Prevention of ventricular fibrillation by betablockers- possible mode of action.

mars 22, 2012

        Lecture for 700  cardiologists in Birmingham 1996, content still relevant, will be extended with recent findings. Figures will be included shortly.

First slide. I will begin with a case report published by Olsson and Rehnqvist in Stockholm.A Holter ECG recording from a 70-year old man, who had recovered well after two myocardial infarctions. Here at 11 pm he is sitting with his wife in his home, relaxed, heart rate 70 beats/ minute. At 11:24 pm he notices that his wallet containg some important documents is missing. He gets worried, the heart rate goes up from 70 to 105, ventricular extrasystoli appear. Sixteen minutes later, next slide, in a period of regular sinus rythm, there occurs a premature ventricular contraction. This initiates ventricular tachycardia, which rapidly degenerates into ventricular fibrillation. Sudden cardiac death has occurred. The mechanisms involved are complex and
largely unknown. This case report shows some features, next slide, which often characterize sudden death victims. 1) Death occurred unexpectedly and outside hospital. 2) Death was due to ventricular fibrillation preceded by ventricular tachycardia. 3) The patient had coronary atherosclerosis. 4) TheVF attack was preceded by increased heart rate. 5) The VF attack was preceded by emotional stress.
As regards  prevention of sudden death, betablockers still are the drugs of choice. Next slide. The sudden death preventive effect of betablockers was well established in large long term clinical trials in the 1980´s, mainly with three drugs: metoprolol, propranolol and timolol. All these are lipophilic and elicit betablockade in the brain as well as in the heart. The two hydrophilic betablockers atenolol and sotalol which are less extensively distributed to brain, have never been shown to prevent arrhythmic sudden death. It has been suggested, that this apparent difference might imply that sudden death prevention requires beta blockade not only in the heart but also in the brain.

This thought was supported, next slide, by studies in conscious pigs, by Skinner and coworkers. If they brought conscious pigs directly to the frustrating environment in the laboratory,coronary artery occlusion led to ventricular fibrillation within 20 minutes in all pigs. Next slide, Ventricular fibrillation could be prevented or greatly delayed by three measures. One was adaptation to the stress, by making the pig accustomed to the laboratory procedures for one week. In these adapted pigs coronary occlusion did not result in ventricular fibrillation. Fibrillation could also be prevented by cryogenic blockade of central pathways involved in the stress response. The third preventive measure was an injection of a low dose of propranolol into a cerebral ventricle. This result suggests that beta-blocker induced prevention of ventricular fibrillation may involve not only cardiac beta-blockade but also beta-blockade in the central nervous system.

Next slide shows the most common response pattern to emotional stress, the so called defence reaction , studied extensively by Folkow, Hilton and others. Stressful stimuli elicit in the limbic system a complex effect pattern, including an increased heart rate, which depends in part on increased sympathetic tone, in part on a decrease of vagal tone.

This differential nerve discharge pattern may be ominous , because, next slide, together with myocardial ischemia, high cardiac sympathetic tone and low cardiac vagal tone are important factors predisposing to V.F. High cardiac sympathetic tone may well be the most important factor, because after complete surgical or chemical cardiac sympathectomy, dogs never develop VF after coronary occlusion.

How do beta-blockers influence these factors? We have studied this in an animal stress model with acute myocardial ischemia. Next slide, We used three groups of rabbits, which for three weeks were given either metoprolol, atenolol or vehicle control by subcutaneous osmotic minipumps. The doses chosen gave therapeutic plasma levels of the two beta -blockers.
These two blockers exert the same degree of beta 1-selectivity, but differ as regards lipophilicity, so that atenolol is less extensively distributed to brain. In the terminal experiment the rabbit was anaesthetised with chloralose. Rabbits exposed to this anaesthetic develop a defence reaction like autonomic outflow pattern with high sympathetic and low vagal tone to the heart. We occluded the coronary circumflex artery branch perfusing the free left ventricular wall . At the end we determined area at risk, that is the portion of left ventricle excluded from perfusion by the coronary occlusion.

