The functional importance of beta1 and beta2 adrenoceptors in the human heart

doi:10.1016/S0002-9149(88)80063-8

The American Journal of Cardiology

Volume 62, Issue 5, 11 August 1988, Pages 24C-29C

https://doi.org/10.1016/S0002-9149(88)80063-8 Get rights and content

Radioligand binding studies have demonstrated convincingly the coexistence of β₁ and β₂ adrenoceptors in the human heart.

Both subtypes are involved in the increase in tissue levels of cyclic adenosine monophosphate in isolated, electrically driven, human right atria and in the activation of adenylate cyclase in human cardiac membrane preparations. In isolated, electrically driven strips of human right atria, isoproterenol increased contractile force through stimulation of both β₁ and β₂ adrenoceptors, while the selective β₂-adrenoceptor agonist, procaterol, caused its positive inotropic effect predominantly through β₂-adrenoceptor stimulation. Norepinephrine, however, increased contractile force solely via β₁-adrenoceptor stimulation. In this preparation, dobutamine also acted as a full agonist, producing a positive inotropic effect through stimulation of both β-adrenoceptor subtypes. Dopexamine hydrochloride, on the other hand, having an approximately 10-fold greater affinity for right atrial β₂ than for β₁ adrenoceptors, acted as a partial agonist (maximal positive inotropic effect: about 30% that of isoproterenol). Similar effects have been obtained in human right and left ventricular strips; thus, there can be no doubt that cardiac β₂ adrenoceptors can contribute to the positive inotropic effects of β-adrenoceptor agonists in the human heart.

Besides mediating positive inotropic effects, right atrial β₂ adrenoceptors may be involved in the regulation of heart rate since, in healthy volunteers, the selective β₂-adrenoceptor antagonist, ICI 118,551, was more potent than the selective β₁-adrenoceptor antagonist, bisoprolol, in antagonizing isoproterenol-induced tachycardia, when both antagonists were administered in doses that selectively occupied more than 90% of β₂ and β₁ adrenoceptors, respectively. In addition, human cardiac β₂ adrenoceptors may be of special functional importance in congestive heart failure, since in end-stage congestive cardiomyopathy, cardiac β₁-adrenoceptor density and functional responsiveness are markedly depressed, while β₂-adrenoceptor function is almost unaffected. Under these conditions cardiac β₂ adrenoceptors may compensate for the loss of β₁-adrenoceptor function and help to maintain contractility.

