Cardiac α1A-adrenergic receptors: emerging protective roles in cardiovascular diseases

Abstract

α1-Adrenergic receptors (ARs) are catecholamine-activated G protein-coupled receptors (GPCRs) that are expressed in mouse and human myocardium and vasculature, and play essential roles in the regulation of cardiovascular physiology. Though α1-ARs are less abundant in the heart than β1-ARs, activation of cardiac α1-ARs results in important biologic processes such as hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) indicate that nonselectively blocking α1-ARs is associated with a twofold increase in adverse cardiac events, including heart failure and angina, suggesting that α1-AR activation might also be cardioprotective in humans. Mounting evidence implicates the α1A-AR subtype in these adaptive effects, including prevention and reversal of heart failure in animal models by α1A agonists. In this review, we summarize recent advances in our understanding of cardiac α1A-ARs.

INTRODUCTION

The sympathetic nervous system (SNS) plays a fundamental role in homeostatic regulation of cardiovascular function. Marked activation of the SNS as manifest by elevation in the endogenous catecholamines, epinephrine and norepinephrine (NE), is a hallmark of many cardiovascular disorders. Catecholamines exert various actions through binding to two major categories of myocardial adrenergic receptors (ARs), α1-AR and β-ARs. The most abundant cardiac ARs—β1-ARs—have been studied extensively, and chronic β1-AR activation is a toxic driving force leading to adverse cardiac outcomes in heart failure. By contrast, cardiac α1-ARs have been historically less intensively investigated. However, emerging evidence from multiple lines of investigation defines an indisputable protective role for cardiac α1-ARs.

EXPRESSION OF α1-ARs IN THE HEART

α1-ARs were initially identified as a postjunctional α-adrenoceptor based on their unique pharmacological characteristics (1). Subsequently, several groups confirmed that α1-ARs were present in the hearts of guinea pigs, rats, and mice (2–4). Based on both ligand-binding and molecular evidence, α1-ARs consist of three subtypes: α1A, α1B, and α1D. Due to the lack of subtype-specific α1-AR antibodies, it is technically a challenge to determine cell-type-specific distribution patterns of three types of α1-ARs (5). By integrating ligand-binding studies and α1-AR-knockout (KO) mice, investigators demonstrated that cardiac myocytes express only α1A and α1B subtypes, whereas no α1-ARs were detected by ribonuclease (RNase) protection assay or radioligand binding assay on rodent cardiac fibroblasts (6, 7).

Moreover, the α1D-AR was identified almost exclusively in the coronary vasculature (8). Data from explanted human heart tissues confirmed that cardiac α1-AR abundance and subtype distribution seem to be very similar to mice (8, 9). More recently, by using a novel knockin-reporter mouse, Myagmar et al. (10) revealed that α1B ARs are ubiquitously expressed on virtually every ventricular myocyte, whereas α1A-ARs are expressed on around 60% of isolated ventricular myocytes. Interestingly, α1A subtype expression is graded in those cardiomyocytes, positively correlating to the expression level of β1-AR, suggesting a foundation for possible intrinsic interactions between those two ARs.

α1-ARs were conventionally thought to localize to the plasma membrane, like most other G protein-coupled receptors (GPCRs). However, compelling evidence suggests that a large portion of functional α1-ARs actually localize to the nucleus in cardiomyocytes. An early study by Buu et al. (11) found that 80% of radionuclide labelled NE was found in nuclear fractions (including both nucleoplasm and nuclear envelope) of cultured neonatal rat ventricular myocytes. Subsequent studies by Wright et al. (12) further demonstrated that α1A and α1B ARs are predominantly localized on the nuclear membrane of cultured adult mouse cardiomyocytes using a fluorescently labeled α1-AR antagonist (boron-dipyrromethene-prazosin). This finding was recapitulated in vivo by using an elegant construction of α1-AR green fluorescent protein (GFP) transgenic mice. Moreover, this group subsequently confirmed that α1-ARs are localized in the inner nuclear membrane and are required for a physiological response to catecholamines (13).

