Acute improvement of peripheral endothelial function in postmenopausal women with coronary artery disease after single oral intake of 17beta-estradiol valerate.

Chronic estrogen supplementation is known to improve endothelial function in postmenopausal women. We studied the acute effect of a single dose of orally administered 17beta-estradiol valerate (E2) on the peripheral endothelial dependent and independent vasodilatation in postmenopausal women with coronary artery disease (CAD). 20 postmenopausal women (age: 64.9 (7.2) y, height: 1.61 (0.04) m. weight: 68.6 (10.6) kg) with angiographically confirmed CAD were randomly examined for flow-associated vasodilatation (= FAD%, a marker for endothelial dependent vasodilatation) and for glyceryltrinitrate (400 microg, p.o.) induced vasodilatation (= GTN%, representing endothelial independent vasodilatation) two hours after placebo controlled, randomized crossover intake of 4 mg E2 p.o. After placebo FAD% was impaired (3.5 (1.7)%) compared to historic controls. After the oral intake of 4 mg E2, FAD% improved to 5.0 (2.8)% (P=0.02). GTN% was not significantly influenced by the oral E2 (E2: 12.6 (5.7) v placebo: 11.2 (6.9)%, P=0.14). Endothelial dysfunction can partially be restored by a single oral dose of 4 mg E2. This indicates an acute vasoprotective effect of E2 beyond its genomic and lipid modifying actions. It remains to be investigated if estrogen might play a beneficial role in the acute treatment of symptomatic coronary artery disease such as angina pectoris or preinfarct syndrome.

Oxidizability of low density lipoprotein and total antioxidative capacity of plasma are differently altered during induction and regression of hypercholesterolemia in rabbits.

Oxidizability of isolated low density lipoprotein (LDL) and total antioxidative capacity of plasma were measured in rabbits fed for 6 weeks a cholesterol-rich diet and for further 34 weeks a normal diet. Whereas the time to induce copper ion-mediated lipid peroxidation in LDL was prolonged during hypercholesterolemia, total antioxidative capacity as determined by a radical-trapping assay was increased at 6 weeks, but decreased during the time when the plasma cholesterol levels declined slowly to normal. Since aortic plaque progression was continued also during the first 15 weeks of normal diet, increased atherogenicity of hypercholesterolemia might be better reflected by the antioxidant capacity of plasma rather than by oxidation of isolated LDL.

Gender-specific differences in the effects of testosterone and estrogen on the development of atherosclerosis in rabbits.

The aim of the present study was to investigate whether there are gender-specific differences in the effects of testosterone and estrogen on the process of atherogenesis. Thirty-two castrated male and 32 ovariectomized female rabbits were separated into 4 study groups of 8 males and 8 females each and received postoperatively a 0.5% cholesterol diet for 12 weeks. During this period either no hormones, estradiol (1 mg/kg body wt/week), testosterone (25 mg/kg body wt/week IMM), or estrogen combined with testosterone in above dosages were administered. Computerized morphometric analysis of the intimal thickening in the proximal aortic arch showed a significant inhibitory effect of estrogen in female and of testosterone in male animals (P < .05). In the group with combined treatment, the plaque size in both sexes was smaller than in the animals of the control group (P < .05). These differences were independent of changes in plasma lipid parameters. The incorporation of 5'-bromo-2'-deoxyuridine, associated with cell proliferation, into cells of the neointima was not significantly affected by the different hormone application regimens in males. In females, the incorporation rate was significantly lowered in the estrogen treated group compared with the control group (P < .05). Due to the observed differences in the sex specific atheroprotective effects of testosterone and estrogen, these data suggest that complex hormone interactions, which are independent of changes in plasma lipids, may play an important role in the process of atherogenesis.

Estradiol concentrations in premenopausal women with coronary heart disease.

