© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
β3-Adrenoceptors in the heart
aDepartment of Cardiology, University Medical Center, Utrecht, The Netherlands
bDepartment of Medical Physiology, University Medical Center, P.O. Box 85060, 3508 AB Utrecht, The Netherlands
t.opthof{at}med.uu.nl
* Corresponding author. Tel.: +31-30-253-8900; fax: +31-30-253-9036.
accepted 1 October 2002
See article by Bosch et al. [4] (pages 393–403) in this issue.
The existence of β3-adrenoceptors has been demonstrated in the human ventricle [1]. The therapeutic indications for β3-adrenoceptor agonists are obesity and obesity linked diabetes [1]. Because negative inotropy has been reported in response to β3-adrenoceptor stimulation in human ventricle [1,2] as well as in guinea pig ventricle [3], a study of effects on cardiac membrane currents is highly relevant.
In this issue of Cardiovascular Research Bosch and colleagues [4] describe the effect of β3-adrenoceptor stimulation on the membrane current IKs (slow component of the delayed rectifier current underlying repolarization) as well as on action potential duration in guinea pig ventricular myocytes. β3-Adrenoceptor stimulation was produced in two ways: either by isoproterenol or noradrenaline in combination with specific blockers of the β1-(atenolol) plus the β2-adrenoceptors (ICI 118,551) or by the administration of a specific β3-adrenoceptor agonist (BRL 37344). The results are convincing. Whatever method was used, there was a prominent blockade of IKs. This is opposite to the effects of β1- or β2-adrenoceptor stimulation, which lead to an increase in IKs. Also, the effect of overall β-adrenoceptor stimulation, i.e. isoproterenol without any blocker, is still an increase and not a decrease of IKs (see Fig. 1B in this study [4]).
The study of the effect of β3-adrenoceptor stimulation on action potential duration was limited to the administration of the specific agonist with about 10% action potential prolongation over the whole range of repolarization as a result.
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1 β3-Adrenoceptor stimulation and membrane currents |
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In the present study [4] there was a decrease in IKs current, but we wonder why the authors focused to such a large extent on the effects at depolarizations to +70 mV in their quantitative analysis. Although it is possible that the effects were largest at this very positive membrane potential, data on what happens in the normal range of the plateau of the action potential might have been of more interest. Secondly, analysis of kinetics of membrane currents requires frequencies of pulse protocols which are incompatible with (guinea pig) life and durations of pulse steps which are much longer than the duration of a (guinea pig) action potential. It would have been of interest to know whether or not this current is affected at all by β3-adrenoceptor stimulation at physiological frequency. Although the current does not reach a steady state during a single voltage clamp step, one may notice whether or not there is ‘accumulation’ of current during subsequent voltage clamp pulses at physiological heart rate. It has been shown that this is the case for IKs in guinea pig ventricle, but not in rabbit ventricle [5] and this helps to explain why blockade of IKs at physiological heart rate produces more action potential prolongation in guinea pig ventricle than in rabbit ventricle.
Little is known about the intracellular signaling pathway. In adipocytes β3-adrenoceptors are linked to Gi proteins [6]. They do not possess putative phosphorylation sites for cAMP dependent protein kinase or β-adrenoceptor kinase [7].
As pointed out by the authors themselves, L-type Ca2+ current (ICa-L) [8] and the cystic fibrosis related Cl– current [9] are modulated by stimulation of β3-adrenoceptors as well.
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2 β3-Adrenoceptor stimulation and action potential duration |
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In this study a moderate prolongation of the action potential in response to BRL 37344 (‘specific’ β3-adrenoceptor agonist) was observed. There were no experiments with noradrenaline and combined blockade of the β1- and β2-adrenoceptors. Although such experiments made no difference with respect to the measurement of IKs, this cannot automatically be transposed to the effect on action potential duration. The authors make an attempt to relate the 10% prolongation of the action potential with a 40% decrease in IKs current. It should be taken into account, however, that IKs was measured at 0.1 Hz (see Fig. 1 in Ref. [4]), but that the effect on action potential duration (see Fig. 6 in Ref. [4]) was assessed at 1 Hz, whereas the physiological heart rate of a guinea pig is 4 Hz at least [10]. For the comparison of data on membrane currents and on action potential duration, it should further be kept in mind that blockade of IKr and ICa-L was present during the measurement of IKs, but—for obvious reasons—not during the measurement of the effect on action potential duration. By and large, the effect of β3-adrenoceptor stimulation (but also blockade; see the section on therapeutic modalities) on action potential duration may not be as solid as the data on IKs.
It is of interest that human and guinea pig ventricle seem to share the feature of negative inotropy in response to β3-adrenoceptor stimulation, although the effect on action potential duration is opposite: prolongation in the guinea pig (Fig. 6 in Ref. [4]) vs. substantial shortening in man [1,9].
More in general, it has been emphasized previously [11] that there is an overwhelming amount of studies with synthetic agonists in combination with synthetic antagonists in an effort to elucidate mechanisms. For studies with the natural transmitters ((nor)adrenaline) one has to go back in time substantially [11] and therefore it is important that the authors confirmed the effect of noradrenaline (Fig. 2A in Ref. [4]) with respect to the effect on IKs.
