Endothelium-independent vascular relaxation by histamine in the rabbit aorta.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
A Wennmalm
Publications and source records attributed to A Wennmalm.
Metabolic and myogenic components of reactive hyperaemia in the human calf.
Explore the source record for details and available documents.
Adult↗
Release of endothelial mediators and sympathetic transmitters at different coronary flow rates in rabbit hearts.
1. The release of three endothelial mediators, namely, endothelial-derived relaxing factor (EDRF), prostacyclin (PGI2) and endothelin, and of two sympathetic neurotransmitters, noradrenaline and neuropeptide Y (NPY), from resting or sympathetically stimulated rabbit Langendorff hearts was investigated at normal or elevated coronary flow. The sympathetic nerves to the hearts were stimulated at 5 Hz for 30 s and the cardiac effluent was analysed for nitrite (metabolite of EDRF) with electron paramagnetic resonance spectrometry, for 6-keto-PGF1 alpha (metabolite of PGI2) with gas chromatography/mass spectrometry, for endothelin- and NPY-like immunoreactivity with radioimmunoassay, and for noradrenaline and purines with liquid chromatography. 2. During perfusion of the hearts at normal flow (35 +/- 1.4 ml min-1) the effluent concentration of nitrite was 0.15 +/- 0.02 microM, that of 6-keto-PGF1 alpha 0.74 +/- 0.08 nM, and that of endothelin-like immunoreactivity 0.18 +/- 0.01 pM. Nerve stimulation augmented the release of 6-keto-PGF1 alpha from 76 +/- 8 to 99 +/- 10 pmol (3 min)-1 (P less than 0.05), but did not affect the release of nitrite or endothelin-like immunoreactivity. Nerve stimulation also facilitated the outflow of noradrenaline and of NPY-like immunoreactivity by 52 +/- 11 pmol (3 min)-1 and 19 +/- 7 fmol (3 min)-1, respectively. 3. Elevation of the coronary flow to 79 +/- 3.2 ml min-1 did not affect the effluent concentrations of nitrite, 6-keto-PGF1 alpha and endothelin-like immunoreactivity, implying that their outflows were augmented. Sympathetic stimulation at elevated coronary flow did not further augment the outflow of endothelial mediators or of NPY-like immunoreactivity, but increased the outflow of noradrenaline by 62 +/- 12%, in comparison to stimulation at normal flow. Perfusion of the heart with the noradrenaline uptake blocker desipramine (5 microM) completely abolished the promoting effecting of elevated coronary flow on noradrenaline outflow during sympathetic stimulation. 4. These data indicate that an increase in coronary flow in perfused rabbit hearts is paralleled by a corresponding facilitation of the formation of the endothelial mediators, EDRF, prostacyclin and endothelin. Such an elevation of mediator formation does not affect nerve stimulation-induced release of sympathetic transmitters in the heart.
Animals↗
Relation between tobacco use and urinary excretion of thromboxane A2 and prostacyclin metabolites in young men.
BACKGROUND: Cigarette smoking is a risk factor for cardiovascular disease. The present study addressed the effect of tobacco use on the formation of two eicosanoids, thromboxane A2 and prostacyclin, which have been implicated in both acute and chronic cardiovascular disorders. METHODS AND RESULTS: In 577 randomly sampled 18-19-year-old men, the urinary excretion of the 2,3-dinor metabolites of thromboxane A2 and prostacyclin (Tx-M and PGI-M, respectively) was analyzed and related to the subjects' self-reported use of tobacco. Sixty-five percent of the subjects used no tobacco, 7.5% were cigarette smokers, 22% used wet (oral) snuff, and the rest reported a mixed use of tobacco. The urinary excretion of Tx-M was higher (p less than 0.001) in cigarette smokers than in those not using tobacco (180 versus 128 pg/mg creatinine) and was correlated (r = 0.35, p less than 0.05) with the daily cigarette consumption. Snuff users had no increase in their urinary excretion of Tx-M, despite urinary cotinine levels comparable to those in the cigarette smokers (1,210 and 1,560 ng/ml, respectively). The excretion of PGI-M did not differ between non-tobacco users, cigarette smokers, and snuff users. CONCLUSIONS: We conclude that cigarette smoking, but not the use of snuff, facilitates the formation of thromboxane A2. We propose that such an increased formation reflects platelet activation in the absence of vascular injury and that it may be of significance for the subsequent development of cardiovascular disease.