BACKGROUND: Because of the beneficial effects of estrogen, premenopausal women are normally protected against coronary heart disease (CHD) and are at lower risk for myocardial infarction; consequently, CHD occurs very rarely in menstrually active women. Given this background, the aim of the present study was to test the hypothesis that decreased concentrations of estrogen are associated with CHD in premenopausal women. METHODS: Fourteen premenopausal women with CHD were investigated and compared with a healthy control group comparable for age and cardiovascular risk factors. Relevant characteristics of patients and controls were assessed: age, blood pressure, body mass index, total cholesterol and high-density lipoprotein cholesterol, triglycerides, former pregnancies, ovariectomy and related surgical interventions, smoking history and former use of oral contraceptives. To ensure the premenopausal status of the participants, the regularity of the menstrual cycle and the follicle-stimulating hormone concentrations were also assessed. Plasma estradiol and progesterone and urine estrone concentrations (24 h urine collection) were measured at day 6 after estimated ovulation to assess the relative increase in plasma estradiol and progesterone during the second half of the menstrual cycle. RESULTS: Compared with the control group, premenopausal women with CHD had significantly lower concentrations of plasma estradiol (408.9 +/- 141 pmol/l and 287.8 +/- 109 pmol/l respectively; P = 0.0228) and total estrogen (2061 +/- 693 pg/mumol creatinine and 1607 +/- 448 pg/mumol creatinine respectively; P = 0.025) in the urine. However, the progesterone concentrations were not significantly different between the groups. These findings might be explained by a partial ovarian dysfunction, as the patient group had a significantly higher number of tubal sterilizations (eight compared with one). CONCLUSION: Our data provide support for the hypothesis that decreased concentrations of estradiol might be an additional pathogenetic factor for the development of CHD in menstrually active premenopausal women.

Bone mineral density in premenopausal women with oestrogen deficiency and symptomatic coronary heart disease.

Serum oestrogen deficiency is one of the main causes of osteoporosis in post-menopausal women. In premenopausal women, oestrogen deficiency is rare. In 13 premenopausal women with symptomatic coronary heart disease (CHD) and significantly reduced serum oestrogen levels, bone mineral density, determined by quantitative computed tomography (QCT), was not reduce. In these women, oestrogen deficiency was probably one risk factor for the development of CHD. The level of serum oestrogen that protects women from the development of CHD might be different from the level that protects them from early loss of bone mineral density. Seven of the 13 women had a history of tubal sterilisation. This might be a possible risk factor, causing ovarial dysfunction and oestrogen deficiency.

Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits. Quantification of cellular proliferation by bromodeoxyuridine.

BACKGROUND: The aim of the present study was to compare the effect of estrogen and progesterone on the development of experimental atherosclerosis in female versus male rabbits to assess possible sex-specific differences. METHODS AND RESULTS: A total of 32 female and 32 male New Zealand White rabbits were ovariectomized or castrated. In addition to a 0.5% cholesterol diet, the rabbits received estradiol alone (1 mg/kg body wt [BW] per week), progesterone alone (25 mg/kg BW per week), or combined estradiol-progesterone in these dosages during 12 weeks. Ovariectomized female and castrated male rabbits served as control groups without hormone treatment. Before excision of the vessels, bromodeoxyuridine labeling was performed to determine the extent of cellular proliferation in the atherosclerotic lesions. The aortic arch was analyzed immunohistologically and morphometrically. An inhibitory effect of estrogen on intimal plaque size was found in female rabbits compared with the ovariectomized control group (0.7 +/- 0.5 versus 3.7 +/- 2.5 mm2, P < .002; proliferating cells, 3.1 +/- 1.8% versus 8.5 +/- 2.6%, P < .002). In combination with progesterone, however, estrogen was not able to reduce intimal plaque size or cellular proliferation. In contrast, estradiol in castrated male rabbits was not associated with an inhibitory effect on cellular proliferation or intimal thickening compared with controls (estrogen treatment, 7.6 +/- 2.1% proliferating cells and 2.8 +/- 1.0 mm2 neointima; control group, 7.2 +/- 2.1% cellular proliferation and 2.9 +/- 1.2 mm2 intimal thickening). CONCLUSIONS: Our data suggest that the atheroprotective effect of estrogen is probably due to a mechanism that is present in female rabbits only.

Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis.

