The sigma enigma: in vitro/in silico site-directed mutagenesis studies unveil σ1 receptor ligand binding.

The σ1 receptor is an integral membrane protein that shares no homology with other receptor systems, has no unequivocally identified natural ligands, but appears to play critical roles in a wide variety of cell functions. While the number of reports of the possible functions of the σ1 receptor is increasing, almost no information about the three-dimensional structure of the receptor and/or possible modes of interaction of the σ1 protein with its ligands have been described. Here we performed an in vitro/in silico investigation to analyze the molecular interactions of the σ1 receptor with its prototypical agonist (+)-pentazocine. Accordingly, 23 mutant σ1 isoforms were generated, and their interactions with (+)-pentazocine were determined experimentally. All direct and/or indirect effects exerted by the mutant residues on the receptor-agonist interactions were reproduced and rationalized in silico, thus shining new light on the three-dimensional structure of the σ1 receptor and its ligand binding site.

Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease.

The peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a member of the steroid hormone super family of ligand-inducible transcription factors, involved in glucose and lipid metabolism. We screened for polymorphisms in the PPAR-alpha gene and detected two known polymorphisms located in exon 5 and intron 7. These polymorphisms were investigated for their possible association with Alzheimer's disease (AD) and for their effect in carriers of an insulin gene (INS) polymorphism. The PPAR-alpha C --> G polymorphism in exon 5 (L162V) was associated with AD, in that the V-allele was more frequent in AD patients than in healthy subjects. Further data analysis revealed that carriers of an PPAR-alpha L162V V-allele and an INS-1 allele presented with an increased risk for AD. Cerebrospinal fluid amyloid-beta levels were influenced by PPAR-alpha L162V genotype. These results suggest, that PPAR-alpha polymorphism may be a risk factor for AD.

[Paradoxical cerebral embolism during fibrinolysis therapy in deep vein thrombosis and pulmonary embolism]. / Paradoxe zerebrale Embolie unter Fibrinolysetherapie bei tiefer Beinvenenthrombose und Lungenembolie.

A 37-year-old woman with increasing dyspnoea over several months suddenly developed severe ortho- and tachypnoea as well as cyanosis of the lips and acrocyanosis. Pulmonary angiography revealed massive bilateral pulmonary emboli with a systolic pulmonary artery pressure of 75 mm Hg. Phlebography demonstrated a thrombotic occlusion of the deep veins of the left leg extending to the distal femoral vein. Thrombolysis treatment was started via an indwelling pulmonary artery catheter (500,000 IU urokinase and 10,000 IU heparin as bolus, then 1 mill. IU urokinase and 1,000 IU heparin per hour). After two hours an incomplete left-sided paresis occurred (involving ocular and facial muscles, dysarthria, left arm and left leg) and the thrombolytic infusion was stopped. But cerebral computed tomography (CT) did not demonstrate any intracerebral haemorrhage. The heparin infusion was restarted (partial thromboplastin time between 70 and 90 s). CT examinations during the next few days showed the development of an ischaemic infarction in the distribution of the right medial cerebral artery. Angiography demonstrated occlusion of the right internal carotid artery. The diagnosis of a paradoxical embolus was supported by easy cardiac catheter passage through a patent foramen ovale. Subsequent pulmonary angiography demonstrated a thrombus-free pulmonary arterial circulation with a normal pulmonary arterial pressure. There was gradual and extensive regression of the incomplete hemiparesis.

[Ventricular late potentials in athletes]. / Ventrikuläre Spätpotentiale bei Sportlern.

Ventricular late potentials detected by signal averaging have a high predictive value for the origin of malignant ventricular tachyarrhythmias in patients with coronary artery disease. We examined 35 male sportsmen aged from 22 to 33 years. Clinical examination, ECG at rest, echocardiography and signal averaging were performed. In nine of the 35 sportsmen (26%) ventricular late potentials were detected. In a control group of 20 nonsportsmen none had late potentials. The nine sportsmen with late potentials all had electrocardiographical and echocardiographical signs of left-ventricular hypertrophy. Of the 26 sportsmen without ventricular late potentials five had left-ventricular hypertrophy. Ventricular late potentials are not rare in sportsmen. They seem always to appear together with left-ventricular hypertrophy.

Frequency of complications of cardiopulmonary resuscitation after thrombolysis during acute myocardial infarction.