6-Ketoprostaglandin F1 alpha↗
Relation between tobacco consumption and urinary excretion of thromboxane A2 and prostacyclin metabolites in 756 randomly sampled young men.
Explore the source record for details and available documents.
Adolescent↗
Differential inhibition of thromboxane A2 and prostacyclin synthesis by low dose acetylsalicylic acid in atherosclerotic patients.
Differential inhibition of thromboxane A2 (TxA2) and prostacyclin (PGI2) biosynthesis has an antithrombotic potential, since it may change the TxA2/PGI2 formation ratio in a favourable direction. Very low doses of acetylsalicylic acid (ASA) have been demonstrated to elicit differential inhibition of TxA2 and PGI2 formation in healthy subjects; whether a similar effect can be obtained in patients with atherosclerosis is still an open question. We addressed this by analyzing the urinary excretion of the 2,3-dinor-metabolites of TxA2 (Tx-M) and PGI2 (PGI-M) in 10 patients with severe atherosclerosis during 10 consecutive days. The first three days were a basal period, under which no treatment was given. During the subsequent seven days a daily 50 mg oral dose of ASA was administered. In the basal state urinary Tx-M did not differ from that of PGI-M, the median excretion rates of the two eicosanoid metabolites being 526 (range 68-1490) and 562 (range 93-1970) pg/mg creatinine, respectively. During ASA treatment urinary Tx-M fell to a lower (p less than 0.001) level than PGI-M. Thus, during the last 5 days of ASA treatment the median excretion of Tx-M was depressed (p less than 0.001) to 148 (range 48-428) pg/mg creatinine, while that of PGI-M was decreased (p less than 0.01) to 313 (range 42-2658) pg/mg creatinine. These data indicate that a daily 50 mg dose of ASA inhibits cardiovascular formation of eicosanoids in patients with severe atherosclerosis and increased platelet TxA2 formation. Furthermore, this dose of ASA inhibits the formation of TxA2 more than that of PGI2.
Aged↗
Acipimox stimulates skin blood flow by a cyclo-oxygenase-dependent mechanism.
The blood flow in the skin and the urinary excretion of the PGI2 metabolite 2,3-dinor-6-keto-PGF1a (PGI-M) were determined in the nine healthy subjects randomly assigned to double-blind oral treatment with a) placebo and acipimox (AC) 500 mg, b) acetylsalicylic acid 1500 mg and AC 500 mg, or c) placebo and nicotinic acid (NIC) 500 mg, on three different occasions. After treatment with placebo and AC there was a transient increase in the skin blood flow, up to about four-times the basal level, and a concomitant increase in skin temperature. After acetylsalicylic acid and AC no increase in skin flow rate or temperature was found. Urinary excretion of PGI-M was insignificantly increased by AC, but fell after acetylsalicylic acid pretreatment. NIC elicited a more marked increase in skin blood flow than AC, and in parallel the urinary excretion of PGI-M was more than doubled. It is concluded that cutaneous flushing induced by AC is cyclo-oxygenase dependent. In comparison to NIC, however, AC appears as a weak stimulant of vascular prostacyclin formation.
6-Ketoprostaglandin F1 alpha↗
Detection of endothelial-derived relaxing factor in human plasma in the basal state and following ischemia using electron paramagnetic resonance spectrometry.
The endothelial-derived relaxing factor is a vasodilator agent that is formed in the vascular endothelium in response to various stimuli. It has been identified as nitric oxide (NO). Due to its short half-life the endothelial-derived relaxing factor offers certain analytical problems. We present here a method for quantitative analysis of nitrite, the oxidation product of NO, in human plasma. NO binds strongly to hemoglobin. If the resulting NO-hemoglobin (Hb) complex is subjected to a magnetic field and microwave radiation, a characteristic electron paramagnetic resonance spectrum is obtained. This spectrum is highly specific and its amplitude can be used for quantitative determination of NO in the nanomolar range. Columns of bovine Hb covalently bound to agarose were prepared, and an excess amount of dithionite was used to ensure that the Hb was reduced to a ferrous, nonoxygenated state. Samples of human plasma were treated with dithionite to convert nitrite to nitric oxide. They were then passed over the columns, which were subsequently analyzed at 77 degrees K in an electron paramagnetic resonance spectrometer. As an external standard nitrite was used. The amplitude of the spectrum was linear in the range 1-100 nmol. In healthy subjects the venous plasma level of nitrite ranged from 0 to 0.6 microM. Following forearm or leg ischemia the plasma level of nitrite increased substantially. These data are the first to demonstrate circulating levels of an index of the endothelial-derived relaxing factor in human plasma.
