The Superselective β1-Blocker Landiolol Enhances Inotropy of Endogenous and Exogenous Catecholamines in Acute Heart Failure

Thomas J Feuerstein¹, Günther Krumpl^2*

¹Sektion für Neuroelektronische Systeme, Klinik für Neurochirurgie, Universität Freiburg, Breisgau, Germany

²Medical Research Network, 1010 Vienna, Austria

*Corresponding author: Günther Krumpl, , Medical Research Network, 1010 Vienna, Austria.

Received: 21 August 2022; Accepted: 06 September 2022; Published: 09 October 2022

1. Introduction

β-Adrenoceptors (β-AR) are G protein coupled receptors on which endogenous catecholamines such as noradrenaline (NA) and adrenaline (A) act as agonists. β-AR can be subcategorized into β₁, β₂ and β₃ receptors, all three acting via the guanine nucleotide-binding regulatory protein G_S to activate an adenylate cyclase which creates cAMP [1]. At the non-failing myocardium β₁-receptors represent 75–80 % while β₂ represent 15-18 % of beta receptors [1]. Classically these receptors mediate positive chrontropy, inotropy, dromotropy and bathmotropy [2]. In the failing heart the percentage of β₁ and β₂ receptors achieves a 50/50 relation [1,3,4]. In the 70es and 80es and even early 90es the use of β-blockers in patients with reduced cardiac function was considered contraindicated [5]. In the absence of representative clinical studies at that time, the rationale to use a negative inotropic agent in case of contractile problems was hard to understand. Groundbreaking results from studies investigating low dose metoprolol, bisoprolol and later carvedilol and nebivolol have indicated that in patients with reduced left ventricular function β₁-AR blockade can improve the hemodynamic situation and eventually prolong survival under long term administration [3]. However, despite that, the clinically beneficial effects of β₁-AR antagonism in chronic heart failure (CHF) has long been doubted. A leading textbook has stated still in 1996 that it is unclear whether β-blockers improve survival in heart failure patients [6], which is nowadays undisputed provided that the patients are not under atrial fibrillation [7].

Several mechanisms are ascribed to the beneficial effect of β-blockers in CHF patients, all based on the antagonism of elevated endogenous catecholamine levels:

1. Heart rate reduction and thus improvement of performance economics [8]
2. Reduction of arrhythmias, specifically atrial fibrillation [9]
3. Decrease of renin angiotensin levels [10]
4. Decrease of ANP (atrial natriuretic peptide) and BNP ( b-type natriuretic peptide) levels [11]
5. Anti-apoptotic and antioxidative activity [12]
6. Improvement of cardiac myocyte metabolism [13]
7. Reduction of β-receptor stimulation via anti β-receptor antibodies [14]
8. Reduction of or reversion of ventricular remodeling [15]
9. Differential blockade of cell-membrane and intracellular located β-receptors [16]
10. Specific effects on myocardial filaments [17]

While in the chronic treatment the use of β-blockers in CHF can now be considered as accepted, this is not the case in the acute setting. Specifically, since some of the beneficial effects of a β-blocker, such as the reduction of remodeling, are the consequences of chronic administration. Moreover, positive inotropic agents are used intravenously for the treatment in the acute situation and β-blockers may inhibit or reduce their effects. Nevertheless, except for the remodeling all the arguments raised for chronic treatment also qualify to explain why an acute intervention can be beneficial.

Moreover, there are further arguments for the co-administration of positive inotropic agents and selective β-blockers in the acute setting:

1. Selective β-blockers might antagonize the β₁-receptor mediated tachycardia and tachyarrhythmias but leave β₂-receptors unblocked for an improvement of the cardiac work.
2. In case of downstream intervention below the β-receptor level with agents such as levosimendan or milrinone, β-blockers might still block special effects of endogenous catecholamines such as tachycardias and/or tachyarrhythmias but leave positive inotropic subreceptor-level-interventions unblocked [18].

