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Biomedical subjects

W Kübler

Publications and source records attributed to W Kübler.

At least 55 records · Page 3Linked to original sources
PubMed2000

Flow cytometric monitoring of glycoprotein IIb/IIIa blockade and platelet function in patients with acute myocardial infarction receiving reteplase, abciximab, and ticlopidine: continuous platelet inhibition by the combination of abciximab and ticlopidine.

BACKGROUND: Improvement of thrombolysis may be achieved by concomitant strong platelet inhibition. To monitor platelet function in patients with myocardial infarction (n=46) who were treated with the fibrinolytic agent reteplase, the glycoprotein (GP) IIb/IIIa blocker abciximab, and the ADP receptor antagonist ticlopidine, we developed a flow cytometric assay. METHODS AND RESULTS: Binding of abciximab to platelets was directly monitored as the percentage of platelets stained by a goat anti-mouse antibody. Blood drawn 10 minutes and 2 hours after the start of therapy with reteplase and abciximab and during the 12-hour infusion of abciximab demonstrated a maximal blockade of GP IIb/IIIa (10 minutes, 86.2+/-10.3%; 12 hours, 85.8+/-7.1%). Starting at 24 hours, abciximab binding gradually decreased (24 hours, 74.6+/-16.2%; 48 hours, 66.8+/-14.9%; 72 hours, 60.5+/-16.7%; 96 hours, 49.4+/-17.8%; 120 hours, 35.8+/-16. 4%; and 144 hours, 29.9+/-15.3%). Binding of a chicken anti-fibrinogen antibody to platelets, indicating the level of functional blockade of GP IIb/IIIa, was inversely correlated with the binding of abciximab (r=-0.72, P:<0.0001). In blood drawn at 10 minutes, platelet aggregation was maximally inhibited but recovered within 48 hours even if the majority of GP IIb/IIIa receptors were still blocked by abciximab. Reteplase did not influence abciximab binding and did not activate platelets, as measured by P-selectin expression, fibrinogen binding, and platelet aggregation. Platelet inhibition that was achieved during the first 24 hours by abciximab was directly maintained by additional treatment with ticlopidine. CONCLUSIONS: Flow cytometric monitoring of platelet function allows differentiation of the effects of reteplase, abciximab, and ticlopidine. The combination of abciximab and ticlopidine is an attractive therapeutic strategy that provides a fast and continuous platelet inhibition.

Abciximab↗
PubMed2000

Myocardial ischemia during physical exercise in patients with stable coronary artery disease: predictability and prevention.

AIMS: We assessed whether exercise-induced myocardial ischemia during intensive group exercise sessions can be predicted in patients with coronary artery disease and stable angina pectoris. METHODS AND RESULTS: Twenty-three patients underwent cardiac catheterization, 201-thallium scintigraphy, and exercise testing prior to participation in group training sessions. Heart rates and myocardial ischemia were documented by Holter monitoring. The individual training heart rate was calculated as a percentage of the maximal heart rate achieved during symptom-limited exercise testing. Myocardial ischemia occurred significantly more often during group exercise sessions (15 of 23 patients) than during treadmill testing (4 of 23 patients, P<0.001). Maximal heart rate (145+/-23 vs. 134+/-21 beats/min, P<0.004) and maximal plasma lactate concentrations (6.0+/-2.9 vs. 4.3+/-2.0 mmol/l, P<0.05) were significantly higher than during symptom-limited exercise testing. Ischemic episodes occurred significantly more often during jogging than during competitive ball games or interval training. Myocardial ischemia occurred in patients who exceeded their individual target training heart rates (43 of 44 episodes; P<0.001). Duration of ischemic episodes did not correlate with any marker obtained at the beginning of the study. CONCLUSION: These data demonstrate that routine diagnostic procedures do not sufficiently identify patients at risk for exercise-induced myocardial ischemia. Ischemic events are only effectively prevented by choosing adequate types of exercise and, above all, by the strict adherence to individual target heart rates.

Coronary Angiography↗
PubMed2000

Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene.