Electron Spin Resonance Spectroscopy↗
Paired analysis of thromboxane and prostacyclin metabolites in urine from healthy mothers and their children.
Eicosanoids have been implicated in the adaptation of the fetal to the neonatal circulation, but biochemical support for an activation of their synthesis in relation to birth has not been presented. We addressed this by assessing in pairs the excretion of two metabolites of thromboxane A2, 11-dehydro-TxB2 (dTx) and 2,3-dinor-TxB2 (Tx-M), and one metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1 a (PGI-M), in the first voided urine from 13 healthy term neonates and in the immediate pre-delivery urine from their respective mothers. The excretion of dTx was higher (p less than 0.01) in the neonates than in their mothers (7430 and 1330 pg/mg creatinine, respectively), and so was the excretion of Tx-M (3730 and 900 pg/mg creatinine, respectively, p less than 0.001). Also the excretion of PGI-M was higher (p less than 0.05) in the neonates than in their mothers (2550 vs. 1510 pg/mg creatinine). Amniotic fluid contained detectable levels of both Tx-M and PGI-M. These data indicate that activation of platelets takes place in the neonate after separation of the fetal and maternal vascular circuits. The possible physiological implication of such activation requires further studies.
Epoprostenol↗
Non-invasive assessment of the cardiovascular eicosanoids, thromboxane A2 and prostacyclin, in randomly sampled males, with special reference to the influence of inheritance and environmental factors.
1. We studied, in a random sample of 385 nonsmoking men born in 1968-1969 and 31 men born in 1913 or 1923, whether inheritance and environmental factors influenced platelet activity and vessel wall prostacyclin formation, as reflected non-invasively by the urinary excretion of the 2,3-dinor-metabolites of thromboxane A2 (2,3-dinor-thromboxane B2, Tx-M) and prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha, PGI-M), respectively. 2. Fathers of young men with high platelet activity did not excrete more Tx-M than fathers of young men with low platelet activity. Men born in 1913 or 1923 displayed higher Tx-M (563 versus 128 pg/mg of creatinine, P less than 0.001) and PGI-M (163 versus 130 pg/mg of creatinine, P less than 0.01) excretion than those born in 1968-1969. Excretion of both Tx-M and PGI-M was correlated to the urinary output of noradrenaline and adrenaline. 3. Well-trained subjects did not differ in their excretion of Tx-M or PGI-M from those who did not exercise regularly. A recent acute infection was also unrelated to the excretion of Tx-M or PGI-M. PGI-M excretion was, however, significantly correlated to Tx-M excretion (r = 0.51, P less than 0.001). 4. This study provides the first non-invasive evidence that advancing age and sympathoadrenal tone are positively correlated to platelet activity in randomly sampled men, and that paternal inheritance, physical fitness and recent infection lack correlation to platelet activity.
6-Ketoprostaglandin F1 alpha↗
Endothelium-derived constricting factor(s): the last novelty--endothelin.
The vascular endothelium is not merely a passive physical barrier between the blood and the tissue surrounding the blood vessel, but may actively participate in key processes of metabolic, secretory, and vasoregulatory character. In addition, the endothelium plays an important role in the control of platelet activation. Under certain conditions endothelial cells have been shown to produce powerful vasodilators, like endothelium-derived relaxing factor (EDRF) and prostacyclin (GPI2), and vasoconstrictors like endothelium-derived constricting factor (EDCF) and endothelin (ET) (Griffith et al., 1988; Vanhoutte & Katusic, 1988). In contrast to the extensive studies performed to characterize the actions and nature of EDRF, recently identified chemically as nitric oxide (Moncada et al., 1988), relatively little is known about EDCF(s). This paper reviews recent data on EDCF, with special emphasis on the newly discovered vasoconstrictor peptide, endothelin (ET).
Amino Acid Sequence↗
Endothelin does not affect aggregation of human platelets.
Endothelin (ET-1) is a recently discovered endothelial-derived peptide with pronounced vasoconstrictor activity. The present study addressed whether ET-1, in analogy with several other vasoactive agents, can induce or modulate aggregation of human platelets in vitro. Venous blood from healthy donors was collected in citrate or heparin and platelet-rich plasma (PRP) was prepared. Portions of the PRP were added to drugs, and platelet aggregation was recorded according to Born & Cross (1963). ET-1 added to the PRP (final concentrations 1-100 nM) did not induce aggregation of platelets, either in citrate- or heparin-containing plasma. Adenosine-diphosphate (0.5-2 microM) or thrombin (0.1-0.4 NIH units ml-1) induced dose-dependent aggregation of platelets in citrate- or heparin-containing PRP; such aggregation was, however, not affected by ET-1 (1-100 microM) either. We conclude that ET-1, in contrast to other endothelial-derived vasoactive agents, lacks direct effect on platelet aggregation in vitro.