The aim of the present study was to determine the effect of progesterone on the action of estrogen in the development of atherosclerosis. A total of 48 female New Zealand white (NZW) rabbits were ovariectomized. The animals were separated into 6 groups of 8 animals each and received subsequently a 0.5% cholesterol diet for 12 weeks. During this cholesterol feeding period, either estradiol (1 mg/kg body weight (BW)/week), progesterone (25 mg/kg BW/week), or combined estradiol/progesterone (in above dosages) was administered intramuscularly in each group (n = 8 each) of ovariectomized rabbits. One additional group of 8 animals received a combined estrogen/ progesterone regimen, but with progesterone at one third of the above mentioned dosage. In another 8 rabbits, progesterone was reduced to one ninth of the maximum dosage above, whereas estrogen was kept the same, at 1 mg/kg BW/week. Eight ovariectomized animals served as the control group and received no hormone treatment. After 12 weeks, the animals were sacrificed and the proximal aortic arch was removed for further histological examination. An inhibitory effect of estrogen of intimal thickening was found, in comparison to the control group (intimal area: 0.7 +/- 0.5 mm2 vs. 3.7 +/- 2.5 mm2, P < 0.01), whereas progesterone alone did not show a significant effect on intimal plaque size (intimal area: 4.0 +/- 2.3 mm2). In combination with progesterone (high dose), estrogen was not able to reduce intimal atherosclerosis (intimal area: 3.4 +/- 2.4 mm2). However, the beneficial effect of estrogen was not affected by progesterone, when this was reduced respectively to one third (intimal area: 0.8 +/- 0.7 mm2), or to one ninth of the highest dosage (intimal area: 0.6 +/- 0.4 mm2). Interestingly, these differences in atherosclerotic plaque development were observed without significant changes in plasma cholesterol concentrations by the administered hormones. In conclusion, progesterone was dose-dependently able to completely inhibit the beneficial effect of estrogen in experimental atherosclerosis, suggesting that progesterone exerts a direct inhibitory effect on the athero-protective action of estrogen. In the context of recently published data, the present work confirms the importance of the 'non-lipid-mediated', anti-atherosclerotic effect of estrogen, probably due to an interaction with six hormone receptors in vascular smooth muscle cells (VSMC).

[Does estradiol modify the NO/cGMP system of blood vessels? Studies of the mechanism of cardiovascular protection by estrogen substitution in the postmenopausal period]. / Beeinflusst Ostradiol das NO/cGMP-System der Gefässe? Untersuchungen zum Mechanismus der kardiovaskulären Protektion durch Ostrogensubstitution in der Postmenopause.

The effect of estradiol on the vasodilating NO/cGMP-system has been investigated in vitro and in vivo. Measurements of cGMP were carried out, cGMP values reflecting NO production. The incubation of human leg vein homogenates (n = 15) for 15 min. with estradiol in the concentrations 10(-6) M, 10(-7) M and 10(-8) M showed at 10(-8) a slight increase of the cGMP-concentrations. Due to high variation compass the difference to the control value was not statistically significant. The clinical part of the study included postmenopausal women, 20 were treated with transdermal estradiol patches (TTS, 0.05 mg/die) and 20 with estradiolvalerate orally (2 mg/die). There were 3 drop outs, 1 in the transdermal estrogen group, 2 in the oral estrogen group. In both groups there were no considerable differences in urinary cGMP concentrations. Thus, these results didn't clearly indicate an involvement of the NO/cGMP-system in the cardioprotective effect of an estrogen substitution therapy in postmenopausal women. Since former investigations are indicative of complex interactions of different vasoactive systems and of the requirement of longer treatment periods for an action of estradiol, an effect on the NO/cGMP-system cannot be ruled out.

Atrial vulnerability and electrophysiology determined in patients with and without paroxysmal atrial fibrillation.

For elucidation of atrial electrophysiology and vulnerability an electrophysiological study was performed in 45 patients with documented paroxysmal atrial fibrillation and a control group (n = 46). Atrial vulnerability was assessed by programmed atrial stimulation with up to two extrastimuli during sinus rhythm and paced cycle lengths of 600 msec, 430 msec and 330 msec. Sustained atrial fibrillation or flutter was induced in 37/45 patients with paroxysmal atrial fibrillation in contrast to 9/46 patients in the control group (P less than 0.001). Left atrial diameter (M-mode echocardiogram), P wave duration, sinus cycle length, sinus node recovery time, and the effective refractory period of the right atrium were not significantly different between the two study groups. Intraatrial conduction time from the high right atrium (HRA) to the basal right atrium (A) and the functional refractory period of the right atrium were significantly longer in patients with paroxysmal atrial fibrillation.

AV nodal reentrant tachycardia using three different AV nodal pathways.

In a patient with frequent paroxysmal supraventricular tachycardia, an electrophysiologic study was performed. Although by programmed atrial stimulation only double AV nodal pathways could be documented, three distinct forms of AV nodal reentrant tachycardia could be induced. By programmed atrial stimulation a typical AV nodal reentrant tachycardia was initiated, by programmed ventricular stimulation, an AV nodal reentrant tachycardia was induced with an antegrade conduction time of 215 ms and a retrograde conduction time of 160 ms. Furthermore, a third form of tachycardia was induced with alternating cycle length due to two different antegrade conduction times, whereas retrograde conduction time was almost identical, irrespective of the antegrade conduction time. The patient received betaxolol (20 mg day-1); during a second electrophysiologic study, the tachycardia could not be induced, and it did not occur spontaneously during a follow-up period of 14 months.