Prolonged external cardiac massage is often regarded as a contraindication for thrombolytic therapy because of the risk of fatal hemorrhage. The influence of cardiopulmonary resuscitation on complications of thrombolytic bleeding was assessed analyzing data of all patients with myocardial infarction admitted to our clinic during the 10-year period between 1978 and 1987. From the total of 2,147 patients with acute myocardial infarction, 590 received thrombolytic therapy (intracoronary in 229, intravenous in 400). Of these, 43 patients underwent prolonged cardiopulmonary resuscitation and received thrombolysis within a time interval of less than 24 hours. In 21 patients, resuscitation was performed within a short period of time (5 minutes to 20 hours) after thrombolysis (10 intracoronary, 10 intravenous, 1 intravenous + intracoronary) had been initiated; 9 of these patients survived (43%). In the other 22 patients, thrombolytic therapy was initiated during ongoing resuscitation (n = 6: intravenous in 5, intravenous + intracoronary in 1) or in the early phase (10 to 120 minutes) after successful resuscitation (n = 16: intracoronary in 10, intravenous in 4, intravenous + intracoronary in 2). From this group, 14 patients survived (in-hospital mortality 36%). The mean duration of cardiopulmonary resuscitation was 36 +/- 32 minutes (range 4 to 120). Autopsy studies were performed in 16 of 20 decreased patients. Bleeding complications occurred in 8 of 43 patients. No case of bleeding was directly related to cardiocompression despite the often traumatic procedure with rib fractures verified in 17 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiofrequency catheter ablation in recurrent ventricular tachycardia.

Catheter ablation by radiofrequency energy was carried out in 10 patients with one type of recurrent monomorphic sustained ventricular tachycardia resistant to medical antiarrhythmic management. Electrophysiological studies before ablation included activation and pace-mapping. In all patients, the origin of the tachycardia was localized in the left ventricle: in the septum in six, at the posterolateral wall in three and anterobasal in one. The earliest onset of endocardial activation preceding the QRS complex during ventricular tachycardia ranged between -45 and -90 ms. Transcatheter ablation was performed with a bipolar or quadripolar catheter using a radiofrequency generator (HAT 100, Osypka). No complications occurred during the ablation procedure. Thereafter, in all patients, the clinical tachycardia was no longer inducible by programmed stimulation. During a follow-up period of 22 to 32 months including eight patients, the tachycardia recurred in two; one of these patients subsequently died suddenly. A third patient had one episode of a new type of sustained ventricular tachycardia some hours after catheter ablation. In the remaining patients, there was no recurrence of symptomatic tachycardia under maintenance of the antiarrhythmic management which, prior to ablation had been ineffective. Thus, our preliminary results suggest that radiofrequency catheter ablation might be beneficial for these high risk patients.

[Effect of thrombolytic therapy in acute myocardial infarct on incidence of ventricular late potentials]. / Einfluss der thrombolytischen Therapie beim akuten Myokardinfarkt auf das Auftreten von ventrikulären Spätpotentialen.

The aim of thrombolytic therapy for acute myocardial infarction is reperfusion of the infarction-related vessel. Ventricular late potentials detected by signal averaging have been demonstrated to be related to slow and inhomogeneous conduction within damaged cardiac tissue. In 75 patients with first myocardial infarction the effect of thrombolysis on ventricular late potentials was studied. Reperfusion of the infarction-related vessel could be demonstrated by coronary angiography in 53 (71%) patients. In 22 patients (29%) there was no reperfusion. In the 53 patients with successful thrombolysis the incidence of late potentials was significantly lower (9%) than in the 22 patients without reperfusion (50%). The lower incidence of late potentials may demonstrate improved ventricular electrical stability.

Effect of pH on the reaction of tris(2,2'-bipyridyl)ruthenium(III) with amino-acids: Implications for their detection.

A new technique for the detection of amino-acids is described, which is based on their chemiluminescence reaction with tris(2,2'-bipyridyl)ruthenium(III). The pH-dependence of this reaction has been investigated and found to be the key experimental parameter in application of this reaction as a detection technique. The chemiluminescence emission obtained is maximal at pH values higher than the N-terminal amino group pK(a) of the amino-acid. The background reaction between the ruthenium reagent and hydroxide ion does not occur with the same efficiency as the amino-acid reaction and the optimum signal to noise ratio is obtained at pH 10. A limit of detection of 30 picomole was found for valine and the response was shown to be linear over two orders of magnitude.