Next slide, From one animal, computer averaged ECG lead V3, recordings before and 5 minutes after coronary occlusion. The occlusion caused ST elevation. The sinus rhythm was maintained. In the next 10 minutes many animals died due to V.F with disappearing pressure pulse.
Next slide shows that after coronary occlusion, almost all control and atenolol animals died in VF. In the metoprolol group there were significantly fewer VF attacks and most metoprolol rabbits survived. Why was only the lipophilic betablocker effective? Next slide shows the heart rate recorded just before the occlusion. The control rabbits had a high heart rate, which indicates an intense sympathetic activation in our animal model.

Metoprolol and atenolol produced similar reductions, not only of the heart rate, as shown here, but also of arterial pressure , and of the acute myocardial
ischemia. The two beta- blockers differed, however , when we studied cardiac vagal tone. Here one index of vagal tone, respiratory sinus arrhythmia, measuredas standard deviation of the R-R intervals.This index suggests that the metoprolol rabbits had significantly higher cardiac vagal tone than tha atenolol animals or controls.
This conclusion is supported by other findings summarized in next slide. In the high sympathetic stress model we found a higher vagal activation after metoprolol than after atenolol, as indicated not only by higher respiratory sinus arrhythmia but also by more pronounced tachycardic response to maximal muscarinic blockade and by higher baroreflex sensitivity, measured by means of i.v. phenylephrine injections as done in patints.
Next slide. So these results suggest that the prevention of VF caused by metoprolol in this animal model was due to a combination of reduced myocardial ischemia, reduced cardiac sympathetic activation and better maintained cardiac vagal tone in the stress situation studied, and this effect was probably due to an action in CNS, since the hydrophilic atenolol was ineffective.

Because of these findings we wanted to study a conscious stress model, next slide, and I will show some results from a free-moving pig, who has implanted radiotransmitters, so that we can record telemetric ECG and arterial pressure. Next slide.

Every Tuesday morning we let one alien pig visit the radiopig for three minutes and they fight for social dominance mainly by using their jaws. The radiopig usually develops a beautiful defence reaction. While this is the most common social interaction, next slide shows, that some pigs prefer love to fight in their first encounter. In these pigs the sympathetic activation is much weaker than in fighting pigs. Back to fighting pigs. Next slide shows that the three-minute fight caused the heart rate to increase from 100 to 250 beats/ minute. The tachycardia was rather transient, however.After 15-20 minutes the pig had calmed down and the heart rate had almost returned to the prefight level. Here we estimate the cardiac vagal tone by means of power spectral analysis of the R-R interval.. We believe we know how to translate the heart rate variability data into cardiac vagal tone. I will go directly to next slide, which shows the magnitude of cardiac vagal tone in 6 pigs, studied in a relaxed state and after fight. Week 1and 4 control, week 2 and 3 randomized treatment with metoprolol or atenolol for one week. In the low stress state the vagal tone was high and about the same in the metoprolol period as on atenolol or control. After stress vagal tone was reduced in all groups, but in the metoprolol period the vagal tone was maintained at a significantly higher level than in the atenolol or control periods. This finding corresponds to that we found in the rabbit stress model.

How does a brief sympathetic stress elicit this rather prolonged decrease of cardiac vagal tone? Next slide outlines one possible concept, which we are exploring with the NPY tycoon Jan Lundberg in Stockholm.

In brief, a short intense sympathetic activation, like the pig fight, results in release of noradrenaline giving beta-receptor mediated increase of the heart rate. This effect is short lasting, about 10 minutes. But, the sympathetic nerve activation also releases the cotransmittor neuropeptide Y, NPY, which elicits vasoconstriction but also, and I will focus on that now, NPY reduces cardiac vagal tone by decreasing neural release of acetylcholine. The effects of NPY are long-lasting, up to one hour, in part because NPY is
eliminated much more slowly than noradrenaline.