[Electrophysiologic effects of the calcium antagonist isradipine, a double-blind placebo controlled study]. / Elektrophysiologische Effekte des Kalziumantagonisten Isradipin, eine doppelblinde placebokontrollierte Studie.

The electrophysiologic effects of the calcium channel antagonist isradipine (0.5 mg) in comparison to placebo were evaluated in a double blind study with nine patients in two groups. The patient groups were not different in respect to the underlying cardiac disease, electrophysiologic parameters at the baseline study, or in blood pressure. Isradipine significantly decreased the systolic (p less than 0.01) and diastolic (p less than 0.05) blood pressure, while sinus cycle length decreased significantly (p less than 0.05) in the placebo group and the isradipine group with no difference between the two study groups. The influence on sinus node recovery time, effective refractory period of the av-node, intranodal conduction time, and PR interval were not significant. In conclusion, isradipine significantly decreased systolic and diastolic blood pressure. The decrease in sinus cycle length after intravenous isradipine was not significantly different from the decrease seen in the placebo group. Atrioventricular conduction was not significantly affected.

Electrophysiologic effects and efficacy of cibenzoline on stimulation-induced atrial fibrillation and flutter and implications for treatment of paroxysmal atrial fibrillation.

The effects of intravenous cibenzoline (1.5 mg/kg) on atrial vulnerability and electrophysiology were assessed in 25 patients with documented paroxysmal atrial fibrillation (AF), in whom sustained (greater than 30 seconds) AF was induced by atrial stimulation with up to 2 extrastimuli and paced rates between 100 and 180 beats/min. In 7 patients AF persisted despite the application of cibenzoline, and in 8 patients the induction of sustained AF was prevented by cibenzoline. Intraatrial conduction time, flutter cycle length and shortest ventricular cycle length during AF were increased by cibenzoline (p less than or equal to 0.01). Sinus cycle length was decreased (p less than or equal to 0.05), whereas sinus node recovery time remained unchanged. The effective refractory period of the right atrium was not significantly affected. Eight patients with frequent episodes of paroxysmal AF received oral cibenzoline for control of paroxysmal AF irrespective of the efficacy of intravenous cibenzoline. Prevention of stimulation-induced AF predicted successful treatment of paroxysmal AF (p = 0.018). Cibenzoline could be effective in the treatment of atrial arrhythmias, and selection of an antiarrhythmic therapy for recurrent AF seems to be useful.

Effects of intravenous cibenzoline on ventricular vulnerability and electrophysiology in patients with sustained ventricular tachycardia in comparison to a control group.

The electrophysiologic effects of intravenous (i.v. 1.5 mg/kg) cibenzoline were investigated in 13 patients with organic heart disease and supraventricular arrhythmias (control group) and 13 patients with drug refractory sustained ventricular tachycardia (VT group). In both groups, cibenzoline increased the effective refractory period (ERP) of the right ventricle (p less than or equal to 0.05), QRS duration (p less than or equal to 0.01), and QTc duration (p less than or equal to 0.01). Cycle length of the VT was increased from 311 +/- 73 to 393 +/- 119 ms (p less than or equal to 0.05) as well. The increase in QTc duration was more pronounced (p less than or equal to 0.05) in the VT group as compared with the control group. In four patients in the VT group with the largest increase in QRS-, QTc duration and cycle length of the VT proarrhythmia was noted after i.v. cibenzoline. Cibenzoline plasma levels were not significantly different between the two study groups. In the VT group, induction of VT was prevented in 2 patients, more difficult in 2 patients, easier in 1 patient, and unchanged in 5 patients. Spontaneous occurrence of the VT or induction by atrial stimulation was noted in 4 patients. In the control group, ventricular vulnerability remained unchanged. Cibenzoline may be effective in selected patients with drug refractory VT. In such patients, the increase in QTc duration was more pronounced as compared with a control group.

[Electrophysiologic properties of cibenzoline in Wolff-Parkinson-White syndrome and atrioventricular nodal reentry tachycardia]. / Elektrophysiologische Eigenschaften von Cibenzolin bei WPW-Syndrom und AV-Knoten-Reentry-Tachykardien.