[Perforation of an automatic implantable cardioverter-defibrillator into the peritoneal cavity]. / Perforation eines automatischen implantierbaren Kardioverter-Defibrillators in die Peritonealhöhle.

The automatic, implantable cardioverter-defibrillator is a new therapy for life-threatening ventricular tachyarrhythmias that are resistant to other therapy. Only a few complications, such as infections, lead defects, and interactions with pacemakers have been reported. We report on a patient whose AICD-generator perforated into the peritoneal cavity.

Prevalence of late ventricular potentials in hypertensive patients.

Late ventricular potentials detected by signal averaging are used for predicting ventricular arrhythmias and sudden cardiac death in patients with coronary artery disease. We studied the prevalence of signal-averaged late ventricular potentials in 37 male patients (mean age of 56 years) with angiographically normal coronary arteries. Seventeen patients were hypertensive (group A) and 20 patients were normotensive (group B). In group A, 5 of 17 patients (29%) had late ventricular potentials. In group B, only 1 of 20 patients (5%) had late potentials (p less than 0.05). Late ventricular potentials detected by signal averaging are more common in hypertensive patients than in healthy controls. Whether late ventricular potentials can be used to predict malignant ventricular arrhythmias or sudden cardiac death in hypertensive patients will have to be investigated in further studies.

Hemodynamic effects of nebivolol at rest and on exertion in patients with heart failure.

Nebivolol is a novel B-1-adrenoceptor-blocking drug with an unusual hemodynamic profile unlike classical B-blockers. In dogs and in healthy volunteers it decreases blood pressure and heart rate but improves left ventricular function. The authors studied 10 male patients with coronary artery disease and heart failure (ejection fraction mean = 46%). A Swan-Ganz catheter was placed into the pulmonary artery, and the mean blood pressure, the heart rate, the pulmonary artery pressure, the pulmonary wedge pressure, the right atrial pressure, the cardiac output, and the stroke volume were measured at rest and on exertion before and after seven days' treatment with oral nebivolol (5 mg/day). While the blood pressure and the heart rate decreased significantly, the pulmonary artery and wedge pressures, as well as the right atrial pressure and the cardiac output, did not change during treatment. The stroke volume increased significantly. The maintained cardiac output cannot be explained by any changes in preload or afterload; instead a positive inotropic mechanism must be assumed. Unlike other B-blockers it seems to be possible to treat patients with heart failure with nebivolol without causing the hemodynamic situation to deteriorate.

[Coronary angioplasty with the implantation of a vascular support (stent)]. / Koronare Angioplastie mit Implantation einer Gefässstütze (Stent).

Coronary angiography in a 55-year-old man with coronary heart disease and typical physical activity-induced angina revealed a subtotal stenosis in the middle third of the right coronary artery while left ventricular function was normal. Percutaneous transluminal coronary angioplasty (PTCA) was performed in January 1989, achieving a residual stenosis of less than 50%. However, restenosis of more than 90% developed within six months, necessitating another PTCA, followed immediately by implantation of a metal (Palmaz-Schatz) stent in the stenotic area. No stenosis was demonstrable afterwards. Maintenance medication with anticoagulants (phenprocoumon) and platelet-function inhibitors (aspirin and dipyridamole) was instituted and repeat angiography three months later demonstrated good dilatation results without any restenosis.

[Ventricular arrhythmia and late potentials in patients with hypertrophic cardiomyopathy]. / Ventrikuläre Rhythmusstörungen und Spätpotentiale bei Patienten mit hypertropher Kardiomyopathie.

Holter monitoring (48 h) and registration of signal-averaged late potentials (method of Simson, high pass filter 40 Hz) were performed in outpatiens with hypertrophic cardiomyopathy. A prevalence of spontaneous ventricular arrhythmias could be determined in 51 patients; the results of 45 patients not taking antiarrhythmic drugs are presented here. 96% of these showed ventricular premature beats, 76% had multiform extrasystoles, 27% showed pairs of ectopic beats and 20% had runs of ventricular tachycardia (more than 3 QRS complexes). Absolute counts of premature beats were low in most patients, but important interindividual differences could be observed: M = 34 extrasystoles/24 h (0-4943). Ventricular tachycardias were of short duration (maximum 11 QRS) with heart rate ranging from 120 to 200/min. All patients were asymptomatic during tachycardia. Signal-averaged late potentials could be registered in 30 patients, 28 of them without antiarrhythmic drug therapy. Mean QRS duration (QRSdur) was 108 +/- 12 ms, mean duration of low amplitude signals (less than 40 microV) in the terminal portion of the QRS (LAdur) was 27 +/- 13 ms, and mean amplitude of the last 40 ms of the filtered QRS (LAamp) was 65 +/- 43 microV. A patient was considered to show late potentials if two of the following criteria were present: QRSdur greater than 120 ms, LAdur greater than or equal to 40 ms, LAamp less than 20 microV. This was found in four patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of long-term treatment with ketanserin on blood pressure, pulmonary artery pressure, and cardiac output in patients with heart failure.