Classic intravenous β-blockers are not easy to dose in such situations, since, as shown for instance with metoprolol, they may lose their selectivity in the upper standard dose range or when given intravenously [19,20]. In case of unwanted side effects their longer duration of action may also lead to significant troubles in acute situations [20-22]. Ultra-short acting β-blockers such as Esmolol and Landiolol provide significant advantages in these circumstances since their effect can be terminated in very short time. Both agents differ as far as their selectivity [23] and their action on ion channels is concerned [24-27]. Esmolol (β₁/β₂ selectivity 30 fold) is also blocking Na, Ca and K channels [24-27] while Landiolol (β₁/β₂ selectivity 210-254 fold) is devoid of membrane activity [28,29] and is thus described as a superselective agent [30,31] with less negative inotropy [32-36] and better blood pressure preservation [36-39] and absence of chaperoning and thus rebound effects [23,38]. It is thus obvious that among i.v. β-blockers Landiolol is best qualified for the acute  treatment of patients with left ventricular dysfunction, also since it is the only i.v. β-blocker with a specific dose recommendation for these patients [40,41]. Consequently, Landiolol has been used in intensive care patients in conjunction with positive inotropic agents with positive outcome [42-53]. Beside the above-described positive effects which speak for the use in the acute situation, we try to establish another rationale why a superselective β-blocker such as Landiolol may not act as a negative inotropic agent, but have a positive inotropic effect in the acute setting, as detailed in the following:

2. Methods

Surprisingly, the consideration of a discrete probability distribution, the binomial distribution, of agonist binding to β-AR is helpful to explain the above-mentioned rationale. To understand how the binomial distribution solves the riddle of negative inotropic β₁-blockers inducing positive inotropic effects, two fundamental properties of β₁-AR in human heart must be recalled. First, β₁-AR have a receptor reserve [spare receptors, 54-57]. In other words, the concentrations of catecholamines (the endogenous agonists at β₁-AR) producing their half-maximum effects (EC_50s) are lower than their agonist dissociation constants K_As at the β₁-ARs. Note, that during CHF the concentration of the endogenous agonists at the β₁-AR may even exceed their K_As [57-59]. For the sake of simplicity, endogenous noradrenaline and adrenaline are combined as single endogenous agonist below, with a single K_A only. When an exogenous agonist, i.e. a β-adrenergic stimulant like dobutamine, is administered in acute heart failure (AHF) patients, as usual in LV dysfunction, this increase in adrenoceptor activation even enhances the distance between the quasi-single concentration of endogenous agonists plus that of the “normalized” exogenous agonist and their common K_A at the β₁-AR. In this context, “normalized” means that the exogenous agonist concentration is expressed in affinity units of the endogenous agonist. Second, β₁-ARs occur as homodimers [60,61]. In addition, agonist activation of one subunit (protomer) is sufficient to maximally induce the inotropic response obtained from this dimer and the binding of the endogenous agonist to the second protomer is negatively influenced after the first one has been occupied [negative cooperativity, 60]. Thus, negative cooperativity means that the binding of an agonist to the first protomer decreases the affinity of the agonist for the second one: Both protomers of a homodimer contribute to the allosteric modulation, and the same agonist molecule is the allosteric modulator (binding to the first protomer) and the modulated target (binding to the second protomer).

Regarding the fractional agonist receptor occupation,, [A] represents the concentration of all β₁-AR agonists and K_A their common (also “normalized”) agonist dissociation constant at the β₁-AR. To make an example: Let us assume that the concentration of the endogenous agonist is 10^-7 M with a K_A of 10^-8 M. What is the normalized concentration of the (often added) exogenous agonist dobutamine?

The normalization expresses the (rather low) affinity of dobutamine in the (much higher) affinity of the endogenous agonist:

According to Sanders Williams and Bishop [62] the K_A of dobutamine at the β₁-AR is 0.5 μM (= 10^-6.30103 M). Thus, its affinity is (10^-6.30103+8 =) 50-fold lower than that of the endogenous agonist. The dobutamine plasma concentration may be 592 nM [63] or 497.7 nM [64]. The “normalized” concentration, e.g. 497.7 nM, is then 497.7/50 = 9.95 nM = 10^-8.0022 M.

Assuming that dobutamine is a pure agonist, the fractional agonist receptor occupation may be written as

This means that 91.7 % of β₁-ARs of all dimers are occupied by the endogenous β₁-AR agonist or the exogenous β₁-AR agonist dobutamine, either by only one agonist molecule or by two agonist molecules.