Adenosine Diphosphate↗
Endothelin has no positive inotropic effect in guinea-pig atria or papillary muscle.
Endothelin is a recently discovered, highly potent vasoconstrictor peptide. In isolated atria from rat and guinea-pig, endothelin has been reported to elicit a positive inotropic effect. The purpose of the present study was to compare the effects of endothelin on electromechanical coupling in guinea-pig atrial and ventricular muscle. In isolated, electrically driven specimens of atria and papillary muscle, action potentials and isometric contractions were recorded in the basal state and 30 min following non-cumulative exposure to endothelin (100 nM). In the atria, endothelin reduced action potential overshoot and relaxation velocity, and increased resting tension. In the papillary muscle the peptide slightly shortened the duration of the action potential. Endothelin did not affect peak tension, either in the atria or in the papillary muscle. These data contrast with earlier reports on a positive inotropic effect of endothelin in guinea-pig atria.
Action Potentials↗
Excretion of thromboxane A2 and prostacyclin metabolites before and after exercise testing in patients with and without signs of ischemic heart disease.
We addressed the hypothesis that platelets are not activated in association with effort-induced myocardial ischemia in stable coronary disease. Seventy-two patients undergoing a diagnostic bicycle exercise test were stratified according to the development of chest pain (yes/no, 33/39) and of exercise-induced ST-segment depression of at least 200 microV in the electrocardiogram (yes/no, 12/60). Noninvasive indexes of platelet activation and of platelet/vessel wall interaction (urinary excretion of the 2,3-dinor-metabolites of thromboxane A2 [Tx-M] and prostacyclin [PGI-M], respectively) were analyzed in samples collected in the basal state and after the test. Basal Tx-M and PGI-M did not differ in patients with (236 +/- 35 and 131 +/- 22 pg/mg creatinine, respectively) and without (185 +/- 16 and 101 +/- 13 pg/mg creatinine, respectively) chest pain, or in those with (178 +/- 45 and 162 +/- 41 pg/mg, respectively) and without (216 +/- 22 and 104 +/- 11 pg/mg, respectively) ST-segment depression during the test. Patients without chest pain or without ST-segment depression moderately increased (p less than 0.05) their urinary Tx-M (by 21% and 13%, respectively) and PGI-M (by 28% and 23%, respectively) after exercise. No significant increases were observed in those developing chest pain or ST depression during exercise. These data indicate that effort-induced myocardial ischemia is not associated with an increase in platelet activation or platelet/vessel wall interaction in patients with stable coronary disease.
Coronary Disease↗
Effects of endothelin on coronary flow, mechanical performance, oxygen uptake, and formation of purines and on outflow of prostacyclin in the isolated rabbit heart.
Endothelin is a 21-residue peptide formed during incubation of isolated porcine endothelial cells. Due to its pronounced vasoconstrictor activity, endothelin has been proposed to play a role in the regulation of vascular tone. We studied the effects of synthetic endothelin (0.1-10 nM) on coronary flow, mechanical performance, myocardial oxygen uptake, and formation of purines, and outflow of 6-ketoprostaglandin F1 alpha (metabolite of prostacyclin) in rabbit hearts perfused with saline by the Langendorff method. Endothelin dose-dependently decreased the coronary flow, at 10 nM, by about 75%. Heart rate, ventricular contractility, myocardial oxygen uptake, and purine release were affected by endothelin no more than by a corresponding mechanical reduction of the coronary flow. In contrast, the diastolic relaxation appeared to be directly diminished by endothelin. The concentration of 6-ketoprostaglandin F1 alpha in the cardiac effluent was dose-dependently elevated by about 14 times by endothelin (10 nM) (p less than 0.001). A corresponding mechanical restriction of the coronary flow insignificantly affected the effluent concentration of 6-ketoprostaglandin F1 alpha. The calcium channel blocker nifedipine (1 microM) completely abolished the decrease in diastolic relaxation induced by endothelin and markedly counteracted the peptide-induced increase in effluent concentration of 6-ketoprostaglandin F1 alpha, but did not affect the vasoconstrictor activity. These data demonstrate that endothelin induces vasoconstriction and facilitates the outflow of prostacyclin in the rabbit heart. In addition, the peptide appears to affect diastolic relaxation in this organ.
