Stress, Sudden death and Neuropeptide Y (NPY).

Our story began with unexpected findings more than 20 years ago. We have presented our ideas concerning the role of NPY in sudden death and heart failure at meetings, and in three publications: see summaries below from 1) stressed rabbits; 2) fighting pigs; 3) angina pectoris patients on bicycle test.

Here we go:

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

BENGT ÅBLAD, THORVALD BJURÖ , JAN-ARNE BJÖRKMAN &
THERESE EDSTRÖM

Scandinavian Cardiovascular Journal. 2007; 41: 221_229

Abstract
Objective. To study whether and how a lipophilic and a hydrophilic beta 1-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 1-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.

Metoprolol, but not atenolol, reduces stress induced neuropeptide
Y release in pigs.
BENGT ÅBLAD, THORVALD BJURÖ, JAN-ARNE BJÖRKMAN, OWE BRAX,
LARS EWALDSSON, EVA FORSHULT, LENA LIDFORS & JAN M. LUNDBERG
Scandinavian Cardiovascular Journal, 2010; 44: 273–278.
Abstract
Objectives . To explore if beta-adrenergic receptors in the brain are involved in acute and delayed cardiovascular responses to a
brief emotional stress, by comparing the effects of the beta1-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 beta-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 beta 1-adrenoceptor blockade.

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

LARS GULLESTAD , JOHN PERNOW , THORVALD BJURÖ , LARS AABERGE ,
RITA SKÅRDAL , ELIN KJEKSHUS , LENA HÖGLUND , ÅSE JOLIN MELLGÅRD , INGER
WAHLQUIST , BENGT ÅBLAD .

Scandinavian Cardiovascular Journal, 2012;46: 23-31.

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 thehemodynamic 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 riseduring 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 fi ndings 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.

To me these findings suggest a paradigm shift as regards stress mechanisms involved in sudden cardiac death and aggravation of heart failure. I will come back to this in future blogs.