Regarding the agonist occupancy of each individual β₁-AR dimer (no protomer occupied, one of the two protomers occupied, both protomers occupied), the fractional agonist receptor occupation, q (running between 0 and 1), is treated as follows according to Feuerstein and Schlicker [65]: Since the total number of receptors per dimer is n = 2, the existence of spare receptors on this functional unit means that the receptor reserve is 50%. Then, the number of occupied receptors is i = 0, 1, or 2 (with i = 1 being the minimal number of β₁-ARs of a dimer to be activated for a maximum agonist effect of this dimer). Then, for 0 < i ≤ n, or 0 < 1, 2 ≤ 2, the number i of occupied receptors has a binomial distribution B(n, q) with parameters n = 2 and q [see 65]. How can negative cooperativity be modeled? Obviously, this phenomenon only occurs when both protomers of a dimer are occupied by two agonist molecules. Let us first consider the condition that one of two protomers is occupied. As detailed in Feuerstein and Schlicker [65] the binomial distribution is embodied in the concentration-response curve, i.e. x-axis as q, y-axis: = B(2, q)-response with (B(2, q) = 2q(1 – q). This condition is displayed in FIG. 1A (taken with permission from [65]), solid black curve. In the case of both protomers being occupied the binomial distribution of the (B(2, q)-response corresponds to q². See FIG. 1A, dashed blue curve. The dashed purple curve, which indicates the probability that no dimer receptor is occupied, does – of course – not translate into inotropy. The black and the dashed blue curves, however, reflect the presence of an agonist and, therefore, translate into inotropy. The gray curve is the sum of the black and the dashed blue curve and reflects a 50% receptor reserve since the activation of one of two dimer receptors yields the same maximum effect (at q = 1) as the activation of two receptors.

Figure 1A: Binominal distribution and possible translation into inotropy of β₁-adrenoceptor agonists at dimer-receptors without consideration of negative cooperativity.

However, this q² does not yet reflect negative cooperativity within the double occupied dimer. Therefore, in order to reflect that two occupied protomers contribute less inotropy from the considered dimer then the condition that only one of two protomers is occupied, the amount of q² has to be reduced. Feuerstein and Schlicker [65] proposed two models for that:

(1) q² → q²/2 (halfing of q²) See FIG. 1B (taken with permission from [65] and modified), dashed blue curve (Model 1).

and

(2) q² → q²·2q(1 – q) (multiplying q² with the factor 2q(1 – q) which also diminishes q² since this factor is always less than unity). See FIG. 1B, dashed brown curve (Model 2).

Figure 1B: Binominal distribution and possible translation into inotropy of β₁-adrenoceptor ligands at dimer-receptors with consideration of negative cooperativity according to model 1 and 2. The vertical blue or brown arrows represent the maximum possible gain in inotropy induced by Landiolol in model 1 or 2, respectively. This is achieved in the concentration dose range of 1-10 μg/KG/min.

The more complicated approach [2] has the advantage that the inotropy from the considered dimer decreases more when the double occupations of dimers increase at the expense of single occupations.

Note that in both cases the condition that one of two protomers is occupied adds to the condition that both protomers are occupied:

1. then yields 2q(1 – q) + q²; see FIG. 1B, solid blue curve.
2. yields 2q(1 – q) + q²2q(1 – q); see FIG. 1B, solid brown curve.

3. Results

The presence of a pure (neutral) β₁-AR antagonist enhances the inotropic action of endogenous agonists, as shown by Feuerstein and Schlicker [65]. This is only true, however, if negative cooperativity prevails, i.e. if binding of an agonist to the first protomer decreases the affinity of the other agonist molecule for the second one (see Methods). Now the β₁-AR antagonist effect comes into play. According to basic principles of receptor theory, a pure antagonist does nothing else than to shift the concentration-response curve of an agonist to the left. Usually, in steadily increasing curves, this means that an antagonist reduces the response. However, in our case of dimer occupations subjected to negative cooperativity, the concentration response curves of models (1) and (2) (see Methods and figure 1B) reflect declining parts of the curves with increasing values of q at the abscissa. To shift the concentration-response curve to the left within its declining part means increasing inotropy. This increase in inotropy is also true for the agonist combination of endogenous catecholamines and exogenous dobutamine in the presence of the ultra-short-acting highly selective β₁- AR blocker Landiolol. Landiolol, with a K_B of 10^-7.045757491 M [23], may, dependent on (too high) doses and setting, antagonize positive inotropy and chronotropy [37] or, predominantly, chronotropy [38,42-58]. The contribution of Landiolol to the opposite, the enhancement of inotropy, can be delineated as follows:

The above-mentioned term of fractional agonist receptor occupation (endogenous + exogenous agonist, endogenous agonists NA and A at a normalized concentration of [10^-7 M], exogenous agonist dobutamine at a normalized concentration of [10^-8.0022] M (see Methods), with a common K_A of 10^-8 M) is changed by Landiolol with an antagonist dissociation constant of K_B = 10^-7.045757491 M to

The antagonist term is made up according to equation 1 in Mantovani et al. [66; see also 67] as follows:

with Lg = log₁₀. Note, that in contrast to the depiction in Feuerstein and Schlicker [65] the dissociation constant of the common agonist is here called K_A, not K_D, and the antagonist dissociation constant is K_B.