6-Ketoprostaglandin F1 alpha↗
Effect of aminophylline on plasma and urinary catecholamine levels during heavy leg exercise in healthy young men.
1. Methylxanthines have been shown to elevate the basal plasma level and/or urinary excretion of noradrenaline (NA) and adrenaline (ADR) in healthy subjects. The present study addressed the hypothesis that the methylxanthine aminophylline also augments plasma and urinary catecholamines during increased sympathoadrenal activity. 2. Eleven healthy young men performed a maximal 2 h bicycle exercise twice, after double-blind intravenous administration of placebo or aminophylline. Femoral venous plasma and urinary concentrations of NA and ADR were analysed in samples representing basal state, exercise and recovery, using liquid chromatography with electrochemical detection. 3. Leg exercise induced eight- and six-fold increases in the plasma concentrations of NA and ADR, respectively, and seven- and four-fold increases in the urinary concentrations of NA and ADR, respectively, indicating that sympathoadrenal activity was considerably elevated. 4. After aminophylline (mean plasma concentration 20-35 mumol/l), the plasma concentrations of NA (P less than 0.001) and ADR (P less than 0.05) were independently higher at rest, during exercise and during recovery, in comparison to after placebo; the mean exercise plasma level of NA was increased by the drug from 13 +/- 1 to 21 +/- 2 nmol/l and the corresponding level of ADR from 2.1 +/- 0.4 to 2.9 +/- 0.5 nmol/l. Also urinary NA (P less than 0.01) and ADR (P less than 0.05) were elevated by aminophylline; the exercise concentrations of NA in the urine were 75 +/- 8 and 97 +/- 10 mumol/mol of creatinine after placebo and aminophylline, respectively, and the corresponding levels of ADR were 12 +/- 3 and 16 +/- 3 mumol/mol of creatinine, respectively.
Adult↗
Coffee, catecholamines and cardiac arrhythmia.
It is generally agreed that a high release of noradrenaline in the heart may elicit cardiac arrhythmia. Furthermore, administration of aminophylline to patients with ischaemic heart disease frequently elicits ventricular premature beats and ventricular tachycardia. Recent data from animal experiments demonstrate that methylxanthines (aminophylline, caffeine, theophylline) can facilitate noradrenaline release from sympathetic nerve endings. Such facilitation of transmitter release is amplified when myocardial oxygenation is impaired, stressing its clinical significance in relation to ischaemic heart disease. If a similar amplification is also operative in man, a dose of methylxanthine causing a very modest increase in myocardial sympathetic transmitter release in the heart of a healthy subject may be sufficient to cause a three- to six-fold elevation in the local myocardial concentration of noradrenaline in a patient with ischaemic heart disease. We hypothesize that such hypoxia-induced facilitation of sympathetic transmitter release lies behind the reported connection between cardiac events and methylxanthines, for instance sudden cardiac death following coffee consumption.
Aminophylline↗
The role of adenosine and prostacyclin in coronary flow regulation in healthy man.
Coronary flow regulation in man is incompletely understood. We addressed the hypothesis that endogenous adenosine and prostacyclin (PGI2) affect basal coronary tone and/or the coronary flow response to increased myocardial work. In healthy volunteers coronary sinus flow and cardiac oxygen extraction were measured at rest and during leg exercise (40-50 W), before and after i.v. administration of theophylline (to block adenosine receptors) and oral administration of ibuprofen (to inhibit prostaglandin synthesis). Before drug, the basal coronary flow was 118 +/- 23 ml min-1 and the cardiac extraction of oxygen 122 +/- 3 ml l-1. Leg exercise elevated coronary flow by 89 +/- 16 ml min-1. Theophylline, at a dose blocking the coronary flow response to dipyridamole (an adenosine-dependent mechanism), induced a moderate increase in myocardial oxygen extraction (by 11%, P less than 0.05), but failed to affect either the basal coronary flow (105 +/- 16 ml min-1) or the increase during exercise (88 +/- 25 ml min-1). Ibuprofen inhibited the urinary excretion of PGI2 metabolite by about 90%, but did not affect basal coronary tone or the coronary response to exercise. These data indicate that endogenous adenosine is of limited importance for normal coronary regulation in man, and that PGI2 has no effect.
Adenosine↗