Next slide shows plasma NPY levels recorded at basal state and 30 minutes after confrontation. The NPY levels were increased in all groups after the fight, but the levels were significantly lower in the metoprolol week than in the atenolol week Our interpretation is that metoprolol, by betablockade in the brain, reduced the sympathetic neural release of NPY. This could contribute to explain the better maintained cardiac vagal tone in metoprolol treated animals exposed to stress, which should reduce the risk for VF.
SUMMARY. Prevention of ventricular fibrillation by betablockers may involve
Betablockade in the heart leading to reduced cardiac sympathetic tone and reduced myocardial ischemia
Betablockade in CNS, for one thing leading to better maintained cardiac vagal tone in psycosocial stress.


Sudden cardiac death involves peripheral release of neuropeptide Y,

februari 12, 2012

Neuropeptide Y ( NPY)  is the most abundant active peptide in the body.  Outside the brain NPY is a co-transmittor with noradrenaline ( NA) in sympathetic nerve endings. High release of NPY occurs  when peripheral sympathetic nerves discharges at high frequencies ,  e.g stress situations eliciting sudden cardiac death or aggravation  of heart failure. Peripheral NPY has a multitude of effects. The schematic figure above shows two important effects: 1) peripheral vasoconstriction, mediated by Y1 receptors and 2) inhibition of acetylcholine release from  e.g vagal nerve endings in the heart mediated  by Y2 receptors. Effects mediated by NPY are much more longlasting than those mediated by NA.

To be contiued!

Metoprolol better than atenolol in therapy of cardiac failure! Role of peripheral NPY!?

januari 19, 2012

The Effects of Atenolol and Metoprolol on Survival Rate of Patients with Mild-to-Moderate Chronic Heart Failure: A Comparative Study

Vera Celic, Biljana Pencic, Milica Dekleva, Sinisa Dimkovic, Maksimilijan Kocijancic

Clinical Medical Centre ”Dr. Dragisa Misovic” – Dendinje, Belgrade

Srp Arh Celok Lek. 133(5-6):242-7, 2005 May-Jun. Translation from Serbian.


Regardless of its grounds and hospital treatments the sum of death outcomes caused by cardiovascular reasons is an indicator of survival rate for patients with mild-to-moderate chronic heart failure and is characterized as a combined case.  The aim of this study was to investigate influence of metoprolol and atenolol on the combined case in patients with chronic heart failure.  The study was comparative, prospective and randomised.  The criteria for including in the study were: age of 70 years or less, NYHA functional class II and III, left ventricular ejection fraction ≤40%.  One hundred and fifty patients who had been treated by angiotensin converting enzyme inhibitor and by diuretics were divided into three numerically equal therapeutic groups: patients treated by atenolol (”the atenolol group”), patients treated by metoprolol (”the metoprolol group”) and a control group of patients who were not treated by beta blockers.  Effects of the treatment were observed for 12 months.  The results were analyzed by the SPSS 10.0 statistical software.  The cumulative survival rate of patients treated by metoprolol (88%) and by atenolol (78%) was greater than survival rate of patients from the control group (48%).  Survival rate of patients treated by metoprolol was also greater then survival rate of patients treated by atenolol.  Metoprolol significantly reduced the risk for occurrence of combined cases (71%) compared to atenolol (53%).  Results of the study have shown that metoprolol and atenolol have a positive effect on the survival rate of patients with chronic heart failure though metoprolol’s effect is significantly better compared to atenolol.

Key words: chronic heart failure; beta-blockers; metoprolol; atenolol


The most important pathophysiological process of chronic heart failure (CHF) is the process of remodeling of the heart ventricles.  The remodeling starts and develops primarily due to angiotensins and catecholamines activities [1, 2].  The hypothesis that the medicines that inhibit or reverses the remodeling can prolong CHF patients’ lives got confirmed by the results of large studies on the angiotensin-converting enzyme inhibitors (ACE inhibitors) and beta blockers (β blockers).  A long-term use of β blockers has a surprisingly positive effect on overall cardiovascular mortality and morbidity [3-5].  These effects have a solid confirmation only for carvedilol, metoprolol and bisoprolol at mild and moderate CHF, even though according to the professor John G. F. Cleland’s statements, atenolol, propranolol, acebutolol, bisoprolol and betaxolol are used in Europe and US as well [6, 7].  The main question is do different β blockers have a significantly different effect on the CHF patient’s survival rate [7, 8].  Results from the comparative studies (COMET and other) as well as from our study could give the answer on that question in the years that follow [9, 10].