BACKGROUND: Familial primary pulmonary hypertension (PPH) is an autosomal-dominant inherited disease with incomplete penetrance and poor prognosis. This study was performed to examine whether asymptomatic carriers of a mutated PPH gene can be identified at an early stage by their pulmonary artery systolic pressure (PASP) response to exercise. METHODS AND RESULTS: Stress Doppler echocardiography during supine bicycle exercise and genetic linkage analysis were performed on 52 members of 2 families with PPH. In 4 PPH patients, the mean PASP was increased at rest (73+/-16 mm Hg). Fourteen additional family members with normal PASP at rest revealed an abnormal PASP response to exercise (from 23+/-4 to 56+/-11 mm Hg) without secondary cause (abnormal response [AR] group). Twenty-seven other members (NR group) revealed a normal PASP response (maximal pressure <40 mm Hg) to exercise (from 24+/-4 to 37+/-3 mm Hg, P<0. 0001). All 14 AR but only 2 NR members shared the risk haplotype with the PPH patients. The molecular genetic analysis supported linkage to chromosome 2q31-32 with a logarithm of the odds score of 4.4 when the 4 patients and the 14 AR members were classified as affected. CONCLUSIONS: We conclude that the pathological rise of PASP in asymptomatic family members is linked to chromosome 2q31-32 and is probably an early sign of PPH. Therefore, stress Doppler echocardiography may be a useful tool to identify persons at risk for PPH even before pulmonary artery pressures at rest are elevated.

Adolescent↗
PubMed2000

Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema.

OBJECTIVE: This prospective single-blinded study was performed to quantitate noninvasive pulmonary artery systolic pressure (PASP) responses to prolonged acute hypoxia and normoxic exercise. BACKGROUND: Hypoxia-induced excessive rise in pulmonary artery pressure is a key factor in high-altitude pulmonary edema (HAPE). We hypothesized that subjects susceptible to HAPE (HAPE-S) have increased pulmonary artery pressure response not only to hypoxia but also to exercise. METHODS: PASP was estimated at 45, 90 and 240 min of hypoxia (FiO2 = 12%) and during supine bicycle exercise in normoxia using Doppler-echocardiography in nine HAPE-S and in 11 control subjects. RESULTS: In the control group, mean PASP increased from 26+/-2 to 37+/-4 mm Hg (deltaPASP 10.3+/-2 mm Hg) after 90 min of hypoxia and from 27+/-4 to 36+/-3 mm Hg (deltaPASP 8+/-2 mm Hg) during exercise. In contrast, all HAPE-S subjects revealed significantly greater increases (p = 0.002 vs. controls) in mean PASP both during hypoxia (from 28+/-4 to 57+/-10 mm Hg, deltaPASP 28.7+/-6 mm Hg) and during exercise (from 28+/-4 to 55+/-11 mm Hg, deltaPASP 27+/-8 mm Hg) than did control subjects. Stress echocardiography allowed discrimination between groups without overlap using a cut off PASP value of 45 mm Hg at work rates less than 150 W. CONCLUSIONS: These data indicate that HAPE-S subjects may have abnormal pulmonary vascular responses not only to hypoxia but also to supine bicycle exercise under normoxic conditions. Thus, Doppler echocardiography during supine bicycle exercise or after 90 min of hypoxia may be useful noninvasive screening methods to identify subjects susceptible to HAPE.

Adult↗
PubMed2000

Construction and functional evaluation of a single-chain antibody fusion protein with fibrin targeting and thrombin inhibition after activation by factor Xa.

BACKGROUND: Recombinant technology was used to produce a new anticoagulant that is preferentially localized and active at the site of the clot. METHODS AND RESULTS: The variable regions of the heavy and light chains of a fibrin-specific antibody were amplified by polymerase chain reaction (PCR) with hybridoma cDNA. To obtain a functional single-chain antibody (scFv), a linker region consisting of (Gly(4)Ser)(3) was introduced by overlap PCR. After the scFv clones were ligated with DNA encoding the pIII protein of the M13 phage, high-affinity clones were selected by 10 rounds of panning on the Bbeta15-22 peptide of fibrin (beta-peptide). Hirudin was genetically fused to the C-terminus of the variable region of the light chain. To release the functionally essential N-terminus of hirudin at the site of a blood clot, a factor Xa recognition site was introduced between scFv(59D8) and hirudin. The fusion protein was characterized by its size on SDS-PAGE (36 kDa), by Western blotting, by its cleavage into a 29-kDa (single chain alone) and 7-kDa (hirudin) fragment, by its binding to beta-peptide, and by thrombin inhibition after Xa cleavage. Finally, the fusion protein inhibited appositional growth of whole blood clots in vitro more efficiently than native hirudin. CONCLUSIONS: A fusion protein was constructed that binds to a fibrin-specific epitope and inhibits thrombin after its activation by factor Xa. This recombinant anticoagulant effectively inhibits appositional clot growth in vitro. Its efficient and fast production at low cost should facilitate a large-scale evaluation to determine whether an effective localized antithrombin activity can be achieved without systemic bleeding complications.