α1-AR SIGNALING PATHWAYS

In most cell types, α1-ARs couple to the G_q/11 family of G proteins (GTP-binding protein), leading to the dissociation of the α-, and β-, γ-subunits and the subsequent stimulation of the enzyme phospholipase C (PLC). Activation of PLC generates the second messengers, inositol [1,4,5]-trisphosphate (IP3) and 2-diacylglycerol (DAG), ultimately ending with the release of intracellular calcium (14). Consistent with the notion that functional α1-ARs are localized in the nuclear compartment, there is evidence that G_q, PLC, and other classical downstream α1-AR signaling partners are detected in isolated nuclei from adult mouse cardiomyocytes (13). α1-ARs activated PLCβ1 at the nuclear envelope, leading to IP3-dependent nuclear Ca²⁺ release and CAMKII-induced nuclear export of histone deacetylase 5 (HDAC5) (15), a central event in the induction of cardiomyocyte hypertrophy (16). In contrast, angiotensin II receptors (AT-Rs) localize only to the sarcolemma and fail to induce nuclear HDAC5 export (15). The authors proposed that the difference in localization accounts for the fact that α1-ARs induce physiological, whereas AT-Rs induce pathological hypertrophy, though this hypothesis has not been tested directly. Collectively, these emerging data suggest a new “inside out” α1-AR signaling paradigm (17). Of note, a recent study revealed G_q coupling is required for cardioprotection by α1A-AR agonists, challenging the classical view of G_q signaling as cardiotoxic (18).

The regulatory mechanisms of α1-AR signaling pathways vary among different receptor subtypes. Diviani et al. (19) reported that G protein-coupled receptor kinase 2 (GRK2) plays an important role in desensitization via phosphorylating the residues in the C-tail of the α1B-AR in a recombinant system, although other groups have shown that GRK3, not GRK2, regulates cardiomyocyte α1-AR responsiveness (20). Glycogen kinase 3 (GSK3) recently was suggested to participate in agonist-mediated desensitization of the α1A-AR (2). The α1B-AR but not α1A-AR displayed robust agonist-induced endocytosis and significant constitutive internalization in a similar recombinant system, likely through efficient interactions between β-arrestin and the α1B (21). These intriguing differences may have broader functional implications as these receptor subtypes link to different physiological functions as reviewed below. At present, however, their physiological significance is uncertain and one should take caution in interpreting these data from recombinant systems; in contrast to supraphysiological levels of receptor in these systems, receptor density on native cardiac myocytes is far lower and signaling does not desensitize (10).

Although GPCRs initially were thought to function exclusively as monomeric entities, evidence accumulated in the past few decades indicates that they can form homomers and heteromers in intact cells. Both types of oligomers have been demonstrated for the three α1-AR subtypes in recombinant systems (22). However, the functional relevance of oligomerization of α1-AR subtypes in physiological systems has not been elucidated, due to lack of appropriate experimental approaches (23). The relatively recent development of powerful techniques, such as high-resolution crystal structure, discrete direct screening, and high-throughput screening (24), have enabled the characterization of receptor dimers. Using such approaches, Albee et al. (25) recently found that α1-ARs function within hetero-oligomeric complexes with chemokine receptor 4 (CXCR4) in vascular smooth muscle to coordinately regulate the vasopressor response to phenylephrine (PE). The relevance of this finding to myocardial α1-ARs remains unclear.

LESSONS FROM EXPERIMENTAL STUDIES

α1-ARs mediate many important functions in numerous organs systems including the cardiovascular system, the genitourinary system, and the central nervous system. Within the cardiovascular system, all three subtypes of α1-AR subtypes have been detected in blood vessels and their activation contributes variably to vasoconstriction [reviewed in a study by McGrath (26)]. The α1D is the predominant and functional subtype in human (8) and mouse (27, 28) coronary arteries. The α1B is the main subtype in human coronary endothelial cells (29), where it presumably mediates vasodilatation (30). Though the focus of the present review is the cardiac α1A-AR, we acknowledge that physiological activities of vascular α1-ARs are paramount to systemic cardiovascular regulation.

