Bengt Åblad

The role of sympathetic activity in atherogenesis: Effects of β-blockade

Abstract Clinical and experimental evidence points to potential antiatherosclerotic effects of certain β-adrenoreceptor antagonists. Long-term treatment with metoprolol resulted in significant reductions of total and cardiovascular mortality or morbidity due to decreased incidence of coronary and cerebrovascular complications both in a primary prevention trial in hypertensive patients and in a secondary prevention trial in patients surviving myocardial infarction. The observations suggest that a retardation of atherosclerosis development might have contributed to the reduced incidence of cardiovascular complications. An antiatherosclerotic effect of β-blockers has been directly demonstrated in animal studies. In cholesterol-fed rabbits, metoprolol significantly reduced the development of atherosclerotic plaques in the aortic intima in the absence of any changes in blood lipids. Similar findings were reported for propranolol, which prevented psychosocial stress-induced atherosclerosis of the coronary artery in monkeys. Furthermore, β-blockers have been shown to prevent stress-induced endothelial injury and platelet accumulation to intima at atherosclerotic predilection sites in animal models. These antiatherogenic effects may be due to biochemical and hemodynamic factors. Two biochemical effects of β-blockade may lead to reduced cholesterol accumulation in arterial intima at unchanged serum cholesterol levels. One is a β-blocker-induced increase of prostacyclin biosynthesis, and the other a metabolic change of low-density lipoprotein, reducing its potential for deposition in the arterial wall. The antiatherogenic effect of these factors may be reinforced by β-blocker-induced hemodynamic changes leading to reductions of arterial flow aberrations and pressure-related wall stress.

Postexercise Ischemia Is Associated With Increased Neuropeptide Y in Patients With Coronary Artery Disease

BackgroundNeurohormones may influence vascular tone both during and after exercise. Neuropeptide Y (NPY), which is costored and released with norepinephrine (NE) during sympathetic activity, is a potent vasoconstrictor with a relatively long half-life. We therefore examined its possible association with the ischemic response to exercise in patients with coronary artery disease. Methods and ResultsTwenty-nine male patients with effort-induced angina pectoris underwent a symptom-limited exercise test. In addition to conventional ST-segment analysis, we examined ischemia on the basis of heart rate (HR)-adjusted ST-segment changes through calculation of the ST/HR slope during the final 4 minutes of exercise and of the ST/HR recovery loop after exercise. Blood samples were taken before, during, and after exercise for an analysis of several neurohormones. Mean ST-segment depression was −223±20.2 &mgr;V (P <0.0001) just before the termination of exercise, followed by a gradual normalization, but it remained significant after 10 minutes (−49±8.9 &mgr;V, P <0.0001). At the end of exercise, the ST/HR slope, which reflects myocardial ischemia, was −6.0±0.77 &mgr;V/HR. In most patients, ST-segment levels at a given HR were lower during recovery than during exercise, here referred to as ST “deficit.” Exercise increased the plasma levels of NPY, NE, epinephrine, and N-terminal proatrial natriuretic peptide, but big endothelin remained unchanged. Although NE and epinephrine peaked at maximal exercise, the highest levels of NPY and N-terminal proatrial natriuretic peptide were observed 4 minutes after exercise. The maximal increase in the NPY correlated significantly with ST-segment depression at 3 minutes after exercise (r =−0.61, P =0.0005), the ST deficit at the corresponding time point (r =−0.66, P =0.0001), and the duration of ST-segment depression after exercise (r =0.42, P =0.02). In contrast, no such correlations were found for NE. ConclusionsThe present study has for the first time demonstrated a correlation between plasma NPY levels and the degree and duration of ST-segment depression after exercise in patients with coronary artery disease, which suggests that NPY may contribute to myocardial ischemia in these patients.

Cardiac Antiischemic Effect of Metoprolol: Role of β-Blockade within the Ischemic Region

Summary: The distribution of metoprolol and atenolol into ischemic and nonischemic myocardium was studied in anesthetized dogs, pigs, and cats. The &bgr;‐blockers were administered intravenously after coronary artery occlusion. Metoprolol was found to be significantly more efficiently distributed to the ischemic myocardium than atenolol in all three species. To investigate the functional implications of this difference in tissue distribution, the antiischemic effects of the two &bgr;‐blockers were studied in the 2‐h period following coronary artery occlusion in anesthetized cats, in which heart rate was kept at a constant level. In this model, metoprolol (0.3 mg • kg−1 + 0.15 mg • kg−1 • h−1) was found to attenuate or delay the developing ischemic process. This is shown by its significant reduction of (a) the decline of CK activity in ischemic myocardium, (b) the ST elevation in a precordial ECG lead, and (c) the decrease of arterial pressure and cardiac output. In contrast to metoprolol, atenolol (0.3 mg • kg−1 + 0.15 mg • kg−1 • h−1) caused no significant antiischemic effect in this cat model. The difference in the effectiveness of the two drugs can most probably be explained by their differential distribution in the ischemic heart. Furthermore, the anti‐ischemic effect of metoprolol shows that the presence of a &bgr;‐blocker in ischemic left ventricular myocardium can favorably affect the early phase of developing infarction.

Prevention of ventricular fibrillation requires central β-adrenoceptor blockade in rabbits

Objective. To study whether and how a lipophilic and a hydrophilic β-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 β-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 β1 adrenoceptors modulating vagal nervous outflow.

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

Abstract 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

Abstract Objectives. To explore if β-adrenergic receptors in the brain are involved in acute and delayed cardiovascular responses to a brief emotional stress, by comparing the effects of the β1-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 cotransmittor 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 β-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 β-adrenoceptor blockade.