Amino Acid Sequence↗
PubMed2000

Serum leptin levels and body weight in postmenopausal women under transdermal hormone replacement therapy.

Leptin, the adipocyte-specific product of the ob gene, is implicated in body weight regulation and energy balance. We investigated the influence of hormone replacement therapy (HRT) on the body mass index (BMI) and serum leptin levels in 20 postmenopausal, nonobese women treated with transdermal HRT (delivery rate 50 microg 17beta-estradiol/24 h, 1 patch per week) for 6 months. Serum leptin levels were measured by ELISA and results were compared by means of the Student's paired t-test or Pearson's correlation. The mean patient age was 55+/-6.04 years. The mean body weight prior to the start of the study was 69.39+/-9.37 kg, and the BMI before HRT was 26.92+/-4.47 kg/m2. Both parameters remained unchanged under therapy. No significant change in absolute serum leptin values (18.8+/-8.4 ng/ml; 20.47+/-9.7 ng/ml; 17.92+/-8.7 ng/ml at 0, 4 and 6 months respectively) or in adiposity-corrected values (serum leptin/BMI) (0.68+/-0.24; 0.75+/-0.29; 0.67+/-0.26 at 0, 4 and 6 months respectively) were found. Serum leptin levels correlated well with BMI (r = 0.7193, p<0.0001). There was no significant correlation of estradiol with serum leptin levels before or during therapy. In summary, low dose, transdermal HRT exhibited no influence on serum leptin levels or BMI in postmenopausal women. These data suggest that low dose HRT does not influence body weight regulation in postmenopausal women.

Administration, Cutaneous↗
PubMed2000

[The 6 minute walking test: a cost-effective alternative to spiro-ergometry in patients with chronic heart failure?].

In contrast to the often debated NYHA classification, the determination of peak oxygen uptake (peak VO2) by cardiopulmonary exercise testing allows an objective assessment of the exercise capacity of patients with congestive heart failure (CHF). However, cardiopulmonary exercise testing is a time consuming and costly diagnostic tool, which requires sophisticated equipment and specially trained personel. Exercise capacity can also be determined by the 6 minute walk test. This test simply measures the distance covered by strong walking on a hallway level within 6 minutes. The 6 minute walk test is a submaximal exercise test, which is associated with much smaller increments in heart rate, blood pressure and plasma catecholamines than cardiopulmonary exercise testing. It is characterized by a very small intraindividual variance. Furthermore, it can be easily performed and, due to low logistic and personal requirements, it is very cost effective. The results of the 6 minute walk test--as well as of cardiopulmonary exercise testing--are influenced by extracardial exercise-limiting disorders, such as pulmonary diseases. Independent from the etiology of CHF, the results of the 6 minute walk test are closely related to peak VO2. In serial exercise testing the distance covered within 6 minutes allow to predict the individual peak VO2. Like peak VO2 the 6 minute walk test has been shown to be a predictor of morbidity and mortality in CHF, with its predictive value being independent from left ventricular ejection fraction and other potential prognostic parameters. In CHF patients a walking distance < 300 m is associated with a one-year-mortality of up to 50%, whereas the one-year-mortality in patients reaching a walking distance > 450 m amounts to only a few percent. In addition, the hospitalization rate of patients reaching a walking distance of < 300 m is several fold higher than in those with a walking distance > or = 450 m. Like cardiopulmonary exercise testing, the 6 minute walk test allows to control the efficiency of specific treatments and to monitor the natural course of the disease. The 6 minute walk test is, thus, a cost effective alternative to cardiopulmonary exercise testing in CHF patients. However, neither the 6 minute walk test alone nor the results of cardiopulmonary exercise testing alone are sufficient for selecting patients, e.g., for cardiac transplantation, as each individual case requires a synopsis of all relevant facts and parameters.