Evolution of Research Tools and Techniques

Since the initial classification of α1-ARs, numerous efforts have been invested to optimize research techniques in this field. In an attempt to explore the direct actions of α1-ARs on heart tissues, a number of in vitro/ex vivo models, such as isolated working heart, trabeculae preparation, and cultured cardiomyocytes, were used and yielded great insights into understanding of cardiac α1-ARs. In vivo gain-of-function studies using nonselective α1-AR agonists, such as PE and norepinephrine, uphold the in vitro findings to a large extent (31). However, caution must be taken in interpreting those findings, as these agonists bind to all three subtypes of α1-AR and even other ARs as well at higher concentrations. Highly selective α1A agonists including A61603 (32) and dabuzalgron (33), mostly developed for the treatment of urinary incontinence, also have demonstrated cytoprotective effects in vivo and in vitro. The pharmacological properties of nonselective and α1A-selective agonists in cardiomyocytes were summarized recently (34).

Transgenic mice overexpressing individual α1-AR subtypes substantially bolster the findings from pharmacological experiments, though phenotypes vary due to very different levels of receptor overexpression (23) and other issues as indicated in Table 1. Those shortcomings prompted the creation of global knockout mouse models for individual or multiple α1-AR subtypes. Toward further understanding actions of individual tissue pools of α1-AR subtypes, we recently used the cre/loxp system to generate cardiomyocyte specific α1A-AR KO mice (51). Table 1 summarizes the strengths and limitations of available pharmacological and genetic tools for studying α1-ARs.

Table 1.

Pros and cons of common research tools in studying α-1A-ARs

	Functional Changes	Example(s)		Phenotype/Finding	Pros	Cons
Pharmacological	GOF	Phenylephrine		Antiapoptotic in cardiomyocytes (35); ↑ myocyte hypertrophy (concentric) (36,37)	Historic standard model, high clinical relevance	Substantial concerns of β1-AR agonism
		Low dose NE		↑ Myocyte hypertrophy, fetal gene induction (38,39)
	GOF	A61603		Positive inotropy on failing hearts (40); prevent myocyte hypertrophy; decrease apoptosis and fibrosis; activate ERK activation (34); regulate intracellular Ca++ entry (14); prevent and reverse heart failure in vivo (41,42).	Selective α-1A AR agonist	Peripheral α-1A AR agonism (requires higher dosing than for therapeutic effects)
		Dabuzalgron		Enhance contractile function, preserve myocardial mitochondrial function (33) prevent and reverse heart failure in vivo
	LOF	Doxazosin		↓ Efficacy of β-blockade with α1-blockade (43)	Historic standard model, high clinical relevance	Peripheral α-1-AR antagonism (e.g. BP, lipid metabolism), nonselective for subtypes
		Prazosin		↑ I-R injury with α1-blockade (second window of preconditioning) (44)
Genetically modified animal	GOF	TG	CAM α1 A (2×)	↑ ischemic preconditioning (45)	Technically feasible to individually enhance signals from subtypes of α1-AR (37).	Inconsistent phenotypes inherent in variable levels of overexpression, variable promoters, wild type vs. constitutively activated receptors; inferior physiologic relevance (23).
			αMHC-α1A (66×)	↑ contractility, no hypertrophy, protection from TAC (24)
			αMHC-α1A (66×)	↑ inotropy, ↓ mortality after MI (25)
			αMHC-α1A (112–170×)	↑ death, fibrosis in aged mice (46)
	LOF	KO (systemic)	α1A-AR KO	Normal heart size, ↓ BP (47)	High physiological relevance, capability to study single or multiple subtypes.	Phenotype varies on genetic background, unable to study contributions from single tissue pool (23).
			α1A/B-AR DKO	↓ physiological HT; normal BP (48)
			α1A/B-AR DKO	↑ HF and death after TAC (49)
			α1A/B-AR DKO	↓ myocardial contractility (50)
	LOF	KO (cardiac)	αMHC-Cre (α1 A )	Normal heart size, ↑ ischemic injury (51)	Capability to study actions from individual cell lineage or tissue	Deletion efficacy varies from different cre promoters, potential cre toxicity
			βMHC-Cre (α1 A)	Normal heart size (51)

CAM, constitutively activated mutant receptors; DKO, double knockout; ERK, extracellular signal-regulated kinase; GOF, gain-of-function; KO, knockout; LOF, loss-of-function; NE, norepinephrine; TAC, transverse aortic constriction; TG, transgenesis.

