with severe heart failure inhaling 20, 40, and 80 ppm in consecutive 10-minute periods. In other healthy subjects, the renal clearance of NO metabolite was measured. The metabolism ex vivo was evaluated by direct incubation of nitrite, the NO oxidation product, in blood from healthy humans. During inhalation of NO, the plasma levels of nitrate increased progressively, both in the healthy subjects (from 26 to 38 mumol/L, P < .001) and in the patients (from 72 to 90 mumol/L, P < .001). Methemoglobin (MetHb) also increased in the healthy subjects (from 7 to 13 mumol/L, P < .001) as well as in the patients (from 19 to 42 mumol/L, P < .01). No change in nitrosohemoglobin (HbNO) was detected, either in the healthy subjects or in the patients. In arterialized blood (O2 saturation, 94% to 99%), incubated nitrite was semiquantitatively converted to nitrate and MetHb. In venous blood (O2 saturation, 36% to 85%) moderate amounts of HbNO were also formed. Plasma and urinary clearance of nitrate in healthy subjects averaged 20 mL/min. We conclude that uptake into the red blood cells with subsequent conversion to nitrate and MetHb is a major metabolic pathway for endogenously formed NO. Nitrate may then enter the plasma to be eliminated via the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Plasma nitrate as an index of immune system activation in animals and man.

The cytotoxic activity of activated macrophages is based upon their formation and release of nitric oxide (NO). In blood NO is rapidly metabolised to nitrate. We analysed plasma nitrate in rats given zymosan, an activator of the immune system, and found 20-fold increases above the basal level. Furthermore, in two human subjects with acute gastro-enteritis plasma nitrate increased from about 30 to 200 microM two days after onset of symptoms. These increased plasma levels of nitrate may reflect macrophage formation of NO. We propose that plasma nitrate may be a useful index for quantitative assessment of cytotoxic activity during immunological challenge.

Acute Disease↗
PubMed1992

Cigarette smoking increases thromboxane A2 formation without affecting platelet survival in young healthy females.

Smoking is a risk factor for the development of atherosclerotic cardiovascular disease, in men as well as in women. An increased urinary excretion of the thromboxane metabolite 2,3-dinorthromboxane B2 (Tx-M) has been observed in smokers of both genders, suggesting that cigarette smoking may facilitate cardiovascular disease via an action on the platelets. The present study addressed the hypothesis that the increased Tx-M excretion in female smokers reflects a true facilitation of platelet reactivity in vivo, rather than an increased destruction of the platelets. In healthy female volunteers (aged 20-46 years, 18 smokers and 17 non-smokers) platelet life-span and indices of platelet activity were determined, together with plasma levels of plasminogen activator inhibitor-1 (PAI-1), fibrinogen, peripheral blood cell counts and hematocrit. The urinary excretion of Tx-M was higher in smokers than in non-smokers (361 vs. 204 pg/mg creatinine, respectively, p < 0.05), while plasma and urinary beta-thromboglobulin, plasma platelet factor 4, platelet mean life-span and platelet production rate did not differ between the groups. PAI-1 activity, white blood cell count and hematocrit were higher in smokers than in non-smokers (p < 0.05). These data indicate that smoking facilitates platelet formation of thromboxane A2 without affecting platelet survival; i.e. it increases the activity of platelets without affecting their viability to a measurable extent. Such an increase in platelet activity, operating in parallel to a reduced fibrinolytic activity and a higher hematocrit and white blood cell count, may play an etiological role in smoking-induced cardiovascular disease in women.

Adult↗
PubMed1992

Co-variation between walking ability and circulatory alterations in patients with intermittent claudication.

Unselected patients (n = 183) with subjective symptoms of intermittent claudication were examined clinically and by various circulatory tests (calf blood-flow, ankle, toe pressures). The aims of the present study were to evaluate to what extent the central or peripheral circulation is limiting in unselected patients with subjective symptoms of intermittent claudication, to determine the co-variation between the maximum walking capacity and traditional haemodynamical measures mentioned above and to evaluate to what extent a traditional bicycle ergometer exercise test and treadmill walking test give similar information regarding maximum performance. Eighty-five per cent of all patients were or had been smokers and 16% were diabetics. The mean ankle/brachial blood pressure index was 0.58 +/- 0.02 and the average post-ischemic maximum calf bloodflow was 13.3 +/- 0.6 ml/min/100 ml tissue. Leg arterial insufficiency was the limiting factor of walking capacity in 90% of all patients at 87 +/- 2 W corresponding to a walking distance of 282 +/- 13 m, while leg exhaustion was the limiting factor in 80% of the patients during test on the bicycle ergometer at maximum 84 +/- 2W. The mean maximum walking capacity for all patients was 86 +/- 3W and the mean maximum capacity on the bicycle ergometer was 87 +/- 2W. The ankle/brachial index showed only a weak correlation (r = 0.30, p < 0.002) to walking capacity. Our results demonstrate that the maximum walking capacity on a treadmill agrees with mean values of maximum exercise capacity on a bicycle ergometer.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

2,3-Dinor metabolites of thromboxane A2 and prostacyclin in urine from healthy human subjects: diurnal variation and relation to 24h excretion.