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Studying β<inf>1</inf> and β<inf>2</inf> adrenergic receptor signals in cardiac cells using FRET-based sensors
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Citation Excerpt :
These experiments demonstrated that CFs and NRVMs can be distinguished based on their βARs signalling using FRET probes. In NRVMs it is well established that β1ARs and β2ARs are differentially expressed, β1 being the predominant ones (Brodde, 1988; El-Armouche and Eschenhagen, 2009; Pönicke et al., 2003), consequently each receptor differently impacts cAMP production in response to ISO. To test whether it was possible to visualize these differences we used a previously validated approach (Burdyga et al., 2018; Burdyga and Lefkimmiatis, 2015) consisting of co-cultures of NRVMs where cells expressing the soluble FRET sensors were mixed with cells expressing versions of these constructs targeted to the OMM (Fig. 1B) enabling us to measure simultaneously the variations of cAMP and PKA-dependent phosphorylation in two subcellular fractions of NRVMs (Burdyga et al., 2018; Di Benedetto et al., 2017; Filadi et al., 2017; Lefkimmiatis et al., 2013; Lefkimmiatis, 2014).
Cyclic 3′-5′ adenosine monophosphate (cAMP) is a key modulator of cardiac function. Thanks to the sophisticated organization of its pathway in distinct functional units called microdomains, cAMP is involved in the regulation of both inotropy and chronotropy as well as transcription and cardiac death. While visualization of cAMP microdomains can be achieved thanks to cAMP-sensitive FRET-based sensors, the molecular mechanisms through which cAMP-generating stimuli are coupled to distinct functional outcomes are not well understood. One possibility is that each stimulus activates multiple microdomains in order to generate a spatiotemporal code that translates into function. To test this hypothesis here we propose a series of experimental protocols that allow to simultaneously follow cAMP or Protein Kinase A (PKA)-dependent phosphorylation in different subcellular compartments of living cells. We investigate the responses of β Adrenergic receptors (β₁AR and β₂AR) challenged with selective drugs that enabled us to measure the actions of each receptor independently. At the whole cell level, we used a combination of co-culture with selective βAR stimulation and were able to molecularly separate cardiac fibroblasts from neonatal rat ventricular myocytes based on their cAMP responses. On the other hand, at the subcellular level, these experimental protocols allowed us to dissect the relative weight of β₁ and β₂ adrenergic receptors on cAMP signalling at the cytosol and outer mitochondrial membrane of NRVMs. We propose that experimental procedures that allow the collection of multiparametric data are necessary in order to understand the molecular mechanisms underlying the coupling between extracellular signals and cellular responses.
β-Adrenoceptors as molecular targets in the treatment of hypertension
2014, Canadian Journal of Cardiology
Citation Excerpt :
Using pharmacologic, biochemical, and molecular biological techniques, 3 subtypes of βARs have now been effectively characterized. The β1AR is mainly found in the heart and represents 75%-80% of the cardiac βAR mass.9 The β2AR is located in a number of sites, such as the lungs, uterus, kidneys, liver, and peripheral blood vessels.10
Regulation of sympathoadrenal activity has been a long-time target in the management of hypertension. Regulation of β-adrenoceptor (βAR) function has been the most therapeutically important of these targets. The development of effective antihypertensive treatments based on βAR antagonism paralleled the elucidation of the molecular basis of β-adrenergic effects by the family of βARs, which are members of the G-protein–coupled receptor (GPCR) superfamily. βARs serve as the extracellular face of the transmembrane signalling pathway that results in the consequent activation of heterotrimeric G-proteins and the activation of several other newly appreciated signalling molecules that include β-arrestins and GPCR kinases (GRKs). The aggregate effect of the activation of these signalling pathways mediates the response to βAR activation. Paradoxically, the hypertensive state is characterized by impaired βAR responsiveness. This defect is common to many other receptor systems linked to the stimulator G protein (G_s) and adenylyl cyclase activation. This impairment is principally mediated by receptor–G-protein uncoupling, which has been linked to increased expression and activity of GRK2.
La régulation de l’activité sympathicoadrénergique a longtemps été une cible dans la prise en charge de l’hypertension artérielle. La régulation de la fonction du récepteur β-adrénergique (RβA) a été la cible la plus importante sur le plan thérapeutique. Le développement de traitements antihypertenseurs efficaces basés sur les antagonistes du RβA se déroulait parallèlement à l’élucidation de la base moléculaire des effets β-adrénergiques par la famille des RβA, qui sont des membres de la superfamille des récepteurs couplés aux protéines G. Les RβA servent de face extracellulaire de la voie transmembranaire de signalisation qui entraîne l’activation des protéines G hétérotrimériques et l’activation de plusieurs autres nouvelles molécules de signalisation, dont les β-arrestines et les kinases des récepteurs couplés aux protéines G (KRG). L’effet cumulé de l’activation de ces voies de signalisation sert de médiateur à la réponse à l’activation du RβA. Paradoxalement, l’état hypertensif est caractérisé par la diminution de la réactivité du RβA. Cette anomalie est commune à plusieurs autres systèmes de récepteurs liés à l’activation de la protéine G stimulatrice (Gs) et de l’adénylcyclase. Cette détérioration est principalement médiée par le découplage du récepteur–protéine G, qui a été lié à l’augmentation de l’expression et de l’activité de la KRG2.
S1P<inf>1</inf> receptor localization confers selectivity for G <inf>i</inf>-mediated cAMP and contractile responses
2008, Journal of Biological Chemistry
Citation Excerpt :
The effects of MβCD were demonstrated to be the direct result of cholesterol depletion and caveolar disruption as the ability of S1P to inhibit isoproterenol-stimulated cAMP accumulation was restored in MβCD-treated cells following cholesterol repletion (Fig. 7B). S1P and SEW2871 Reduce Isoproterenol-stimulated Positive Inotropy—Isoproterenol treatment leads to increases in cAMP and is known to exert its positive inotropic effect on cardiomyocytes through cAMP-dependent pathways (26, 27). Because we established that S1P and SEW2871 both reduce isoproterenol-stimulated cAMP accumulation, we hypothesized that these agonists would also reduce isoproterenol-stimulated myocyte contractility.