Cardiomyopathy, Dilated↗
PubMed2000

Medical progress and rationing of cardiological services.

Due to the financial restrictions imposed on all national health services, the problem of allocating medical resources has gained new economical and political dimensions. Although each patient expects optimal treatment, the rationing of medical services make it increasingly difficult to provide the most adequate therapy. Health politicians and medical doctors have all advocated that health expenditures can be reduced by effective prevention of coronary heart disease, one of the main cost factors for all health services. Due to the introduction of statins, primary and secondary prevention of coronary heart disease can now be accomplished effectively. However, such treatment does not induce cost reduction, but rather an increase in costs. This applies predominantly to primary prevention. Treatment of all who would benefit from lipid lowering by statins would be prohibitively expensive for all national health care systems.

Anticholesteremic Agents↗
PubMed2000

[Evaluation of syncope in geriatric patients: normal values, complications and outcome of invasive electrophysiological study].

Invasive electrophysiologic study (EPS) is an important tool in the assessment of patients with unexplained syncope. Especially in the elderly, the need for a complete diagnostic work-up is counterbalanced by the fear of complications associated with invasive procedures. Thus, the present study specifically addressed the question whether the risk/benefit ratio of EPS in geriatric patients with unexplained syncope justifies this invasive procedure. An invasive EPS was performed in 96 patients between 70 and 80 years and 21 patients older than 80 years. The control group consisted of 65 patients younger than 40 years. With increasing age, the diagnostic yield of EPS also increased (positive EPS finding in 20% of the control group and in 54% of the oldest patients). The majority of complications were of minor clinical significance and no significant differences were found between the three groups. Finally, no age-related difference in measured standard electrophysiological parameters was evident. Due to the high diagnostic value and the low complication rate, EPS can be recommended in elderly patients with unexplained syncope. An age-specific standardization of electrophysiologic parameters, measured during EPS, does not seem to be required.

Aged↗
PubMed2000

[Fibrinolytic therapy in thrombosis of a mitral valve prosthesis].

A 48-year-old woman presented with progressive dyspnea due to thrombosis of a mitral valve prosthesis. The patient had undergone mitral valve replacement (St. Jude Medical) six years prior to admission because of mitral stenosis (Class III); three years later the prosthesis had to be replaced (St. Jude Medical) because of valve thrombosis. At admission, transesophageal echocardiography showed a thrombus on the atrial side of the fixed valve leaflet and a thrombus (2.4 x 1.6 cm) floating from the left atrial roof. Because of the previous thoracotomies, thrombolysis was initiated despite the mobile thrombus with the attendant risk of embolization. Urokinase was infused in a dose to maintain the fibrinogen level around 100 mg/dl. After 24 h, the mean pressure gradient across the prosthetic mitral valve (measured by doppler echocardiography) had decreased from 23 to 11 mmHg. After 13 days of this modified thrombolytic regimen, the clinical symptoms of the patient had resolved and echocardiography showed a normal function of the prosthetic mitral valve without evidence of residual thrombosis. This patient demonstrates that prolonged cautious thrombolysis can be effective for the treatment of prosthetic valve thrombosis in hemodynamically moderately compromised patients.

Echocardiography, Doppler↗
PubMed2000

Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells.

The potent vasoconstrictor peptide endothelin-1 (ET-1) has been implicated in the pathophysiology of atherosclerosis and its complications. Since inflammation of the vessel wall is a hallmark of atherosclerosis, the purpose of the present study was to investigate the influence of ET-1 on cytokine production in human vascular smooth muscle cells (SMC) as a marker of inflammatory cell activation. ET-1 (100 pM - 1 microM) stimulated interleukin-6 (IL-6) secretion from human vascular SMC in a concentration-dependent manner. The ET-A-receptor antagonist BQ-123 (10 microM), but not the ET-B-receptor antagonist BQ-788, inhibited IL-6 release. ET-1 also transiently increased IL-6 mRNA compatible with regulation of IL-6 release at the pretranslational level. Electrophoretic mobility shift assays demonstrated time- and concentration-dependent activation of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in ET-1-stimulated human vascular SMC. A decoy oligodeoxynucleotide bearing the NF-kappaB binding site inhibited ET-1-stimulated IL-6 release to a great extent suggesting that this transcription factor plays a key role for cytokine production elicited by ET-1. Moreover, the antioxidant pyrrolidine dithiocarbamate (10 microM) inhibited ET-1-induced IL-6 release indicating involvement of reactive oxygen species in ET-1 signaling. ET-1-stimulated IL-6 secretion was also suppressed by diphenylene iodonium (40 microM), an inhibitor of flavon-containing enzymes such as NADH/NADPH oxidase. The results demonstrate the ability of ET-1 to induce an inflammatory response in human vascular SMC. These observations may contribute to a better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.

