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Biomedical subjects

F Waagstein

Publications and source records attributed to F Waagstein.

At least 73 records · Page 4Linked to original sources
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

Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy.

A peptide corresponding to the sequence 169-193 of the second extracellular loop of the human muscarinic acetylcholine receptor-2 was used as an antigen to screen sera from patients with idiopathic dilated cardiomyopathy (DCM, n = 36) and healthy blood donors (HBD, n = 40). The sera from 14 patients with DCM (38.8%) and 3 HBD (7.5%) recognized the muscarinic receptor peptide at dilutions varying from 1:20 to 1:160 in ELISA. A highly significant correlation (P = 0.006) was found between the presence of antimuscarinic receptor-2 autoantibodies and anti-beta-adrenoceptor-1 autoantibodies in the patients' sera. Affinity-purified autoantibodies from positive sera of patients with DCM recognized on the electrotransferred protein of rat ventricular membrane a major band of about 80 kD. Incubation of autoantibodies with membrane resulted not only in a decrease in the maximal binding sites (Bmax) but also in an increase in Kd of radioligand binding in a concentration-dependent manner. This suggests a mixed-type of inhibition. Moreover, preincubation with atropine abolished the inhibitory effect of autoantibodies on the receptor binding whereas carbachol appeared to have no effect on the activity of the autoantibodies. These data define a subgroup of patients with idiopathic DCM who have in their sera functionally active autoantibodies against muscarinic receptor-2.

Adult↗
PubMed1993

Cardiac noradrenergic function one year following cardiac transplantation.

Controversy exists whether or not cardiac nerves regrow into a human transplanted heart. The present study examined cardiac noradrenergic function one year following cardiac transplantation. Eight male cardiac transplant recipients having standard triple immunosuppressive treatment were catheterized diagnostically one year after heart transplantation. They had normalized cardiac hemodynamics and showed no histological rejection in biopsies. A second study group, with intact cardiac innervation, consisted of 19 patients with stable angina pectoris class I to III. Cardiac sympathetic nerve activity was assessed by measurements of cardiac noradrenaline (NA) extraction and spillover, using infusion of tritium-labelled NA (3H-NA). To further characterize cardiac noradrenergic function (synthesis and metabolism) arterial and coronary venous plasma concentrations of the NA precursor, dihydroxyphenylalanine (DOPA), the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), and the intra-neuronal NA metabolite, dihydroxyphenylglycol (DHPG), were also examined. In transplant recipients, cardiac sympathetic function was also examined before and during supine bicycle exercise and after administration of desipramine to block neuronal uptake. Significant dilution of 3H-NA with endogenous NA from arterial to coronary venous plasma in cardiac transplant patients indicated detectable spillover of NA into plasma from transplanted hearts. However, cardiac spillover of NA in heart transplant patients was only a quarter of that observed in angina patients. Also, transplanted hearts showed no production of DOPA, DOPAC, DHPG or 3H-labelled DHPG, whereas there were positive arterial-venous plasma gradients in all these catechols across the hearts of angina patients. Cardiac fractional extraction of NA was 74% in the angina patients, but only 13% in transplant patients. In transplant patients, cardiac spillover of NA and extraction of 3H-NA were not affected by desipramine or exercise. The present study shows little evidence of any functional activity of cardiac sympathetic nerves in the transplanted heart, as assessed by biochemical indices of release, reuptake, metabolism and synthesis of NA. This argues against cardiac reinnervation of functional importance, at least within the first postoperative year.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Increase in functional activity rather than in amount of Gi-alpha in failing human heart with dilated cardiomyopathy.

OBJECTIVE: The aim was to investigate whether or not increased pertussis toxin catalysed ADP ribosylation correlates with increased amount of Gi-alpha in failing human heart. DESIGN: Antisera raised against unique synthetic peptides corresponding to alpha subunits of Gs and Gi 1-3 were used in immunoblotting and ELISA to determine amounts of various G proteins. Adenylyl cyclase activity, beta adrenoceptors, and muscarinic receptors were then measured in cardiomyopathic hearts (n = 6) obtained at transplant in order to study whether or not an altered expression of G proteins has relevance to the integrity and function of the receptor--adenylyl cyclase system. Six non-failing control hearts were also studied. RESULTS: No significant differences in the peptide equivalent amounts of either Gs or Gi were found in the failing human heart as compared to the non-failing heart. However, functional activity of Gi was shown to increase significantly since there was a decrease in basal (57%), isoprenaline stimulated (60%), and guanyliminodiphosphate stimulated (52%) adenylyl cyclase activity. In contrast the density of beta adrenoceptors was markedly decreased (51%) in failing human heart in comparison to non-failing hearts. Neither the density nor the affinity of muscarinic receptors changed in the failing human heart. CONCLUSION: These results suggest that in the failing human heart, there is an increase in functional activity rather than in amount of Gi, and an important part of functional expression of Gi-alpha may be regulated at the post-translational level.