1. Urinary levels of the 2,3-dinor metabolites of thromboxane A2 (2,3-dinor-thromboxane A2, Tx-M) and prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha, PGI-M) are frequently analysed as indices of platelet and endothelial activity and interaction in vivo. Despite this, little is known about the possible diurnal variations in urinary Tx-M and PGI-M in healthy human subjects, and how the urinary levels of Tx-M and PGI-M in single samples reflect their respective 24 h excretion rates. We addressed this by determining Tx-M, PGI-M and creatinine in consecutive portions of urine collected during 24 h in 15 healthy non-smoking subjects. 2. The total 24 h excretion of Tx-M and PGI-M did not differ between men (223 +/- 31 and 132 +/- 27 ng, respectively) and women (215 +/- 44 and 127 +/- 29 ng, respectively). Neither the excretion of Tx-M nor that of PGI-M displayed any significant diurnal variation. 3. The excretion of Tx-M during a 3 h period and the Tx-M/creatinine ratio in a urine sample accurately reflected the 24 h excretion of Tx-M (correlation coefficient ranges 0.74-0.94 and 0.74-0.86, respectively). The excretion of PGI-M during a 3 h period and the PGI-M/creatinine ratio in a urinary sample were accurate measures of 24 h excretion of PGI-M (correlation coefficient ranges 0.76-0.94 and 0.72-0.83, respectively). Urinary Tx-M and PGI-M expressed as simple concentrations were poor indices of their respective 24 h excretion. 4. We conclude that time-related excretions of Tx-M and PGI-M may be the best indices ex vivo of the cardiovascular formation of thromboxane A2 and prostacyclin, but that urinary creatinine-related concentrations of Tx-M and PGI-M in a urine sample are accurate measures as well.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Endothelium-dependent and -independent vasodilation and reactive hyperemia in healthy smokers.

Although cigarette smoking elicits a transient increase in peripheral vascular resistance in humans, the basal blood pressure (BP) is usually slightly lower in smokers. We hypothesized that this may be due to a compensatory increase in sensitivity in smokers to endogenous vasodilators. To test this, we studied endothelium-dependent and -independent vasodilator responses, and reactive hyperemia (RH) in the forearm of 25 healthy subjects [11 smokers (S) and 14 nonsmokers (NS)]. Endothelium-dependent vasodilation was induced by infusion into a brachial artery of stepwise increasing dosages of acetylcholine (ACh, 10-60 micrograms/kg/min) and endothelium-independent vasodilation by a similar infusion of nitroprusside (N, 1-6 micrograms/kg/min). RH was induced by release of a 5-min upper arm arterial occlusion. Forearm blood flow (FBF) was recorded by plethysmography. Endothelium-dependent vasodilation was more pronounced in S than in NS (p < 0.01), the maximal FBF during infusion of ACh being 20 +/- 6 and 14 +/- 4 ml/100 ml/min, respectively. Endothelium-independent vasodilation was also larger in S than in NS (p < 0.001), the maximal FBF during infusion of N being 14 +/- 3 and 12 +/- 2 ml/100 ml/min, respectively. ACh-induced vasodilator responses in S and NS were completely blocked by atropine. They were not decreased by trimethaphan, a nicotinic receptor inhibitor. RH was slightly more pronounced in S than in NS (p < 0.02), the postocclusive FBF 15 s after release of the occlusion being 25 +/- 4 and 21 +/- 3 ml/100 ml/min, respectively We propose that cigarette smoking increases the sensitivity of the vascular smooth muscle to vasodilator stimuli.

Acetylcholine↗
PubMed1992

Formation of prostacyclin during administration of beta 1-selective and non-selective beta-adrenergic antagonists in healthy humans.