Antioxidants↗
PubMed2000

Cardiac alpha-actin in smooth muscle cells: detection in umbilical cord vessels and in atherosclerotic lesions.

Phenotypic modulation of smooth muscle cells (SMC) is a key event during the development of atherosclerotic and restenotic lesions. During this process, the composition of the cytoskeleton is substantially altered, with changes predominantly in actin expression reflecting a shift from smooth muscle alpha-actin to the non-muscle beta-isoform. We now demonstrate that yet another actin isoform, cardiac alpha-actin, is synthesized, de novo, in SMC of various atherosclerotic lesions. Using a highly specific monoclonal antibody against cardiac alpha-actin, we analyzed and compared the accumulation of this actin isoform in diverse SMC by immunofluorescence microscopy and immunoblotting. As expected, cardiac alpha-actin was present in human myocardium but not in healthy SMC of adult aorta, coronary arteries, trabeculae of the spleen, colon, stomach or skeletal muscle. Interestingly, the presence of cardiac alpha-actin was detected in umbilical cord vessels, human myometrium, in atherosclerotic coronary lesions and atherosclerotic lesions from peripheral vascular disease. The distribution of cardiac alpha-actin often paralleled that of cytokeratins 8 and 18, intermediate filament proteins typically found in dedifferentiated SMC. Taken together, the data presented here illustrate the expression of cardiac alpha-actin to be limited to either fetal vessels or those vessels or tissue having suffered damage or atrophy, outside its 'native' environment in the heart. The demonstration of cardiac alpha-actin in SMC of umbilical cord vessels and in atherosclerotic lesions but not in apparently healthy vessels supports the notion that SMC in atherosclerotic lesions exhibit a dedifferentiated phenotype.

Actins↗
PubMed2000

Cesium chloride induced ventricular arrhythmias in dogs: three-dimensional activation patterns and their relation to the cesium dose applied.

INTRODUCTION: Cesium chloride has widely been used in experimental models to produce various ventricular arrhythmias. The study was designed to evaluate whether type and mechanism of these arrhythmias are dose-dependent. METHODS: In 7 dogs with acute AV-block, 60 pins containing 4 bipolar electrodes each were inserted into both ventricles to provide 240 endo-, epi- and midmyocardial recording sites. A computerized mapping system was used to determine three-dimensional activation patterns of ventricular arrhythmias induced by three injections of 1 mmol/kg cesium chloride at 20 minute intervals. RESULTS: Out of all arrhythmias induced, 25 ventricular extrasystoles, 31 monomorphic and 47 polymorphic ventricular tachycardias were mapped. Nonsustained ventricular tachycardias were readily inducible by a single bolus of cesium chloride, whereas sustained episodes required repetitive injections (1.45 +/- 0.61 vs. 2.61 +/- 0.57 doses, p < 0.05). Polymorphic tachycardias were observed more commonly than monomorphic tachycardias (87 vs. 31). Initiation and maintenance of cesium induced arrhythmias were exclusively based on focal mechanisms originating from the subendocardium, irrespective of morphology and dosage. All monomorphic arrhythmias were caused by repetitive firing of single immobile foci located in either the right or the left ventricle. Bi- and multifocal mechanisms, however, were found to underlie the polymorphic episodes. CONCLUSIONS: Although there is a dose-dependence as to the sustenance of mono- or polymorphic tachycardias, this does not reflect on the three-dimensional activation pattern of cesium induced arrhythmias, which are due to mono- or multifocal activation originating from the subendocardium.