Adenylyl Cyclases↗
PubMed1992

Oxygen free radical injury and Gs mediated signal transduction in the stunned porcine myocardium.

OBJECTIVE: The aim was to investigate involvement of oxygen free radicals and any changes in the Gs mediated beta adrenergic signalling system of stunned porcine myocardium. METHODS: Myocardial stunning was induced in eight pentobarbitone anaesthetised pigs by brief occlusions of the distal left anterior descending coronary artery for periods of up to 10 min. Segment length function was measured in the ischaemic region and in a control region supplied by the circumflex artery. Left ventricular biopsies were obtained from the two regions 1 h after the last occlusion for ultrastructural and biochemical studies. Timolol has been used to prevent arrhythmia during ischaemia. RESULTS: At the time when biopsies were obtained, percent systolic shortening was reduced to 58% in the region subjected to ischaemia and was only minimally reduced in the control region. In the biopsies from the stunned region: (1) electron microscopy showed mild and reversible intracellular changes in the stunned myocardium; (2) the activities of superoxide dismutase and glutathione peroxidase were decreased by 66% and 52%, respectively; (3) the content of malondialdehyde was increased by 49%; (4) neither density nor affinity of beta adrenoceptors showed any changes; (5) there were no alterations in messenger RNA encoding for the alpha subunit of the stimulatory guanine nucleotide binding protein (Gs), demonstrated by northern and dot-blot hybridisations; (6) ELISA technique utilising a specific antipeptide antibody showed no quantitative change in Gs; (7) the activity of adenyl cyclase was unchanged. CONCLUSIONS: Even though the stunned porcine myocardium showed substantial evidence of free radical injury, the beta adrenergic signalling system was intact.

Adenylyl Cyclases↗
PubMed1991

Beta-adrenergic blockade in dilated cardiomyopathy, ischemic cardiomyopathy, and other secondary cardiomyopathies.

Beta-blockers were initially given to patients with chronic heart failure due to ischemic heart disease and resting tachycardia. The prompt effect on severe backward heart failure was directly associated with an immediate fall in heart rate. This observation led to long-term administration to patients with idiopathic dilated cardiomyopathy and, later, to patients with ischemic cardiomyopathy and secondary cardiomyopathies as well. Due to marked down-regulation of beta receptors, patients with heart failure are extremely sensitive to beta blockade. A test dose of metoprolol 5 mg b.i.d. for 2 days is recommended to select patients for long-term beta-blockade, followed by careful titration with increment in dose over 6 weeks. One important effect of beta-blockade in the early phase of treatment is a reduction in the myocardial energy demand early after the onset of long-term treatment. After 1 month of treatment with beta-blockers, marked improvement of diastolic function is observed. This effect might be attributed to inhibition of calcium overload. After 3 months of treatment, an increase in ejection fraction can be observed, which might be attributed to upregulation of beta receptors. The withdrawal of long-term treatment was followed by a deterioration of heart function in 61% of patients and improvement was seen after reinstitution of beta-blockade. There was an increase in cardiac index and stroke work index at rest as well as during supine exercise. A marked fall in left ventricular filling pressure at rest and unchanged filling pressure during supine exercise was noted, while exercise capacity increased by 25%. A similar pattern was seen in patients with ischemic cardiomyopathies and other secondary cardiomyopathies. However, the increase in ejection fraction in the ischemic cardiomyopathy group was lower (0.06) compared to the groups with dilated cardiomyopathy and other secondary cardiomyopathies (0.18).

Adrenergic beta-Antagonists↗
PubMed1991

G proteins and calcium channels in myocardium.

Calcium mobilization has been demonstrated to possess functional importance in myocardial excitation-contraction as well as cellular metabolism. So far, much progress has been made to explore the possibility of involvement of guanine nucleotide binding regulatory protein in the opening and closing of calcium channels as well as intracellular second messenger (cyclic adenosine monophosphate and inositol triphosphate) -mediated calcium mobilization, although such work is still in its preliminary stage, the results have proved highly interesting and significant.

Animals↗
PubMed1991

Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure.