Aim of the work

Aim of the study was to investigate and compare effect of atenolol and metoprolol on the survival rate of patients with CHF of NYHA (New York Heart Association) functional class II and III by observing the combined case as clinical indicator of survival rate.  A combined case is defined as the total of death outcomes due to cardiovascular reasons regardless of its grounds and hospital treatments.


The CHF diagnosis was set based on the guideline of the European Society of Cardiology’s Task Force for Diagnosis and Treatment of Chronic Heart Failure [6].  Echocardiografic examination was performed according to the standardized assessment protocol of American Society of Echocardiography [11].  The criteria for including in the study were: age of 70 years or less, NYHA functional class II and III, left ventricular ejection fraction ≤40%.  The criteria for excluding from the study were: systolic blood pressure of 100 mm Hg or less, bradicardia (heart frequency of up to 60 beats per minute) and all degrees of atrioventricular block or sinoatrial node disease, instable angina or myocardial infarct in the last three months, percutan coronar intervention or aortocoronary bypass in the last six months, obstructive or restrictive cardiomyopathies, congenital heart disorder, primary valvular disease or artificial valves, terminal diseases of other systems or organs, all known contraindications to beta-blockers application and the information about current treatment by β blockers.  Patients were divided into three numerically equal therapeutic groups: patients treated by ACE inhibitor and diuretic – the control group (50 patients), patients treated by atenolol, ACE inhibitor and diuretic – the atenolol group (50 patients) and patients treated by metoprolol, ACE inhibitor and diuretic – the metoprolol group (50 patients).

The study was comparative, prospective and randomised.  β blockers application start was determined by the phase when a patient was clinically ”dry” for two weeks.  The initial atenolol dose was 25 mg once daily and initial dose of metoprolol tartrate was 25 mg divided in two daily doses.  Farther titrational scheme was individual; target dose for both atenolol and metoprolol was 100 mg daily.  The therapeutic effect has been followed for 12 months.  The control examinations were performed after 1, 3, 6 and 12 months from start of the treatment.  The study has been ongoing for 39 months.  At each control we followed: possible negative effects of the β blockers treatment (symptomatic aggravation of CHF, symptomatic hypotension, symptomatic bradycardie), new cardiovascular diseases and new additional diseases independent of the cardiovascular system, bad compliance, death of a patient regardless of the cause.  During the study we excluded from examinations all patients who had permanently discontinued intake of β blockers due to bad compliance or due to new additional disease independent of the cardiovascular system.

The statistical analyses were performed in the SPSS 10.0 program package and they comprised: X2-test, analysis of variance for investigation of differences in demographic characteristics and frequency of unfavorable events, Kaplan-Meier survival model curve for distribution of combined cases as function of time, equality test performed by log-rank statistics, Wilcoxon statistics for the determination of survival rate between two patients groups, Cox regression model FW (Forward Wald) for examination of relative risk for occurrence of combined case in the three groups of patients. In the beginning of study there were no significant differences in age, gender, systolic blood pressure and heart frequency, etiology CHF, NYHA class, ejection fraction, i.e. other diseases as hypertension and diabetes, between the CHF patients from three therapeutic groups (Table 1).