To make an example: With the values assumed (see Methods, dobutamine supposed to be a weak, but pure agonist at the β₁-AR), the fractional receptor occupation in the presence of [Landiolol] = 10^-7.045757491 M, i.e. at a concentration equalling its K_B = 10^-7.045757491M for instance, is calculated to

Thus, the presence of the antagonist Landiolol at a concentration equalling its K_B slightly reduces the agonist occupation of the β₁-AR from 0.917 (see Methods) to 0.846. In other words, at this small concentration, landiolol seemingly doubles K_A and shifts the bell-shaped concentration-response relationship slightly to the left (see FIG. 1B, solid blue upwards directed arrow and solid brown upwards directed arrow). The horizontal blue (Model 1) or brown line (Model 2) below the blue or brown arrow in FIG. 1B shows the extent of this left shift. The probabilities that, at different agonist and antagonist concentrations, no protomer, one of two protomers, or both protomers of the dimers are activated can be calculated. Table 1 displays agonist binding probabilities at the dimer receptors in the absence and presence of Landiolol. Clinically realistic concentrations of the endogenous agonists, of dobutamine and of Landiolol are introduced in the described models of probabilities for agonist activations. According to the above considerations we assume that the agonist binding to at least one dimer receptor is the basis of the translation of agonist occupation into inotropy. The following table shows agonist binding probabilities at the dimer receptors in the absence and presence of the β₁-AR antagonist Landiolol at different concentrations (expressed as Lg [Landiolol]) at 1, 7, 28 and 70 K_B szenarios: It is obvious that in both models positive inotropy is achievable with Landiolol in a range between 1-7 K_B whilst 28 K_B in Model 1 and 70 K_B in both models do not achieve additional inotropy but the contrary, lead to decreased inotropy.

Table 1:

Table 2:

Table 2: Table 2 extends the calculation to further K_B values. In addition, it also relates the responses to the corresponding steady state Landiolol blood concentrations achieved by the administration of the corresponding clinical doses. Furthermore, the percentages in inotropic shifts are indicated in absolute values, delta values (+ abs.%)  and relative changes (+ rel.%).

From table 2 it is clear that, according to model 1 in relative terms a double digit percentage inotropic increase (up to +16%) is achievable between 2.9 and 10 μg/KG/min. In model 2 a triple digit percentage increase occurs between 4.3 and 14.3 μg/KG/min (up to +130%). In both models it is however obvious that beyond 4.3 μg/KG/min no substantial further gain in inotropy occurs. At the highest recommended permanent-infusion-dose for patients with normal left ventricular function (40 μg/KG/min which corresponds to 28 K_B) Landiolol starts to worsen the agonist binding probabilities at the dimer receptors, i.e. positive inotropy starts to turn into negative inotropy in model 1 (-24% ) whilts model 2 still shows a positive shift (+53%). The Landiolol bolus-dose of 100 μg/KG/min which is applied for 1 min in patients with normal left ventricular function leads to a decrease in inotropy of 58 % and 16 % in both models. It has to be mentioned that the corresponding plasma concentration is calculated for a steady state situation which is not the reality for the bolus as the infusion is applied for 1 min only. However, immediately after application, blood concentration levels may achieve 1500-2600 ng/ml, the range for 50 K_B in table 2. At this blood concentration model 1 shows a -46 % reduction in inotropy and model 2 shows no reduction but also almost no gain (+7%).