Hemodynamics and myocardial metabolism at rest and during exercise were investigated in 21 patients with heart failure. The patients were evaluated before and after long-term treatment (14 +/- 7 months) with the beta-adrenergic blocking agent metoprolol. Clinical improvement with increased functional capacity occurred during treatment. Maximal work load increased by 25% (104 to 130 W; p less than 0.001). Hemodynamic data showed an increased cardiac index (3.8 to 4.6 liters/min per m2; p less than 0.02) during exercise. Pulmonary capillary wedge pressure decreased at rest (20 to 13 mm Hg; p less than 0.01) and during exercise (32 to 28 mm Hg; p = NS). Stroke volume index (30 to 39 g.m/m2; p less than 0.006) and stroke work index (28 to 46 g.m/m2; p less than 0.006) increased during exercise and long-term metoprolol treatment. The arterial norepinephrine concentration decreased at rest (3.72 to 2.19 nmol/liter; p less than 0.02) but not during exercise (13.2 to 11.1 nmol/liter; p = NS). The arterial-coronary sinus norepinephrine difference suggested a decrease in myocardial spillover during metoprolol treatment (-0.28 to -0.13 nmol/liter; p = NS at rest and -1.13 to -0.27 nmol/liter; p less than 0.05 during exercise). Coronary sinus blood flow was unchanged during treatment. Four patients produced myocardial lactate before the study, but none produced lactate after beta-blockade (p less than 0.05). There was no obvious improvement in a subgroup of patients with ischemic cardiomyopathy. In summary, there were signs of increased myocardial work load without higher metabolic costs after treatment with metoprolol.

Adrenergic beta-Antagonists↗
PubMed1991

Activity of receptors coupled to guanine nucleotide binding regulatory protein in doxorubicin induced cardiomyopathy.

STUDY OBJECTIVE: The aim was to study the activity of receptors coupled to guanine nucleotide binding regulatory proteins (G proteins) in doxorubicin induced cardiomyopathy, with special attention to G proteins, beta adrenoceptors, muscarinic receptors, and adenylyl cyclase. DESIGN: Messenger RNA of G proteins, densities and high affinity agonist binding of beta adrenoceptors and muscarinic receptors, activity of adenylyl cyclase, calcium influx, and in vivo lipid peroxidation were determined before, in the early stage, and in the later stage of doxorubicin cardiomyopathic heart failure. SUBJECTS: Sprague-Dawley rats between 150-200 g were used. Doxorubicin was given intravenously at two doses of 4 mg.kg-1 and 6 mg.kg-1 every third week (1st, 4th, 7th week) for nine weeks. Doxorubicin treated rats plus corresponding controls were killed at 3 weeks (n = 7), 6 weeks (n = 7), and 9 weeks (n = 6), respectively. MEASUREMENTS AND MAIN RESULTS: Northern blot and dot blot hybridisations of the total RNA revealed that messenger RNA of both stimulatory and inhibitory G proteins were identical between doxorubicin treated rats and controls. No alterations in the densities of beta adrenoceptors and muscarinic receptors were observed, neither did the high affinity agonist binding of beta adrenoceptors and muscarinic receptors change. Furthermore, modulation of adenylyl cyclase was unimpaired. In contrast, Ca(2+)-ATPase and serum water soluble fluorescent substance, a product of in vivo lipid peroxidation, were shown to increase dramatically in doxorubicin treated rats (4 mg.kg-1 for 6 and 9 weeks, 6 mg.kg-1 for 3, 6 and 9 weeks) as compared with corresponding controls. CONCLUSIONS: The findings suggest that, despite increased calcium influx and lipid peroxidation in doxorubicin induced cardiomyopathy, the activity of receptors coupled to G proteins remained normal.

Adenylyl Cyclases↗
PubMed1991

New therapeutic strategies in chronic heart failure: challenge of long-term beta-blockade.