Though the diverse signaling cascades induced by nonselective α1-AR activation have been characterized fairly extensively, relatively little is known about the differential signaling downstream of the α1A versus the α1B-AR. In vitro studies demonstrated that extracellular signal-regulated kinase (ERK)1/2 is necessary for the cytoprotective effects of α1A-AR activation (12) and that a novel transgenic mouse with a knockin α1A-AR mutation that prevented Gq binding demonstrated that coupling to Gq with subsequent activation of ERK1/2 is essential to α1A agonist cardioprotection in vivo (18). In addition to elucidating in vivo α1A signaling pathways, these findings challenged the conventional paradigm that Gq signaling is inherently detrimental. α1A-ARs enhance contractility by signaling through protein kinase C delta (PKCδ) to phosphorylate troponin I (52) and by promoting translocation of snapin and transient receptor potential canonical 6 (TRPC6) to the plasma membrane (53). α1A-ARs facilitate cytoprotective cardiomyocyte glucose uptake through PKCδ to induce glucose transporter (GLUT1/4) translocation and mTOR signaling (54). Interestingly, mice that constitutively overexpress the α1A-AR have decreased serum triglycerides and glucose, whereas global α1A KO mice exhibit the opposite findings.

Inotropic Effect and Contractility

The positive inotropic effect elicited by α1-ARs has been demonstrated in cultured myocytes, isolated trabeculae, and the perfused heart for many decades. Interestingly, activation of α1-ARs confers negative inotropic effect in the normal mouse right ventricle (RV) and a positive inotropic effect in normal left ventricle (LV) (55, 56). Those findings from in vitro or ex vivo systems were nicely recapitulated in various in vivo models and even human patients (57). Data from transgenic mice suggest that α1A-AR overexpressing mice have enhanced contractility, whereas α1B overexpressers have blunted inotropic response (58). Moreover, our recent work shows that that mice lacking α1A-AR only on cardiomyocytes have virtually identical contractile function as their wild-type (WT) littermate controls (unpublished observations), suggesting that α1A-AR-mediated inotropic responses might not be required for basal contractile function. This finding is consistent with previous reports from global α1A or α1B KO mice (6). Lastly, Landzberg et al. (59) found that stimulation of human myocardium by infusing PE through the left main coronary artery exerts a concentration-related positive inotropic effect, but no effect was observed in the same patients when coinfused with α1-AR antagonist phentolamine. Importantly, recent studies show that an α1A subtype agonist (A61603) elicits comparable inotropic response to isoproterenol in ex vivo human heart preparations (60, 61). Collectively, these data demonstrate a potential compensatory role for α1-AR in mediating inotropic response, particularly in the context of injury. The inotropic response to α1-AR stimulation likely arises from multiple mechanisms such as increased myofilament Ca²⁺ sensitivity by α1-AR via intracellular alkalization and myosin light chain 2 phosphorylation [reviewed in a study by Endoh (62)].

Cardiac Hypertrophy

Myocardial hypertrophy develops in response to various hemodynamic, metabolic, genetic, and neurohormonal stimuli. Maladaptive (pathological) hypertrophy typically is associated with cardiomyocyte death, fibrosis, and impaired mechanical performance. Adaptive (physiological) cardiac hypertrophy, in contrast, is characterized by preserved mechanical performance and the absence of cardiomyocyte death and fibrosis. A number of seminal experiments have demonstrated that activation of α1-AR by various pharmacological agonists induces a hypertrophic response that is characterized by activation of immediate early genes (c-Fos, c-Jun) and reactivation of “fetal” genes [c-myc, atrial natriuretic peptide (ANP), α-skeletal actin, and β-myosin heavy chain] (63, 64). Similarly, animals develop cardiac hypertrophy without alteration of normal cardiac function after chronic infusion of low dose NE or PE (65).