The electrophysiologic effects of the new class-1 antiarrhythmic drug cibenzoline (1.5 mg/kg within 10 min, followed by an infusion of 0.5 mg for 30 min) were investigated in six patients with atrioventricular (av) nodal reentrant tachycardia and nine patients with atrioventricular tachycardia. Sinus cycle length, sinus node recovery time, effective refractory period (ERP) of the atrium and the ventricle as well as the ERP of the av node were not significantly affected by cibenzoline. Retrograde conduction via the av node was prevented by cibenzoline in 6/15 patients, retrograde ERP was increased in 4/15 patients and in 5/15 patients determination of the retrograde ERP of the AV node was impossible. Intranodal conduction time (AH-interval) and infranodal conduction time (HV-interval) was increased from 96 +/- 27 ms to 117 +/- 40 ms (p less than 0.01) and 36 +/- 12 ms to 62 +/- 12 ms (p less than 0.01), respectively. In four patients with antegrade conduction along the accessory pathway no antegrade conduction was seen after the application of cibenzoline. Retrograde ERP of the accessory pathway was increased in two patients, it was unchanged in three patients, and no retrograde conduction along the accessory pathway was seen in four patients. AV nodal reentrant tachycardia was not inducible, after cibenzoline in 4/6 patients and in 5/9 patients with AV reentrant tachycardia. If tachycardia remained inducible, an increase in tachycardia cycle length from 333 +/- 46 ms to 402 +/- 24 ms was observed (p less than 0.01). In conclusion the electrophysiologic effects of cibenzoline make it a suitable drug for the treatment of av nodal reentrant tachycardia and atrioventricular tachycardia.

Comparison of the effects of intravenous and oral betaxolol on antegrade and retrograde conduction in patients with atrioventricular nodal reentrant and atrioventricular reentrant tachycardia.

The electrophysiologic effects of intravenous (0.15 mg kg-1) and oral (20 mg day-1) betaxolol have been investigated in 11 patients with atrioventricular (A-V) nodal reentrant tachycardia and eight patients with orthodromic A-V reentrant tachycardia. Betaxolol significantly (P greater than 0.01) prolonged sinus cycle length, sinus node recovery time, intranodal conduction time, and the antegrade functional refractory period of the A-V node. When the effective refractory period of the A-V node could be determined it was increased by betaxolol, whereas no significant electrophysiologic effects were observed in the atrium, the ventricle or the accessory pathway. Intravenous betaxolol prevented tachycardia in 8 out of 11 patients with A-V nodal reentrant tachycardia, whereas oral betaxolol was effective in 10 patients, primarily by acting on the antegrade limb in two patients and on the retrograde limb in eight patients. In those with A-V reentrant tachycardia, intravenous betaxolol did not prevent tachycardia in any patient, while it was effective after oral treatment in two patients. When the tachycardia remained inducible, cycle length of the tachycardia increased in all patients, due to prolongation of the antegrade and retrograde conduction time in patients with A-V nodal reentrant tachycardia, and due to an increase in the antegrade conduction time, i.e. the A-V node, in the patients with A-V reentrant tachycardia. In conclusion, betaxolol proved to be effective in the treatment of supraventricular tachycardia; for chronic treatment, a single oral dose (20 mg) seems to suffice.

[Flecainide-induced hepatitis]. / Flecainidinduzierte Hepatitis.

Flecainide was given to a patient in a dose of 150 mg twice daily to convert a newly developed atrial fibrillation; concomitant therapy was unchanged. After the fourth dose the patient complained of upper abdominal pain and nausea. GOT and GPT, normal at admission to the hospital, became markedly elevated and reached a maximum of 960 IU/I (GOT) and 993 IU/I (GPT) one day later, although the enzymes which indicate cholestasis remained at a normal level or did not increase. On the assumption of a drug-induced allergic reaction, flecainide was withdrawn, after which liver enzymes rapidly returned to control values. Although neither a reexposition with flecainide nor a liver biopsy was obtained, a flecainide-induced hepatitis seems probable.

[Effect of a new class I anti-arrhythmia agent cibenzoline in patients with therapy refractory, sustained ventricular tachycardias]. / Wirkung des neuen Klasse-I-Antiarrhythmikums Cibenzolin bei Patienten mit therapierefraktären, anhaltenden ventrikulären Tachykardien.