4.Discussion

In view of negative cooperativity, i.e. binding of an agonist to the first protomer decreases the affinity of the agonist for the second one, an extreme example can convincingly explain why a pure (neutral) β₁-AR antagonist must enhance inotropy: Let us assume that all dimers are doubly occupied by agonist which may just about be compatible with a basic pumping capacity of the heart, i.e. this most extreme case of negative cooperativity may just about be compatible with survival. Then, the addition of only one β₁-AR antagonist molecule will improve the inotropic condition at one single dimer. This is because the single β₁-AR antagonist molecule ensures that this dimer is no longer double agonistically occupied: the antagonistic molecule displaces one agonistic molecule. The benefit of antagonistic displacement of agonists will prevail as long as antagonist addition produces more singly activated dimers but few doubly antagonistic ones. This benefit can be assessed using the approach of the present paper. The results show that Landiolol, in presence of other inotropes, can, in certain low dose ranges, recruit positive inotropy. In both models the ideal dose and plasma concentration range seems to be between 2.9 and 4.3 μg/KG/min, although doses as low as 1.4 μg/KG/min can already deliver extra positive inotropy. Interestingly according to the European guidelines for the treatment of acute tachycardic atrial fibrillation, Landiolol is the only beta blocker with an indicated dose range for patients with left ventricular dysfunction [40,41]. This dose range (1-10 μg/KG/min) overlaps in a perfect manner with the dose range we have characterized as being able to recruit positive inotropy. Within this dose range it is possible to define the lowest dose which is able to recruit the maximum possible positive inotropy (7.1 and 10 μg/KG/min in model 1 and 2, respectively). In clinical praxis this dose is of course influenced by several factors such as the degree of left ventricular function, pre- and after load as well as the actual doses of positive inotrope agents in use and the actual heart rate. Thus, it must be emphasized that the ideal positive inotropy dose range varies between individual patients and even within a patient and is always the consequence of a distinct dose finding and dose titration process. It is thus no surprise that Landiolol has already been used successfully in intensive care patients in conjunction with positive inotropic agents [42-53]. The dose range described in these clinical studies was comparable to what we have used as low doses in our model (1-10 μg/KG/min) and was more often between 1-5 μg/KG/min which is the distinct dose range where we observed the lowest possible dose that already achieved substantial possible inotropic response.

5. Conclusion

This article explains that during co-administration of β₁-receptor agonists and antagonists, the antagonist may, based on the specific behavior of homodimeric β₁-ARs, dose dependently induce a positive inotropic effect in patients with AHF. The approach considers well-established prerequisites, i.e., (i) that the β₁-ARs are spare [54-56], (ii) dimer receptors with activation of one receptor dimer are already leading to the maximum effect [60,61], and (iii) that the concentration of the endogenous agonist at the β₁-AR are higher than their K_A values [K_A – instead of K_D -: agonist dissociation constant, 57-59]. Our calculation, based on the binomial receptor distribution, shows that, due to the negative cooperativity of the receptor dimers [60], negative inotropy is converted into positive inotropy at moderate to rather low concentrations of the β₁-AR antagonist. Both proposed modeling approaches indicate a reduction in positive inotropy again if the concentration of the antagonist becomes too high that it shifts q too far to the left. Then q is in the ascending part of the solid blue or brown curve of Figure 1B. The question can be raised whether this condition with decreasing benefit corresponds to the clinical observation that too high concentrations of β₁-adrenoceptor antagonists can worsen heart failure. We have simulated that and can say that such a phenomenon is also described for the clinical situation [68]. To cope with that, the aspect of a short pharmacokinetic half-life in conjunction with a rapid context sensitive half-life is a big advantage in case of Landiolol [37-39]. Former publications on this topic have raised the question whether increased and possibly harmful concentrations of β₁-adrenoceptor antagonists can be estimated accurately enough on the basis of the proposed modeling approaches to avoid clinical deteriorations in patients with heart failure [65]. A general answer to this question cannot be drawn as head-to-head studies with β₁-blockers in such patients are scarce. Studies have shown that short action duration seems to help when a β₁-blocker induces negative inotropy [37,53,68,69] and higher selectivity seems to be a key element [36-39]. Modelling theories such as the current one and other explanations as mentioned above, deliver a molecular theory and a physiological and pathophysiological explanation basis and provide a rational for a concomitant therapy of β₁-blocker and positive inotropic agents. In case of Landiolol multiple clinical examples as well as specific dose recommendations in the SmPC and the European guidelines and the short half-life of this substance provide support as far as the specific dosing and handling in such situations is concerned. We therefore believe that this publication along with the already existing clinical evidence may help to erase the skeptic attitude towards the use of β₁-AR antagonist in patients with acute left ventricular dysfunction.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

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