Adult mouse ventricular myocytes express S1P₁, S1P₂, and S1P₃ receptors. S1P activates Akt and ERK in adult mouse ventricular myocytes through a pertussis toxin-sensitive (G_i/o-mediated) pathway. Akt and ERK activation by S1P are reduced ∼30% in S1P₃ and 60% in S1P₂ receptor knock-out myocytes. With combined S1P_2,3 receptor deletion, activation of Akt is abolished and ERK activation is reduced by nearly 90%. Thus the S1P₁ receptor, while present in S1P_2,3 receptor knock-out myocytes, is unable to mediate Akt or ERK activation. In contrast, S1P induces pertussis toxin-sensitive inhibition of isoproterenol-stimulated cAMP accumulation in both WT and S1P_2,3 receptor knock-out myocytes demonstrating that the S1P₁ receptor can functionally couple to G_i. An S1P₁ receptor selective agonist, SEW2871, also decreased cAMP accumulation but failed to activate ERK or Akt. To determine whether localization of the S1P₁ receptor mediates this signaling specificity, methyl-β-cyclodextrin (MβCD) treatment was used to disrupt caveolae. The S1P₁ receptor was concentrated in caveolar fractions, and associated with caveolin-3 and this localization was disrupted by MβCD. S1P-mediated activation of ERK or Akt was not diminished but inhibition of cAMP accumulation by S1P and SEW2871 was abolished by MβCD treatment. S1P inhibits the positive inotropic response to isoproterenol and this response is also mediated through the S1P₁ receptor and lost following caveolar disruption. Thus localization of S1P₁ receptors to caveolae is required for the ability of this receptor to inhibit adenylyl cyclase and contractility but compromises receptor coupling to Akt and ERK.
Emerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling
2005, Pharmacology and Therapeutics
The stimulation of β-adrenergic receptor (βAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct βAR subtypes, β₁AR, β₂AR, and β₃AR, are identified in various types of cells. While both β₁AR and β₂AR, the predominant βAR subtypes expressed in the heart of many mammalian species including human, are coupled to the G_s–adenylyl cyclase–cAMP–PKA pathway, β₂AR dually activates pertussis toxin-sensitive G_i proteins. During acute stimulation, β₂AR–G_i coupling partially inhibits the G_s-mediated positive contractile and relaxant effects via a G_i–G_βγ–phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent β₁AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP–PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent β₂AR activation protects myocardium by a cell survival pathway involving G_i, PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these βAR subtypes and discuss how these subtype-specific properties of βARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain β-blockers in the treatment of congestive heart failure.
Cardiovascular drug class specificity: β-blockers
2004, Progress in Cardiovascular Diseases
β-Adrenergic blockers are one of the most frequently prescribed cardiovascular drugs. Numerous β-blockers are available for clinical use. Although these agents differ substantially, it is not clear whether (and which) differences are clinically relevant.
Most of the important differences among agents reflect the relative specificity for β₁-, β₂-, and α-adrenergic receptors. Selection of a particular agent and target dose is probably best guided by available trial data, even though data are limited. Nonselective agents (with or without α-blocking properties) devoid of intrinsic sympathetic activity (ISA) are most appropriate postinfarction. Evidence exists demonstrating a mortality benefit postinfarction for propranolol, timolol, metoprolol, and, in the presence of left ventricular dysfunction, carvedilol. In the setting of heart failure, the selective agents metoprolol and bisoprolol as well as the nonselective agent carvedilol (which possesses α-blocking properties) have a demonstrated mortality benefit. Not all tolerated β-blockers are associated with a survival benefit and it is probably not advisable to extrapolate benefits to all drugs with similar (although probably not identical) properties.
Carvedilol may possess advantages over other β-blockers and a possible survival advantage, suggested by the recent Carvedilol or Metoprolol European Trial (COMET), although these findings are not universally accepted. Ultimately, selection of a specific agent avoids obvious contraindications and uses trial data to guide selection and dose as long as side effects are absent or tolerable.
Left atrial functional reserve in patients with nonischemic dilated cardiomyopathy: An echocardiographic dobutamine study
2002, Chest
Citation Excerpt :
This is in keeping with previous reports suggesting that dobutamine infusion decreases left ventricular end-diastolic pressure in patients with normal left ventricular function,16 and increases early filling velocity15 in patients with systolic heart failure, leading to an increase in left atrial conduit volume.25 Dobutamine, by its well-known inotropic stimulation, acts through β1 and β2 receptors and increases the contractility of both left atrium and left ventricle.26 In this respect, as observed in this study following dobutamine infusion, there is an improvement in LAEV and LAEF.
To evaluate left atrial functional reserve in patients with chronic heart failure and nonischemic dilated cardiomyopathy (DCM).
Left ventricular functional status has been investigated using echocardiographic dobutamine.
In 35 consecutive patients (29 men and 6 women; mean ŷ SD age, 42.37 ŷ 13.5 years), peak oxygen consumption (V˙o₂max) was measured; the day after, a low-dose dobutamine (5 to 10 μg/kg/min, of 5 min each step) study was performed. Left atrial volumes at mitral valve opening, onset of left atrial systole, and mitral valve closure were measured by using two-dimensional echocardiography. Left atrial active emptying volume (LAEV) [volume at onset of atrial systole − minimal volume] was calculated, as was left atrial active emptying fraction (LAEF): [(volume at onset of atrial systole − minimal volume)/volume at onset of atrial systole] × 100. The changes (values obtained after inotropic stimulation minus those obtained at baseline) of the above-mentioned echocardiographic variables were considered as left atrial functional reserve.
In the entire study group after dobutamine infusion, increases in LAEV (3.34 ŷ 7.54 mL, p = 0.01) and LAEF (6 ŷ 13.2%, p = 0.01) were observed. The changes in the above-mentioned parameters were correlated with V˙o₂max values (r = 0.73 and r = 0.71, respectively; p < 0.001). After inotropic stimulation, LAEV and LAEF were increased in patients with V˙o₂max values > 14 mL/kg/min (5.62 ŷ 7.28 mL and 10.04 ŷ 13.13%, respectively) and decreased in patients with V˙o₂max values < 14 mL/kg/min (− 1.08 ŷ 6.13 mL and − 1.6 ŷ 9.9%, respectively; p = 0.01 for both).
Echocardiographic dobutamine can evaluate left atrial functional reserve in patients with nonischemic DCM.