Ketanserin is a selective serotonin2-receptor blocker and by this mechanism decreases peripheral resistance and blood pressure in hypertensives. We examined the hemodynamic effects of ketanserin during long-term treatment in patients with heart failure. Five male patients with coronary artery disease and heart failure (NYHA classes II-III) were treated with ketanserin (80 mg daily) for 12 months. Before treatment, after 4 weeks, and after 12 months treatment, a Swan-Ganz catheter was placed into the pulmonary artery and pulmonary wedge pressure, cardiac output, mean arterial pressure, and heart rate were measured at rest and on exertion. The pulmonary wedge pressure at rest decreased from 8 mmHg before to 6 mmHg after 4 weeks and 12 months treatment; on exertion, it decreased from 31 mmHg before treatment to 24 mmHg after 4 weeks treatment and to 21 mmHg after 12 months treatment. The mean arterial pressure also decreased at rest and on exertion after 4 weeks treatment as well as after 12 months treatment. Cardiac output increased slightly and heart rate was unaltered. No serious side effects occurred. Ketanserin could become an alternative vasodilator drug in the treatment of patients with heart failure.

Prevention of an early re-occlusion after thrombolytic therapy of acute myocardial infarction by ketanserin.

A problem after successful thrombolytic therapy of acute myocardial infarction is the early occurrence of re-occlusions. An incidence between 10 and 30% is reported. All efforts made so far to reduce the re-occlusion rate using a variety of agents have been disappointing. In a pilot study 20 patients with acute myocardial infarction were treated, in whom a successful lytic therapy with urokinase or rt-PA was documented by means of coronary angiography 90 min after the beginning of treatment. Subsequently the patients were heparinised (thrombin time greater than 30 s), and in addition the selective serotonin-2 receptor-blocking agent ketanserin was given intravenously (4 mg/h). After 24 h the occurrence of early reocclusions was investigated by control angiography. None of the 20 patients showed reocclusions. The degree of stenosis in the infarcted vessel was 72% immediately after lytic therapy, and 68% after 24 h. These preliminary results may suggest a possible reduction in the re-occlusion rate after thrombolytic therapy with a combination of heparin and ketanserin.

Serotonin antagonism in the treatment of cardiac insufficiency.

One approach in the therapy of cardiac insufficiency is the administration of vasodilator substances for afterload reduction. Ketanserin selectively blocks the serotonin-2 receptors and thus inhibits the vasoconstrictor effect of serotonin. A hypotensive action of ketanserin has been documented in several studies. In 10 patients with coronary heart disease and cardiac insufficiency we investigated the haemodynamic effects of ketanserin after 24 h of intravenous administration (4 mg/h) and after 4 weeks of oral therapy (80 mg/day). Five patients received ketanserin for 12 months and were then re-examined. The resting mean arterial pressure dropped from 97.1 to 89.3 mm Hg after intravenous administration (p less than 0.05) and to 89.3 mm Hg after 4 weeks of oral intake (p less than 0.05). The resting mean pulmonary arterial pressure dropped from 15.2 to 12.0 mm Hg after intravenous administration (p less than 0.05) and to 11.7 mm Hg after 4 weeks of oral ingestion (p less than 0.01). Under exercise the pressure dropped from 35.3 to 28.1 mm Hg after intravenous administration (p less than 0.0025) and to 29.9 mm Hg after 4 weeks of oral intake (p less than 0.0025). Heart rate and cardiac output did not show any significant differences. The measured values after 12 months (in 5 patients) did not differ significantly from those measured after 4 weeks. In view of its low side effect liability ketanserin could be used as an afterload-lowering agent in patients with cardiac insufficiency.