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.

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.