The differences in deaths rates between the examined CHF patients groups were not statistically significant (Table 2).  A statistical significant difference among the patients from the three therapeutic groups was found in the number (frequency) of hospitalisations due to cardiovascular diseases and in the number (frequency) of the combined cases.  Frequency of hospitalisation in the metoprolol group (4%) was significantly less compared to the atenolol group (12%) and compared to the control group (26.3%). Combined case frequency in the metoprolol group (8%) was significantly less compared to the atenolol group (16%) and compared to the control group (26.3%) (Table 2).  Kaplan-Meier’s survival rate curves were significantly different for different therapeutic groups of patients (log-rank 16.46; df=2; p=0.0003) as shown in the Graph 1.  In the end of investigation the cumulative survival rate in the metoprolol group was 0.88 (88%), in the atenolol group 0.78 (78%) and in the control group 0.48 (48%).  The survival rate of patients treated by atenolol was significantly greater compared to control group  while the survival rate of patients treated by metoprolol was significantly greater compared to the control group as well compared to patients treated by atenolol (Table 3).  It was determined that metoprolol significantly reduces the relative risk for emerging of combined cases (71.3%; ExpB 0.287; p=0.020) compared to atenolol (53.4%; ExpB 0.466; p=0.050).  In the end of the study average daily doses of atenolol were 50±12.25 mg and average daily doses of metoprolol were 65.50±20 mg.


Results of our study are further confirmation of the β1 selective antagonists’ favorable effect on development and outcome of chronic heart failure.  The ground for this favorable effect lies in the deformations of adrenergic signaling in insufficient myocardium [1, 12].  A long and intensified stimulation by catecholamines leads to devastating biological effects on the myocytes level due to stimulation of β adrenergic receptors.  These effects cause remodeling signals and evolution of malignant arrhythmia [12, 13].  As the ratio of β1 receptors and β2 receptors in the heart ventricles is 80:20% and due to the fact that noradrenalin performs its effects mainly through the β1 receptors, the adaptation of myocytes against the exaggerated stimulation happens foremost by reducing the number and sensitivity of β1 receptors.  Another adaptive response of the myocytes is stimulation of iRNA and β adrenoceptor kinase (β-ARK) activities, as well as stimulation of activity of inhibitory subunit guanin-protein (Gi), what causes phosphorylisation of β receptors and prevents connecting to agonist (so called, functional uncoupling).  These transformations in β adrenergic signaling explicitly disturb ability of the heart to increase its contractility to meet the hemodynamic needs.  Application of the β1 blockers establishes a beneficial balance in so called cross-talk of the β1 and β2 receptor molecules, as proved in many studies [12-16].  The primary aims of the large studies as the total or cardiovascular mortality, cardiovascular morbidity or hospitalisation due to CHF progression and combined cases, have proved as acceptable clinical indicators of survival rate.  More than 90% of the patients who were treated by β blockers, from the studies performed so far, had been previously treated by ACE inhibitor and diuretic [17, 18].  Reports from all finished studies confirm that β blockers significantly reduce mortality and morbidity.  Results of our study are just another contribution to the previous studies.  The most recent meta-analysis of the β blockers in CHF, published in 2000, includes 22 randomised, placebo-controlled studies, comprising more than 10,000 patients.  The authors have concluded that treatment by β blockers reduces occurrence of combined case (the total mortality and hospitalisation due to CHF) by almost a 100% among the patients of NYHA class II and III.  What practically means 3.8 saved lives out of 100 treated patients.  At the same time β blockers reduce number of hospitalisations by four out of a 100 treated patients [1, 19].  The main question is do different β blockers have a significantly different effect on the CHF patient’s survival rate.

Results from the biggest comparative study (COMET) as well as the other smaller studies show that carvedilol has a more favorable effect on the survival rate than metoprolol.  Number of death outcomes by all causes in the COMET study was significantly lower among the carvedilol patients group (34%) compared to the metoprolol group (40%), but numbers of the combined cases (death and hospital treatments regardless of its grounds) were not significantly different between patients treated by carvedilol (74%) and metoprolol (76%) [9].  The assumption that carvedilol’s ”advantage” over metoprolol lies ”outside” β1 blockade was disturbed by the observation that extent of β1 blockade by metoprolol (tartrate formulation, average daily dose 85 mg) in the COMET study was significantly lower than in the previous studies in which patients were treated by metoprolol.  This observation impels carefulness while estimating some β blockers’ ”advantage” and opens a question about dosage and formulation of the medicine in other comparative studies, regardless of applied β blocker [20].