Moreover, transgenic mice overexpressing constitutively active mutant (CAM) α1B-AR have variable levels of hypertrophy at baseline (likely due to variable levels of expression), but a consistently amplified pathological hypertrophic response to PE infusion or transverse aortic constriction (TAC) (66, 67). By contrast, α1A-AR transgenics have no baseline hypertrophy at even grossly supraphysiological expression levels (>100-fold) and exhibit preserved LV contractile function without worsening pathological hypertrophy in the TAC model (68). This notion has been further supported by studies on mice deficient of the α1A and/or α1B. Mice lacking α1A had normal heart size and BP, whereas α1B KO mice have small hearts, implicating a role for α1B in developmental hypertrophy (6). These differences observed from transgenic mice suggest that the α1B, and not the α1A-AR subtype, regulates hypertrophy.

In the pressure-overload model, mice lacking both α1A and α1B have worse dilated cardiomyopathy, but similar levels of hypertrophy as indexed by heart weight/body weight ratio and myocyte cross-sectional area (49). Further analysis of heart tissues revealed that ABKO impaired the transcriptional response of fetal genes (β-myosin heavy chain and α-skeletal actin) to TAC. A much worse cardiac phenotype in ABKO (α1-A/B double knockout) mice was identified when compared with wild-type (WT) mice after a 2-wk period of TAC, implying a beneficial effect of α1A- and/or α1B-AR under these conditions (49). Subsequent work showed that the α1A is the subtype mediating cardioprotection, and not the α1B (33). Interestingly, stimulation of α1A AR by the selective α1A agonist A61603 successfully rescues cardiac dysfunction after LV pressure load, along with near normalization of transcriptional response of fetal genes, and also rescues RV pressure load-induced dysfunction (40). Taken together, these results suggest that the α1A-AR mediates adaptive responses but not hypertrophy in response to cardiac insults.

Myocardial Ischemia

Extensive experimental data indicate that α1A-ARs protect against myocardial ischemic injury via different mechanisms such as preconditioning and postinfarction remodeling. Earlier studies found that both acute and chronic ischemia/hypoxia enhance α1-AR signals (32, 48). Pharmacological agonists targeting α1-ARs protect against ischemic injury in multiple species (69, 70). Similarly, transgenic mice with α1A but not α1B overexpression demonstrate blunted myocardial ischemic injury as determined by infarct size and functional recovery (71). This finding was further confirmed in an α1A-AR cardiac transgenic rat model (47). Activation of α1-AR induces both the first and second preconditioning window via activation of PKC and further downstream mechanisms such as iNOS, COX-2, and others (44).

Furthermore, a role has also been proposed for the α1-AR system in postischemic remodeling. Du et al. (71) reported that heightened cardiac α1A-AR activity in transgenic mice substantially improves LV remodeling determined by serial echocardiography in a period of ∼4 mo after permanent left anterior descending artery (LAD) ligation. In addition, Yeh et al. (72) found that systemic KO of the α1A-AR confers worse pathologic remodeling as early as 4 wk after LAD ligation. Of note, these authors also demonstrated that deficiency of α1A-AR links to exaggerated cardiomyocyte apoptosis and interstitial fibrosis after ischemic injury. Moreover, we recently found that cardiomyocyte-specific α1A-AR disruption renders mice more susceptible to LAD ligation as evidenced by increased mortality and larger infarct size (51).

Cardiomyocyte survival

In contrast to the well-recognized detrimental cardiotoxic effect of chronic β1-AR activation, emerging evidence suggests that stimulation of α1-ARs promotes cardiomyocyte survival. In cultured adult cardiac myocytes, β-ARs but not α1-ARs mediate NE-induced cell death (73, 74). Further studies suggest that α1-AR antiapoptotic signaling involves multiple pathways including phosphorylation of B-cell lymphoma-2 (BCL-2) family, activation of ERK1/2 signal pathway and regulation of critical transcriptional factors [GATA-binding protein 4 (GATA4), nuclear factor of activated T-cells (NFAT)] (75).

Studies from cultured α1AB KO adult cardiomyocytes found reconstitution of α1A, but not α1B abrogates cell death induced by various stimuli (34, 76). These findings, reinforced by observations from animal models treated with different α1 A-selective agonists, posit α1A-AR as the primary cytoprotective α1-AR subtype (32, 33, 42).