We have emphasized in the past that the overall response to β-adrenoceptor stimulation in ventricle appears to be action potential shortening in most mammalian species [11,12], but possibly action potential prolongation in man [12]. At that time we made a caveat, because the human ventricular cells were obtained from hearts explanted from patients with heart failure [12]. Therefore it could not be determined whether the opposite effects should be explained by species differences or by pathophysiological changes. With respect to this it is relevant that upregulation of β3-adrenoceptors—assessed at the protein level—has been reported in patients with heart failure [2].
Finally, we point to the fact that adult male guinea pigs (400–500 g) were used in this study [4]. In selected patient groups with the long QT syndrome 1 (with decreased IKs current) we [13] have demonstrated that age and gender are involved in the response of the corrected QT interval to β-adrenoceptor blockade.
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3 Evolutionary and teleological considerations |
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What could be the advantage of having several types of β-adrenoceptors with an opposite response to an identical (neuro)humoral stimulus? We have seen that at the (sub)cellular level stimulation of β1-adrenoceptors increases IKs, whereas stimulation of β3-adrenoceptors decreases IKs. Also, at the functional organ level stimulation of β1-adrenoceptors increases inotropy, whereas stimulation of β3-adrenoceptors decreases inotropy, although the latter is at dispute (see Ref. [4] for references).
At first sight the sympathetic and parasympathetic (vagal) limbs of the autonomic nervous system should suffice for maintenance of balance of electrophysiological and hemodynamical function. The existence of vagal acceleration of the heart underscores that the picture of the parasympathetic nervous system as a brake and the sympathetic nervous system as a gas pedal is too simple [14–17]. Also, the direct electrophysiological effects of vagal stimulation on the ventricles are virtually absent [18]. During evolution the vagal system developed relatively late, probably because euthermia, which marked the evolutionary transition between reptiles at one side and birds and mammals at the other side, required a system that was able to cope with a more intensive metabolism and more dynamic physiology. In heart rate variability the low-frequency component is considered to reflect sympathetic activity with the well-known 0.1 Hz component, whereas vagal activity is associated with the high-frequency component. It is not possible to adapt the resistance of our peripheral vasculature within one and the same heart cycle after, e.g., standing up on the basis of our sympathetic nervous system. It is simply too slow for that function. Thus, the balance between increase and decrease of function had to be established within the sympathetic nervous system long before the evolutionary development of the vagal nervous system. With respect to this it is of interest that the human β3-adrenoceptor shares only 40–50% of the amino acid identity with the β1- (and β2-) adrenoceptor, pointing to an early digotomy during evolution [19].
A separation between different types of β-adrenoceptors in different organs makes sense. The functional advantage of a combination of systemic (β1-adrenoceptor mediated) vasoconstriction and pulmonary (β2-adrenoceptor mediated) bronchodilatation is obvious. This, however, still does not answer the question of the advantage of different types of β-adrenoceptors with opposite effects on contractility within the ventricle. We might postulate two possible advantages; one is of regional nature and the other is based on developmental aspects. We have not sought a pathophysiological background, because we think that this would not lead to biological selection power.
Concerning the regional aspect, it is known—at least in the dog—that the inotropic response to sympathetic stimulation is stronger at the base than at the apex of the heart [20]. This has been explained by more dense sympathetic innervation at the base of the ventricles than at the apex [21], but a higher ratio of β1- vs. β3-adrenoceptors at the base than at the apex would have a comparable effect. Another explanation could be developmental in nature. Sympathetic stimulation increases cardiac output by increasing both heart frequency and stroke volume. Downregulation of β3-adrenoceptors after birth may cause a positive inotropic effect, desirable for the transition from fetal towards neonatal hemodynamics. Although both explanations may seem far-fetched, they can easily be tested by experiments.
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4 Could β3-adrenoceptor antagonists be useful in heart failure? |
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Therapeutic indications for β3-adrenoceptor agonists are obesity and obesity-associated diabetes. If it is accepted that the concomitant cardiac side effect is decreased inotropy [1–3], one may wonder whether β3-adrenoceptor antagonists may be useful in heart failure. In heart failure both β1- and β2-adrenoceptors are downregulated [22]. Interestingly, the β3-adrenoceptor protein is upregulated 2–3 times in patients with heart failure [2]. If this upregulation is relevant for decreased contractility in patients with heart failure, β3-adrenoceptor antagonists might be beneficial in such patients. Interestingly, β3-adrenoceptor agonists have been reported to have a positive chronotropic effect in dogs [23] and in man [24]. Antagonists thus might have a negative chronotropic effect, which would constitute another advantage because patients with heart failure have a reversed (negative) frequency–force relationship. The sparse data on the chronotropic effect of β3-adrenoceptor modulation should be regarded with caution, because in dogs positive effects of stimulation were absent in denervated animals [23], which strongly suggests that the baroreflex was involved and in patients the positive chronotropy of β3-adrenoceptor agonists was prevented by β2-adrenoceptor blockade, which suggests promiscuity of the supposed selective agonists. Nevertheless, even in the absence of relevant chronotropic effects of β3-adrenoceptor blockade, its direct prevention of negative inotropy might be beneficial in patients with heart failure.
At this stage it cannot be decided whether the relationship between β3-adrenoceptor stimulation and decrease of IKs as demonstrated by Bosch and colleagues in this issue of Cardiovascular Research [4] can be translated in a stronger increase of IKs when noradrenaline is combined with a β3-antagonist compared to the action of noradrenaline alone. Also, the consequences for (the prevention of) negative inotropy require another type of experiment.
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