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A Symposium: Focus On Heart Failure-Current Experiences In Basic Research And Clinical Studies On Dopexamine Hydrochloride (Dopacard®)The functional importance of beta1 and beta2 adrenoceptors in the human heart

J Mol Cell Cardiol

Trends Pharmacol Sci

Life Sci

Life Sci

Differentiation of receptor systems activated by sympathomimetic amines

Nature

Cardiac beta adrenergic receptors

ISI Atlas Sci: Pharmacology

Beta adrenergic receptors: biochemical mechanisms of physiological regulation

Physiol Rev

Cardiac effects of beta adrenergic antagonists

Adv Cardiol

Human cardiac beta adrenoceptors: both beta1 and beta2 adrenoceptors are functionally coupled to the adenylate cyclase in right atrium

J Cardiovasc Pharmacol

The affinity of (—)-propranolol for beta1 and beta2 adrenoceptors in human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (—)-noradrenaline and (—)-adrenaline

Naunyn Schmiedebergs Arch Pharmacol

Beta2 adrenoceptor-mediated positive inotropic effect of epinephrine in human ventricular myocardium. Quantitative discrepancies with binding and adenylate cyclase stimulation

Naunyn Schmiedebergs Arch Pharmacol

The role of cyclic AMP in the positive inotropic effect mediated by beta1 and beta2 adrenoceptors in isolated human right atrium

Naunyn Schmiedebergs Arch Pharmacol

Some aspects of the biological role of adenosine 3′,5′-monophosphate (cyclic AMP)

Circulation

Human myocardial beta adrenoceptors: demonstration of both beta1 and beta2 adrenoceptors mediating contractile responses to beta agonists on the isolated right atrium

Naunyn Schmiedebergs Arch Pharmacol

Bisoprolol (EMD 33,512), a highly selective beta1 adrenoceptor antagonist: in vitro and in vivo studies

J Cardiovasc Pharmacol

Dopexamine: a novel agonist at peripheral dopamine receptors and beta2 adrenoceptors

Br J Pharmacol

Beta1 and beta2 adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta1 receptor down-regulation in heart failure

Circ Res

In support of cardiac chronotropic beta2 adrenoceptors

Am J Cardiol

A Symposium: Focus On Heart Failure-Current Experiences In Basic Research And Clinical Studies On Dopexamine Hydrochloride (Dopacard^®)
The functional importance of beta₁ and beta₂ adrenoceptors in the human heart

Human cardiac beta adrenoceptors: both beta₁ and beta₂ adrenoceptors are functionally coupled to the adenylate cyclase in right atrium

The affinity of (—)-propranolol for beta₁ and beta₂ adrenoceptors in human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (—)-noradrenaline and (—)-adrenaline

Beta₂ adrenoceptor-mediated positive inotropic effect of epinephrine in human ventricular myocardium. Quantitative discrepancies with binding and adenylate cyclase stimulation

The role of cyclic AMP in the positive inotropic effect mediated by beta₁ and beta₂ adrenoceptors in isolated human right atrium

Human myocardial beta adrenoceptors: demonstration of both beta₁ and beta₂ adrenoceptors mediating contractile responses to beta agonists on the isolated right atrium

Bisoprolol (EMD 33,512), a highly selective beta₁ adrenoceptor antagonist: in vitro and in vivo studies

Dopexamine: a novel agonist at peripheral dopamine receptors and beta₂ adrenoceptors

Beta₁ and beta₂ adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta₁ receptor down-regulation in heart failure

In support of cardiac chronotropic beta₂ adrenoceptors