Dabuzalgron (Ro 115-1240) was initially developed as an oral selective α1A-AR partial agonist for treatment of urinary incontinence. We recently found that subpressor doses of dabuzalgron prevented doxorubicin-induced cardiac dysfunction and fibrotic changes. Mice deficient of α1A-ARs had worse survivability and even more profoundly impaired contractile function than WT mice after doxorubicin exposure. Moreover, dabuzalgron failed to rescue either of these parameters in the α1A knockout mice, indicating that intact α1A-ARs are essential to the cardioprotective effects of dabuzalgron. Interestingly, our work further suggested that dabuzalgron protects cardiomyocytes through augmenting cardiac survival signals ERK1/2 and transcription of genes related to mitochondrial function (33).

Heart Failure

Activation of the SNS is a hallmark of heart failure. Unlike markedly downregulated β1-ARs, we found mRNA expression and binding affinity of α1 subtypes are preserved or even increased on human failing myocardium, magnifying a potential compensatory role for α1-AR in the setting of heart failure (9). Importantly, only less than 10% of total α1A-ARs are occupied by elevated NE in the setting of heart failure (77), indicating that exogenous stimulation of α1A-ARs is spatially feasible and functionally required. As we summarized above, current experimental evidence indicates that α1A-AR stimulation augments contractility, promotes adaptive hypertrophy, induces ischemic preconditioning, and prevents cardiac myocyte death. All these protective features support the notion that the α1A-AR may represent a novel target for heart failure therapy.

Given the well-recognized vasoconstrictor response to vascular smooth muscle α1-AR activation, it is possible that a nonselective α1-AR agonist might exacerbate heart failure by enhancing afterload. To address this rational concern, we have identified at least two selective α1A-AR agonists that protect against heart failure at doses that do not alter blood pressure in various models (33, 34). In two slightly different doses of doxorubicin-induced cardiomyopathy model (20) (25 mg/kg once ip), we found that infusion of A61603 at low dose improved survival rates and cardiac function (determined by echocardiogram) (34). Moreover, A61603 treatment from week 2 to week 4 after TAC rescues the decline in fractional shorting almost to normal (42), and similarly rescues reduced RV function after pulmonary artery constriction (78). More strikingly, in ischemic cardiomyopathy mice, 4 wk treatment of A61603 fully reverses the deterioration of contractility (42). Importantly, the cardioprotective effects of α1A agonists are completely absent in mice lacking the α1A (42), confirming the necessity for the α1A in the therapeutic response. Along with our findings on dabuzalgron, these data provide preliminary justification for further studies of using selective α1A-AR agonists as novel heart failure therapies. Of note, dabuzalgron was well tolerated without any blood pressure effects in multiple clinical trials for treatment of urinary incontinence (79), implying a potentially viable path to clinical use.

Interestingly, likely through changes in coupling to myosin light chain kinase, heart failure switches right ventricular (RV) α1-adrenergic inotropic response from negative to positive, suggesting the α1A subtype as a therapeutic target to improve the function of the failing RV (80) as well. Recent studies from two different animal models bolstered this notion, showing that chronic infusion of α1A agonist (A61603) indeed improved or even restored RV function and associated injuries (40, 81). These findings may heighten the implications of therapeutic cardiac α1A-AR activation in heart failure, as RV failure in the setting of chronic heart failure is a strong predictor of poor outcomes (65).

LESSONS FROM CLINICAL STUDIES

In contrast to the broad understanding of α1 ARs in the pathogenesis of HF from experimental studies, the exploration of α1-adrenergic drugs among patients with heart failure is more limited.