Vascular formation of prostacyclin is increased by propranolol in patients with essential hypertension. However, the possible effect of beta-adrenoceptor blocking drugs in healthy subjects is, however, not known. We studied this issue by analysis of the urinary excretion of the prostacyclin metabolite, 2,3-dinor-6-keto-prostaglandin F1a during intake of a beta 1-selective (metoprolol) or a non-selective (propranolol) beta-adrenoceptor antagonist. After 14 days of metoprolol treatment (100 mg d-1) the urinary excretion of PGI-M did not differ from control (253 +/- 77 vs. 220 +/- 33 pg mg-1 creatinine, respectively). Five days of randomized cross-over treatment with propranolol (80 mg day-1) or placebo did not affect urinary PGI-M significantly either (177 +/- 11 vs. 202 +/- 11 pg mg-1 creatinine, respectively). Furthermore, a daily increasing dose of propranolol (80-480 mg) progressively lowered resting blood pressure and heart rate, but failed to influence urinary excretion of PGI-M. The data demonstrate that metoprolol and propranolol do not affect basal cardiovascular formation of prostacyclin in healthy subjects. Thus, the biosynthesis of prostacyclin does not appear to be regulated by beta-adrenoceptor activity under normal conditions.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Dependence of the metabolism of nitric oxide (NO) in healthy human whole blood on the oxygenation of its red cell haemoglobin.

Plasma or whole venous or arterialized blood from healthy human donors was incubated with NO (50-300 microM), and the resulting formation of methaemoglobin (MetHb), nitrosyl haemoglobin (HbNO), and plasma nitrite and nitrate were measured. In plasma, NO was converted to nitrite and nitrate in a ratio of 5:1. In arterial blood (O2 sat. 94-99%) NO was almost quantitatively converted to nitrate and MetHb. No nitrite was detected and HbNO formation was low. In venous blood (O2 sat. 36-85%) more HbNO and less nitrate was formed, in comparison to arterialized blood. We propose that NO liberated from endothelium of conductance and resistance vessels is taken up by red blood cells and inactivated by HbO2 via stoichiometric conversion to MetHb and nitrate.

Dose-Response Relationship, Drug↗
PubMed1992

Tobacco use and urinary excretion of thromboxane A2 and prostacyclin metabolites in women stratified by age.

BACKGROUND: Activated platelets have been implicated in both acute thrombus formation and atherogenesis. Because smoking is a risk factor for cardiovascular disease in men and women and male smokers have biochemical evidence of increased platelet activation, we found it of interest to study whether smoking augments platelet activity in women as well. METHODS AND RESULTS: Data on smoking habits and a urinary sample were obtained from 125 healthy female nonsmokers and an equal number of smokers, stratified by age in five groups from 18 to 59 years old. Urinary samples were analyzed with gas chromatography/mass spectrometry for the 2,3-dinormetabolites of thromboxane A2 (Tx-M), reflecting platelet activity, and prostacyclin (PGI-M), representing platelet/vessel wall interaction. Urinary Tx-M in smokers was higher than in nonsmokers (p < 0.001), increasing with the number of cigarettes smoked per day and with age. In nonsmokers, there was no difference in Tx-M between the age groups. Urinary PGI-M in smokers was higher than that in nonsmokers (p < 0.001) and decreased with age in nonsmokers but not in smokers. There was no difference in Tx-M between previous smokers and lifelong nonsmokers. CONCLUSIONS: The elevated Tx-M in women who smoke cigarettes indicates an increased platelet activity that is dependent on smoking intensity. In parallel, PGI-M is augmented, suggesting that platelet/vessel wall interaction is stimulated. Quitting smoking is an effective means to restore platelet function. We propose that the observed increase in platelet activity in women who smoke cigarettes may be related to subsequent development of cardiovascular disease and that quitting smoking should be considered a high-priority medical target also in this sex.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Cigarette smoking and urinary excretion of markers for platelet/vessel wall interaction in healthy women.

1. Cigarette smoking is known to increase the risk of cardiovascular disease in both men and women. Experimental and epidemiological studies have demonstrated that cigarette smoking is associated with several indices of increased platelet activation and platelet/vessel wall interaction in men. The aim of the present study was to test the hypothesis that cigarette smoking is linked to an increased platelet activity in women also. 2. In 26 healthy smoking and non-smoking women (age 21-49 years) the urinary excretion of the thromboxane A2 metabolite 2,3-dinor-thromboxane B2 (an index of platelet activation) and of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha (an index of platelet/vessel wall interaction) were analysed by g.c.-m.s. in samples collected on days 3, 10 and 20 of their respective menstrual cycles. 3. The urinary excretion of 2,3-dinor-thromboxane B2 did not vary significantly during the menstrual cycle, either in the smokers or in the non-smokers. It was consistently higher (P less than 0.004) in the group of smokers (average of day 3, 10 and 20, 395 +/- 61 pg/mg of creatinine; mean +/- SEM) than in the group of non-smokers (average 188 +/- 22 pg/mg of creatinine). 4. The urinary excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha did not differ between the groups on any of the days studied (average on days 3, 10 and 20 in the smokers and non-smokers was 281 +/- 50 and 227 +/- 30 pg/mg of creatinine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