In our study we compared the effects of metoprolol-tartrate, a β1 blocker, with another β1 blocker – atenolol.  This way we observed the effects of adrenoreceptor antagonists on combined case only within the β1 blockade.  The both β1 blockers showed positive effect on the clinical development and outcome of CHF among the patients from the control group.  While the effect of metoprolol (tartrate formulation, average daily dose 65.50±20 mg) was significantly better compared to atenolol’s effect (average daily dose 50±12.25 mg).  It is possible that reasons for the variance could be connected to the different moduling of β adrenergic signaling.  Namely, metoprolol has dominant β1 receptor activity and proved ability to recover the number and sensitivity of β1 adrenoreceptors [12].  Regardless of the negative inotropic effect, metoprolol in some way makes the β2 receptors sensible, redirects adrenergic signaling towards the β2 receptors, normalises the β-ARK and Gi activity and puts into balance the receptorial stimulation and inhibition of myocytes [1, 12, 21, 22].  Atenolol normalises β1 adrenergic signaling as well.  But the β1 and β2 receptorial activities ratio is much greater.  The expected result of such receptorial activity could be symptomatic bradycardia or symptomatic deterioration of CHF i.e. reduced drug tolerance.  Which mechanisms initiate the favorable and which initiate the unfavorable occurrences during the β1 blockade is not clear yet [1, 21, 22].  Metoprolol tartrate, unlike atenolol, is liposoluble i.e. can easily pass emato-encefalic barrier.  It has been proved that its primarily effect can prevent occurrence of lethal arrhythmia [23].  All the stated influences that metoprolol has on adrenergic signaling can – to some extend – explain the better tolerance and more favorable effects of metoprolol on the survival rate of patients with mild-to-moderate CHF, compared to atenolol, even though the molecular mechanisms that lie as a ground for the different effects of these β blockers of the same generation, are for the time being not sufficiently investigated.


In patients with chronic heart failure NYHA functional class II and III of different etiologies, previously treated by ACE inhibitors and diuretics, both of the β1 blockers (metoprolol-tartrate and atenolol) reduce the total mortality and cardiovascular morbidity compared to the control group of patients, while the metoprolol’s effect on the survival rate is significantly better and the application safer compared to the effect and application of atenolol.


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odyssey in chronic heart failure. CHF 2002; 8(5):262-9.

2. Bristow MR. Why does the myocardium fail? Insights from basic

science. Lancet 1998; 352(Suppl I):8-14.

3. SOLVD Investigators. Effect of enalapril on survival in patients

with reduced left ventricular ejection fraction and congestive heart

failure. N Engl J Med 1991; 325:293-302.

4. CONSENSUS Trial Study Group. Effects of enalapril on mortality

in severe congestive heart failure: results of the Cooperative North

Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J

Med 1987; 316(23):1429-35.

5. MetraM, Nodari S, D’AloiaA, et al. A rationale for the use of betablockers

as standard treatment for heart failure. Am Heart J 2000;


6. The Task Force for the Diagnosis and Treatment of Chronic Heart

Failure, European Society of Cardiology. Guidelines for the diagnosis

and treatment of chronic heart failure. Eur Heart J 2001;


7. Adams KF.Which beta blocker for heart failure? Am Heart J 2001;


8. Bristow MR.What type of beta blocker should be used to treat

chronic heart failure. Circulation 2000; 102:484-6.

9. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of

carvedilol and metoprolol on clinical outcomes in patients with

chronic heart failure in the Carvedilol Or Metoprolol European

Trial (COMET): randomised controlled trial. Lancet 2003;


10. Metra M, Giubbini R, Nodari S, et al. Differential effects of betablockers

in patients with heart failure: a prospective, randomized,

double-blind comparison of the long-term effects of metoprolol

versus carvedilol. Circulation 2000; 102:546-51.