Animals↗
PubMed2000

Influence of intercellular junctions on endothelin secretion of human umbilical vein endothelial cells in vitro.

The endothelium plays a pivotal role in the rheological regulation of blood flow by the secretion of vasoactive factors. The interaction between shear forces and the endothelium is determined by the mechanical properties of the endothelial cell layer which are associated with intercellular junctions. Cell-cell contacts could therefore modulate the secretion of vasocative factors in response to rheological stimuli. We investigated the relationship between intercellular junctions and the secretion of the vasoconstrictor peptide endothelin and the coagulation co-factor von Willebrand factor (vWF). Human umbilical vein endothelial cells (HUVECs) were used as in vitro endothelial model system. Intercellular junctions were reversibly disrupted by calcium chelation or hypertonic stress; alternatively, the formation of intercellular junctions was inhibited by culturing the cells in suspension or by plating them in the presence of an inhibitory anti-VE-cadherin antibody. The opening of intercellular junctions was verified by assessing transmonolayer electrical resistance (TMR) and immunofluorescence morphology. The concentration of endothelin and vWF was measured in the cell culture supernatants using specific ELISAs. The secretion of endothelin was inhibited by EGTA (5 mM) and stimulated by incubation with tumor necrosis factor alpha (TNFalpha, 40 ng/ml). Treatment with hypertonic medium (glycerol, 1,200 mosmol/l) for 10 minutes opened intercellular junctions and markedly reduced the secretion of endothelin. HUVECs in suspension culture did not secrete endothelin and failed to respond to TNFalpha, but readily resumed these functions upon forming a new monolayer on plastic. The reconstitution of intercellular junctions after suspension culture could be inhibited using a specific anti-VE-cadherin antibody. This antibody, but not a non-specific anti-human-IgG antibody reduced endothelin secretion. The secretion of von Willebrand Factor was less dependent on intercellular junctions. The opening of intercellular junctions did not induce cell death, since the cells continued to exclude trypan blue. The results of this study suggest a novel and potentially pathophysiologically/clinically relevant correlation between intercellular junctions and the secretion of endothelin in endothelial cells.

Cadherins↗
PubMed2000

Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure.

The extent and time-course of changes in lung volumes, ventilatory efficiency at rest and during exercise, and respiratory muscle function and their influence on exercise limitation in congestive heart failure (CHF) are unclear. It is unknown whether respiratory muscle function may predict changes in exercise limitation or may be impaired in patients with poor outcome. 145 male patients (54 +/- 1 years) suffering from CHF (NYHA class I-III, mean 2.3 +/- 0.1), with a LVEF of 23 +/- 1%, and a mean peak O2 uptake (VO2peak) 15.0 +/- 0.5 mL X min(-1) X kg(-1), were studied. They were grouped in Weber functional classes A to D according to their VO2peak. Significant increases in ventilatory equivalents for O2 and CO2 (VE/VCO2peak) and in dead space ventilation at rest and during exercise were found with increasing exercise limitation. Moreover, there was a correlation of static and dynamic lung volumes (inspiratory vital capacity, IVC, r = 0.43, P < 0.01), as well as of maximal inspiratory pressure (MIP; r = 0.46, P < 0.01) with VO2peak. Patients who died (n = 26) or were heart transplanted (n = 20) during a follow-up (mean 800 +/- 10 days) had a reduced MIP (6.4 +/- 0.4 kPa) as compared with survivors (n = 82; 9.3 +/- 0.7 kPa, P < 0.01). In a subgroup of 33 patients re-evaluated after six months, individual changes in IVC and VE/CO2peak, but not in MIP, correlated to changes in VO2peak (r = 0.69 and r = 0.72 respectively; P < 0.01). In CHF, exercise limitation is associated with reversible lung restriction and inefficient ventilation at rest and during exercise. Patients with severe CHF have a significant reduction in MIP, a finding that is associated with poor outcome.

Adult↗
PubMed2000

The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction.

OBJECTIVE: The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). METHODS: Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. RESULTS: In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV. CONCLUSIONS: Both BRS and HRV are reduced in rats early after MI, indicating a depressed reflex and tonic vagal activity. Treatment with zatebradine enhances both BRS and HRV. These data suggest that the drug has both peripheral and central effects, leading to an increase of vagal control of heart rate.

Analysis of Variance↗