Differential effects of metoprolol and atenolol to neuropeptide Y blockade in coronary artery disease.

OBJECTIVE: To explore possible differential effects between metoprolol and atenolol in patients with coronary artery disease. DESIGN: The study was randomized, double blind, two-way crossover with the Y1 antagonist AR-H040922 given as IV infusion for 2 h or placebo. Most patients were treated with metoprolol or atenolol. In a post hoc analysis we compared the hemodynamic response to exercise of the Y1 antagonist in patients on metoprolol (n = 16) and atenolol (n = 5), and assessed respiratory sinus arrhythmia (RSA), an indirect measurement of cardiac vagal activation, in the placebo phase in patients on metoprolol (n = 26) and on atenolol (n = 24). RESULTS: 1) The Y1 antagonist reduced the systolic blood pressure rise during and after exercise during atenolol, but not during metoprolol, while heart rate and maximal load were similar with the two beta-blockers and not affected by the Y1 antagonist. 2) At equal heart- and respiration-rate 7-8 min after exercise the RSA was significantly lower in atenolol than in metoprolol patients, while no difference was seen at rest before exercise. CONCLUSION: These findings from this hypothesis generating study indicate that peripheral effects of NPY contribute less to cardiovascular stress reactions in patients on metoprolol than in those on atenolol.

Metoprolol, but not atenolol, reduces stress induced neuropeptide Y release in pigs.

OBJECTIVES: To explore if ß-adrenergic receptors in the brain are involved in acute and delayed cardiovascular responses to a brief emotional stress, by comparing the effects of the ß1-blockers metoprolol (lipophilic) and atenolol (hydrophilic). DESIGN: Male dominant pigs, singleliving, freely moving, with telemetric recordings of intra-arterial pressure and ECG and assay of plasma levels of the adrenergic cotransmitter neuropeptide Y (NPY), were confronted with four alien pigs for three minutes at weekly intervals. Weeks 1 and 4 were controls, in weeks 2 and 3 randomized crossover treatment with metoprolol or atenolol were given. RESULTS: The confrontation caused instant and transient tachycardia and more prolonged effects in terms of increased plasma NPY levels, increased arterial pressure and reduced cardiac vagal activation. The two ß-blockers inhibited the tachycardia equally, but only metoprolol reduced the prolonged effects. CONCLUSIONS: Emotionally induced sympathetic activation involves peripheral release of NPY causing a prolonged increase of arterial pressure and a reduction of cardiac vagal activity. These effects are prevented by central nervous ß-adrenoceptor blockade.

Heart rate adjustments and analysis of recovery patterns of ST-segment depression in type 2 diabetes.

AIMS: To investigate the diagnostic value for coronary artery disease (CAD) detection of evaluating time- and heart rate (HR)-related ST-segment changes (the ST/HR-slope) and the post-exercise recovery pattern (the ST/HR-recovery loop) in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Ninety-one patients (22 female, age 59+/-9 years) with T2DM (diabetes duration 6+/-6 years) performed an exercise ECG-test that was evaluated using the ST/HR slope (cut-off/=1 mm ST-segment depression criterion and dobutamine stress echo-cardiography, all evaluated against coronary angiography irrespective of stress test results. Coronary angiography revealed CAD in 20 men and 3 women (25%). Sensitivity for the conventional exercise test and stress echocardiography was low (0.35 and 0.30), but increased significantly using the ST/HR-slope (0.45), the recovery loop (0.86) or the combined ST/HR slope and recovery loop criterion (0.91). The associations between angiographic CAD-detection and the different tests expressed by the Odds ratio demonstrated an added value of performing ST/HR analysis both over pre-test CAD risk profile and the established techniques. CONCLUSION: T2DM patients capable of performing an exercise test could be assessed with the ST/HR-analysis for selecting patients to angiography. However, further studies including a higher number of patients are needed to confirm the diagnostic value of this approach.

Prevention of ventricular fibrillation requires central beta-adrenoceptor blockade in rabbits.

OBJECTIVE: To study whether and how a lipophilic and a hydrophilic beta-adrenoceptor antagonist affects ventricular fibrillation (VF) after coronary artery occlusion in a rabbit model with high sympathetic and low cardiac vagal activation. DESIGN: Rabbits were treated for 3 weeks (series 1) or 2 hours (series 2) with metoprolol, atenolol or control vehicle. Finally the animals in series 1 were exposed to coronary artery occlusion. Heart rate response to cholinergic blockade was studied in series 2. RESULTS: The incidence of postocclusion VF in metoprolol animals was lower (p<0.05) than that in atenolol or control animals. The two beta-blockers caused similar reductions of heart rate, arterial pressure and myocardial ischemia. However, metoprolol animals had more respiratory sinus arrhythmia higher baroreflex sensitivity and more pronounced tachycardic response to cholinergic blockade than atenolol animals. CONCLUSION: Metoprolol reduced the incidence of VF by a better maintained discharge than atenolol in efferent cardiac vagal nerves, possibly due to inhibition of central nervous beta(1) adrenoceptors modulating vagal nervous outflow.

Evaluation of ST-segment changes during and after maximal exercise tests in one-, two- and three-vessel coronary artery disease.

OBJECTIVE: To relate ECG and heart rate (HR) variables during and after exercise testing with the presence of one-, two- or three-vessel disease defined by angiography. DESIGN: Seventy-three male patients with stable angina pectoris and angiographically verified coronary artery disease underwent a maximal exercise test. From 12-lead ECG recordings and computer averaging ST-amplitude and HR data were measured in consecutive 10-s intervals. RESULTS: In univariate analysis, patients with three-vessel disease had lower maximal exercise capacity, a shorter time to >1 mm ST-depression, more often a clockwise ST/HR recovery loop, more frequently a post-exercise downward ST-segment slope, and a greater ST-deficit at 3.5 min after exercise than patients with one-vessel disease. In multivariate analysis, time to >1 mm ST-depression discriminated between patients with three- and one-vessel disease. In patients with an intermediate time to >1 mm ST-depression a clockwise ST/HR recovery loop and/or a downsloping ST-segment in the post-exercise period were significantly more prevalent in severe vessel disease. CONCLUSION: Patients with three-vessel disease had a significantly shorter time to >1 mm ST-depression during exercise and more often an abnormal post-exercise ST/HR reaction than those with one-vessel disease.