11. Shiller N, Shah PM, Crawford M, et al. Recommendations for

quantitation of the left ventricle by two dimensional echocardiography.

J Am Soc Echocardiography 1989; 2:358-68.

12. Brodde OE, Michel MC. Adrenergic and muscarinic receptors in

the human heart. Pharmacological Reviews 1999; 51(4):651-90.

13. Remme WJ. The sympatetic nervous system and ischaemic heart

disease. Eur Heart J 1998; 19(Suppl F):F62-F71.

14. Ceconi C, Curello S, Ferrari R. The neuroendocrine and sympathetic

nervous systemin congestive heart failure. Eur Heart J 1998;

19(Suppl F):F45-F51.

15. Liggett SB. β-adrenergic receptors in the failing heart: the good, the

bad, and the unknown. J Clin Invest 2001; 8:947-8.

16. Houser SR, Margulies KB. Is depresed myocyte contractility centrally

involved in heart failure? Circ Res 2003; 92:350-8.

17. Eichhorn EJ. Experience with beta blockers in heart failure mortality

trials. Clin Cardiol 1999; 22:(Suppl V):V21-V29.

18. Lechat P, Packer M, Chalon S, et al. A meta-analysis of doubleblind,

placebo-controlled, randomized trials. Circulation 1998;


19. Brophy JM, Joseph L, Ruleau JL. Beta blockers in congestive heart

failure. A Bayesian meta-analysis. Ann Intern Med 2001;


20. Dogrell SA. Has COMET solved the controversy as to whether

carvedilol is better than metoprolol in heart failure. Expert Opinion

on Pharmacotherapy 2004; 5(1):205-8.

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failure. Am J Cardiol 1997; 80:26L-40L.

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Bengt Åblad comment:  This interesting paper contains three tables and one figure ( see below).

Stress, Sudden death and Neuropeptide Y (NPY).

november 6, 2011

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.


Scandinavian Cardiovascular Journal. 2007; 41: 221_229

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.
Scandinavian Cardiovascular Journal, 2010; 44: 273–278.
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.


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

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.

First: Must go through recent literature.

oktober 21, 2011

I realized this morning, that I must go through recently published papers on mechanisms involved in heart failure and sudden cardiac death, before explaining how we believe that neuropeptide y ( NPY) is involved. Impressive data in an enormous literature, but I see an open place for NPY!

Pathophysiological role of neuropeptide Y revealed.

oktober 17, 2011

I will soon describe how results obtained by our group, and by some others, appear to explain the importance of the peripheral adrenergic cotransmitter neuropeptide Y for common disease conditions such as sudden cardiac death and aggravation of heart failure. – More on this soon. First I must go to renal dialysis.

It is a mercy to have flow at the age of 77.

oktober 16, 2011

It is a mercy to have flow at the age of 77.
The concept of flow is exciting. As far as I remember, it is invented by a Russian with complicated names that live in the U.S.. My daughter Bodil says it means to be 100% present in the moment. Flow occurs well when you have an intense commitment to a project, practical or theoretical. I deal with such a project right now. One must also have peace of mind. I am grateful to have it by being part of a wonderful relationship with my wife, my children and grandchildren. I am indeed happy that this Google translation of what I wrote in 2009 still is valid today  October 16 , 2011, although I am now 79.

Det är en nåd att ha flow vid 77 års ålder.

december 6, 2009

Begreppet flow är spännande. Såvitt jag minns är det påhittat av en ryss med komplicerat namn som bor i USA. Min dotter Bodil säger att det betyder att vara 100% närvarande i nuet. Flow uppkommer väl när man har ett intensivt engagemang i ett projekt, praktiskt eller teoretiskt. Jag sysslar med ett sådant projekt just nu.  Man måste också ha frid i sinnet.  Jag är tacksam att ha det genom  att vara del i en fantastisk gemenskap med min hustru, mina barn och barnbarn.

Detta är min första blog!

november 28, 2009

Hello world!

november 28, 2009

Welcome to This is your first post. Edit or delete it and start blogging!