The effectiveness of Cibenzoline was assessed by means of programmed ventricular stimulation in 13 patients with sustained, drug refractory ventricular tachycardia. Besides Cibenzoline, an average of 3.5 antiarrhythmic drugs were tested, or were clinically ineffective. Cibenzoline was applied, i.v., in a dose of 1.5 mg/kg within 10 min. Cycle length was significantly shortened (p less than or equal to 0.05) while increases were noted for effective refractory period of the right ventricle (p less than or equal to 0.05), intranodal (AH-interval) and infranodal (HV-interval) conduction time (p less than or equal to 0.01), QRS-duration (p less than or equal to 0.001), QT-interval corrected for frequency (p less than or equal to 0.001) as well as cycle-length of the tachycardia (p less than or equal to 0.05). After i.v. Cibenzoline, induction of tachycardia was more difficult in two patients and unchanged in five patients. Spontaneous occurrence of the tachycardia was noted in three patients, and in one patient tachycardia was sustained by atrial stimulation. Cibenzoline i.v. prevented tachycardia in two patients respectively induction of tachycardia was not reproducible. It is concluded that Cibenzoline may be effective in individual patients with sustained ventricular tachycardia unresponsive to other antiarrhythmic drugs.

[Electrophysiologic effects of betaxolol on conduction properties of the antegrade and retrograde pathway in patients with typical atrioventricular node reentry tachycardia following intravenous and oral administration]. / Elektrophysiologische Effekte von Betaxolol auf Leitungseigenschaften der antegraden und retrograden Bahn bei Patienten mit typischer AV-Knoten-Reentrytachykardie nach intravenöser und oraler Gabe.

The electrophysiologic effects of the beta-1 selective beta adrenergic blocking drug Betaxolol were investigated after intravenous (0.15 mg/kg body weight) and oral (20 mg/day) administration in 11 patients with atrioventricular-nodal reentrant tachycardia. Betaxolol significantly (p less than 0.01) prolonged cycle length, sinus node recovery time, AH-interval, as well as the antegrade functional refractory period of the slow and fast AV-nodal pathway. The effective refractory period of the fast AV-nodal pathway was also markedly increased (p less than 0.05). In only six patients could the effective refractory period of the slow AV-nodal pathway be determined; in the other patients, it was shorter than the effective refractory period of the atrium. The effective refractory period of the atrium and the ventricle was not significantly altered by Betaxolol. Intravenous administration of Betaxolol suppressed induction of tachycardia in eight patients, whereas after oral Betaxolol, tachycardia was not inducible in ten patients. Betaxolol prevented induction of tachycardia in two patients by prolonging antegrade conduction over the slow AV-nodal pathway. The retrograde fast AV-nodal pathway was blocked in eight patients. Presumably the increased effectiveness of oral Betaxolol can be attributed to higher Betaxolol plasma concentrations, reached after oral treatment (58 +/- 38 ng/ml), as compared to intravenous administration (40 +/- 40 ng/ml). There were no false positive results after intravenous testing of Betaxolol.

[Syncope in the act of swallowing (swallowing syncope)]. / Synkopen beim Schluckakt (sog. Schlucksynkopen).

In a 30-year-old female patient with recurrent syncope during swallowing, intermittent complete AV-block was documented as the underlying mechanism. This phenomenon could be provoked by inflating a balloon positioned in the lower esophagus. The His-bundle electrocardiogram, recorded simultaneously, showed a progressive increase of the normal AH-interval, up to complete block distal to the A-wave. Atropine prevented induction of the block. After implantation of a VVI pacemaker, the symptoms disappeared completely. This very rare phenomenon of swallowing syncope is probably due to a pathologic vago-vagal reflex.

Exercise blood pressure and heart rate reduction 24 and 3 hours after drug intake in hypertensive patients following 4 weeks of treatment with bisoprolol and metoprolol: a randomized multicentre double-blind study (BISOMET).

In a 4-week randomized, double-blind study, 87 patients with essential hypertension received either 10 mg bisoprolol (B) or 100 mg metoprolol (M) once daily (o.d.). The effects of the beta blockers on systolic blood pressure, heart rate and rate-pressure product during exercise, 24 h (E2) and 3 h (E3) after administration (p.a.) were compared with the values obtained in the baseline exercise test (E1). 24 hours p.a. the effects of B were significantly stronger than of M (E1-E2: B vs M; P less than 0.01) whereas 3 h p.a. no significant differences were detectable between B and M. The residual effects 24 h p.a. in relation to the effects 3 h p.a. (E1-E2/E1-E3) were significantly greater with B (86-93%) than with M (53-66%). In contrast to the findings with 100 mg M o.d., 10 mg bisoprolol o.d. guarantees a persistent reduction in exercise blood pressure and heart rate throughout the entire dosage interval of 24 h.