α1-Blockers were initially introduced to treat benign prostatic hypertrophy, though their use subsequently has expanded to hypertension and post-traumatic stress disorder. In the landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the incidence of heart failure in the subjects who received the nonselective α1-blocker doxazosin was twofold higher than in the subjects who received other blockers; thus, the doxazosin arm was stopped prematurely by the data safety monitoring board (82). In addition, in Vasodilator Heart Failure Trial (V-HeFT), another nonselective α1-blocker prazosin was associated with no benefit and a trend toward increased mortality (49.7% vs. 38.7%) compared with other vasodilators (the combination of isosorbide dinitrate and hydralazine) (78). More recently, Dhaliwal et al. (83) noticed that concurrent use of α1-blockers increased the risk of heart failure hospitalization. Interestingly, bucindolol, a nonselective β blocker with sympatholytic properties, failed to improve mortality in patients with heart failure (84). This nonsuperior result, along with similar findings from earlier trials of sympatholysis for the treatment of heart failure, provides additional support to the notion that residual α1-AR signals are likely protective in human heart failure, in contrast to well-recognized detrimental β1-AR signals (85).

Consistent with this concept, studies found that midodrine, an oral α1-AR agonist prodrug, improves outcomes of patients with advanced heart failure with hypotension (80, 86, 87). It has been suggested that improved blood pressure due to peripheral activation of α1-AR allows those patients to tolerate more goal-directed medical therapies. However, the aforementioned extensive preclinical data suggest that direct stimulation of cardiac α1-ARs may also contribute as well.

Carvedilol, a mixed β1/β2/α1 blocker, conferred additional benefit over the selective β1-AR antagonist, metoprolol tartrate alone in the Carvedilol or Metoprolol European Trial (COMET) in heart failure (88). Though some initially attributed these findings to β2 and/or α1-AR blockade (89), the results of this trial are more widely viewed with skepticism due to inequivalent dosing of metoprolol and carvedilol and the inappropriate choice of metoprolol tartrate rather than metoprolol succinate (52, 77). Subsequent mechanistic studies showed that chronic carvedilol treatment does not inhibit but actually potentiates vascular α1-AR-mediated vessel contraction in humans, and counterregulates peripheral α1-AR-mediated metabolic effects (90, 91). Moreover, carvedilol has a relatively high affinity for the α1B compared with α1A-AR and normalizes exaggerated cardiac α1B AR signals in hypertrophied rodent hearts (92, 93). Carvedilol is a biased β1-AR ligand that transduces signaling through NOS3 and guanosine 3′,5′-cyclic monophosphate to enhance cardiomyocyte contractility (94) and through β-arrestin to favorably alter cardiomyocyte metabolism (95, 96), possibly contributing to the observed clinical benefits. The mixed pharmacologic activities of carvedilol highlight the importance of better understanding the contributions of α1A-AR from individual tissue pools and indicate that α1-AR blockade is not essential for its clinical efficacy. Taken together, current available data from clinical studies substantiate the concern of worse cardiac outcome from α1-AR blockade, and may imply a potential cardioprotective role for stimulation of α1A-ARs, thus holding promise for shifting the paradigm from purely adrenergic blockade to comprehensive adrenergic modulation (Fig. 1).

Figure 1.

A proposed paradigm of enhanced adrenergic modulation in cardiovascular disease.

SUMMARY AND PERSPECTIVE

Recent work and studies from the last several decades provide compelling evidence to support adaptive and protective roles for cardiac α1A-ARs. These characteristics include positive inotropy (especially in failing myocardium), physiologic hypertrophy, protection from ischemic injury, and promoting cardiomyocyte survival. More importantly, recent work from related preclinical models provides proof-of-concept evidence of feasibility and benefits of therapeutic selective activation of the myocardial α1A-AR subtype without affecting blood pressure. These features have significant clinical relevance and imply an apparent advantage of a more comprehensive adrenergic modulatory strategy in cardiovascular diseases. Further work is needed to elucidate the mechanisms of those cardioprotective effects of individual cardiac α1-AR subtypes, as well as their potential extracardiac effects.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grant R01-HL140067 (to B.C.J.).

DISCLOSURES

UCSF and UNC own patents with PCS and BCJ as inventors for the use of alpha-1A agonists in heart failure. PCS and BCJ are involved in a company to pursue this concept.

AUTHOR CONTRIBUTIONS

J.Z. prepared figures; J.Z. drafted manuscript; P.C.S. and B.J. edited and revised manuscript; J.Z., P.C.S., and B.J. approved final version of manuscript.