It is claimed that long-term treatment with beta-blockers improves cardiac function and exercise capacity in patients with various forms of congestive heart failure. This was first reported by Waagstein and coworkers in patients with idiopathic dilated cardiomyopathy in 1975 and was later confirmed in 8 further studies in this type of patient. A total of 211 patients with idiopathic dilated cardiomyopathy were treated for 12-19 months. About two thirds of the patients have improved to some extent. Seven other studies reported favourable long-term effects of beta-blockers in 120 patients with other forms of dilated cardiomyopathy, e.g. caused by coronary artery disease, adriamycin, diabetes, or valvular heart disease. Pooled data from 10 studies on 153 patients with various forms of cardiomyopathy, showed that ejection fraction was improved by 40% from 27 to 38%. Only two studies were inconclusive, both with only one month's treatment. In all studies with favourable effects of long-term beta-blockade, treatment was given for more than 2 months and in most cases for about 6 months. A number of beta-blockers have been used in the studies, including acebutulol, alprenolol, bucindolol, labetalol, metoprolol, practolol and propranolol. In most cases, a rather low dose was given initially and there was a stepwise increase in the dosages. After 6-8 weeks most patients were given beta-blockers in daily doses comparable to those given in patients with angina pectoris and hypertension. There is at present no indication that one beta-blocker is superior to others. It therefore seems reasonable to believe that the effects are due to beta 1-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1991

Changes in arterial levels and myocardial metabolism of catecholamines during pacing-induced angina pectoris.

In order to elucidate the effects of atrial pacing on cardiac catecholamine metabolism, 11 patients were studied during cardiac catheterization. Blood samples were drawn from a peripheral artery and the coronary sinus for estimation of catecholamine concentrations. Heart rate was increased by 10 beats/min each minute, and all patients experienced chest pain at maximal pacing rate. Coronary sinus blood flow rose from 122 +/- 19 at rest to 208 +/- 25 ml/min at final pacing rate, and myocardial lactate extraction ratio decreased. There was no significant change in arterial epinephrine levels, whereas the extraction ratio decreased (p less than 0.05). The norepinephrine arterial levels increased at the final pacing rate (p less than 0.01). The calculated myocardial release increased as well, but not to a statistically significant degree. The exact mechanisms of the rise in sympathetic activity and arterial norepinephrine levels cannot be ascertained with the present study design. Myocardial ischemia with subsequent chest pain seems to be a probably cause for the increased sympathetic outflow.

Aged↗
PubMed1990

Effects of thoracic epidural anesthesia on coronary arteries and arterioles in patients with coronary artery disease.

The effect of cardiac sympathetic blockade by high thoracic epidural anesthesia (TEA) (T1-T6, bupivacaine) on the luminal diameter of normal and diseased portions of epicardial coronary arteries was determined by quantitative coronary angiography in patients (n = 27) with severe coronary artery disease (CAD). In a separate group of patients (n = 9) with severe CAD, the effects of TEA on coronary arterioles (resistance vessels) were studied, by measuring total and regional myocardial blood flow and metabolism with the retrograde coronary sinus thermodilution technique. At the stenotic segments, TEA induced an increase in luminal diameter from 1.34 +/- 0.11 to 1.56 +/- 0.13 mm (P less than 0.002), but did not change the diameter of the nonstenotic segments (3.07 +/- 0.13 to 2.99 +/- 0.13 mm). In the second group of patients, TEA induced no changes in coronary perfusion pressure, total or regional myocardial blood flow, coronary venous oxygen content, coronary blood flow distribution, regional myocardial oxygen consumption, or lactate extraction or uptake. Two patients had chest pain in the control situation and had regional myocardial lactate production that was attenuated by TEA. We conclude that TEA may increase the diameter of stenotic epicardial coronary artery segments in patients with CAD without causing a dilation of coronary arterioles. These effects may be beneficial when high TEA is used to treat severe ischemic chest pain in patients at rest.

Aged↗
PubMed1990

Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy.

The presence and properties of serum autoantibodies against beta-adrenergic receptors in patients with idiopathic dilated cardiomyopathy were studied using synthetic peptides derived from the predicted sequences of the human beta-adrenergic receptors. Peptides corresponding to the sequences of the second extracellular loop of the human beta 1- and beta 2-adrenergic receptors were used as antigens in an enzyme immunoassay to screen sera from patients with dilated cardiomyopathy (n = 42), ischemic heart disease (n = 17), or healthy blood donors (n = 34). The sera of thirteen dilated cardiomyopathy patients, none of the ischemic heart disease patients, and four of the healthy controls monospecifically recognized the beta 1-peptide. Only affinity-purified antibodies of these patients had a inhibitory effect on radioligand binding to the beta 1 receptor of C6 rat glioma cells. They recognized the receptor protein by immunoblot and bound in situ to human myocardial tissue. We conclude that a subgroup of patients with idiopathic dilated cardiomyopathy have in their sera autoantibodies specifically directed against the second extracellular loop of the beta 1-adrenergic receptor. These antibodies could serve as a marker of an autoimmune response with physiological and/or pathological implications.

Adult↗