Combined blockade of β- and α₁-adrenoceptors in left ventricular remodeling induced by hypertension: Beneficial or not?

Adrenergic stimulation has a crucial role in the physiological regulation of cardiac function. In addition, chronic adrenergic stimulation is one of the main signaling pathways contributing to the progression of left ventricular (LV) remodeling in pathophysiological states.^{1, 2} Catecholamines released from the sympathetic nervous system act on adrenoceptors (ARs) in cardiac myocytes to regulate heart inotropy, chronotropy and growth.^{1, 2, 3, 4, 5, 6} ARs are part of the large family of seven transmembrane receptors that interact with heterotrimetric G proteins (G protein-coupled receptors). AR subtypes couple to different G proteins, activating distinct signaling pathways.

In the human heart, β₁-, β₂- and α₁-ARs are the main receptor subtypes expressed,^{1, 2, 5} with β₁-AR being the most abundant. Acute stimulation of β-ARs regulates cardiac excitation–contraction coupling through phosphorylation of various Ca²⁺-handling proteins, producing a strong positive inotropic effect.^{3, 4} Myocardial α₁-AR density in the human heart is considerably lower than that of β-ARs (about 20%), and, consequently, the contribution of α₁-ARs to AR-mediated cardiac inotropy is less prominent.^{1, 3}

Chronic AR stimulation promotes pathological remodeling, leading to hypertrophy and/or heart failure.^{2, 7, 8} β₁-AR signaling shows strong down-regulation in pathophysiological conditions, whereas α₁-AR expression does not change.⁵ Relative increases in α₁-AR expression levels raise this receptor subtype to a more important role in the regulation of cardiac function in pathophysiological conditions.⁵

In this conceptual framework, adrenergic blockade is one of the central targets for preventing the progression of LV remodeling and for reverse remodeling in human heart failure.^{2, 9} The beneficial role of blocking β-ARs has been widely investigated. However, the importance of α₁-AR blockade is still unclear and controversial, despite the fact that α₁-AR blockers are widely used for the treatment of hypertension and heart failure. Early clinical trials have shown that treatment with selective α₁-AR antagonists, such as doxazosin and prazosin results in an increase in cardiovascular events in hypertensive and heart failure patients.⁵ In contrast, carvedilol, a combined β-AR/α₁-AR antagonist, was shown to reverse remodeling and survival in human heart failure.⁹ Here, three important questions have been raised: (1) can combined blockade of β-ARs and α₁-ARs suppress the LV remodeling induced by hypertension compared with selective β-AR antagonists? (2) If so, what is the mechanism underlying the beneficial role of combining β-AR and α₁-AR blockade? (3) Finally, why is α₁-AR blockade alone harmful, whereas the combined blockade of β-ARs and α₁-ARs is beneficial?

In this issue of Hypertension Research, Chen and colleagues test the hypothesis that non-selective AR blockade is more efficient in suppressing LV remodeling when compared with AR subtype-selective antagonists in a spontaneously hypertensive rat model.¹⁰ A previous study compared non-AR subtype-selective and AR subtype-selective inhibition on LV dysfunction and remodeling induced by chronic coronary stenosis and coronary occlusion,¹¹ showing benefit from a non-selective inhibitor; however, a detailed mechanism was not investigated in that study. Chen and colleagues compared the effect of the β₁-AR antagonist bisoprolol, the β₁- and β₂-AR antagonist propranolol and the α₁-, β₁- and β₂-AR antagonist carvedilol on LV remodeling by hypertension (see also Figure 1). The authors showed that AR blockers inhibited LV remodeling in hypertensive animals and affected receptor expression and post-receptor signaling using multiple experimental approaches (in vivo assessments of cardiac function, morphological studies and biochemical studies). It is surprising that, overall blockade of ARs (α₁-, β₁- and β₂-ARs) by carvedilol was not found to be superior to bisoprolol and propranolol in suppressing LV remodeling in their animal model. However, carvedilol was the most effective in attenuating cardiomyocyte apoptosis and normalizing downstream signaling by changing the expression level of ARs and G proteins compared with other AR antagonists.

Figure 1

Cardiac adrenoceptor subtypes and their antagonists. EPI, epinephrine. NE, norepinephrine. PI3K, phosphoinositide 3-kinase. PLC, phospholipase C.

In the healthy human heart, β₁-AR has been shown to be more abundant than β₂-AR, with a ratio of approximately 7:3.² β₁-ARs are known to couple with G_s proteins and stimulate intracellular cyclic AMP production, whereas β₂-AR couples with G_i proteins and inhibits cyclic AMP signaling (Figure 1).¹ In addition, β₂-ARs strongly activate a protective anti-apoptotic pathway (phosphoinositide 3-kinase-Akt), which counteracts pro-apoptotic G_s—cyclic AMP–PKA signaling.^{2, 6} Thus, selective activation of cardiac β₂-ARs may provide beneficial effects under pathophysiological conditions. In their study, Chen et al. found decreases in the expression levels of β-ARs (β₁- and β₂-AR) due to enhanced sympathetic stimulation, which recovered spontaneously in hypertensive rats treated with AR antagonists.¹⁰ Moreover, the expression level of β₂-AR was increased in proportion to β₁-AR in the carvedilol-treated group compared with animals treated with propranolol (a β₁- and β₂-AR antagonist); however, carvedilol is known to be relatively selective to β₁-AR.¹² This specific recovery of β₂-AR signaling by carvedilol may, in part, contribute to the attenuation of cardiomyocyte apoptosis. However, further studies are needed to clarify the mechanism of carvedilol protection of β₂-AR signaling in the hypertensive heart.

In the human heart, three α₁-AR subtypes (α_1A-, α_1B- and α_1D-ARs) are expressed (Figure 1).⁵ The α_1A- and α_1B-ARs couple mainly to G_q proteins, activating protein kinase C (PKC) signaling.^{5, 13} However, little evidence has been reported regarding the effect of stimulating α_1D-AR on the activation of functional downstream signaling pathways in cardiac myocytes. Transgenic mice overexpressing α_1B-AR showed a more severe hypertrophic heart phenotype and heart failure compared with that of α_1A-AR-overexpressing mice.⁵ In contrast, α_1A-AR-overexpressing mice showed high contractility without hypertrophy.⁵ At the cultured cell level, α_1A-AR signaling enhanced survival signaling in cardiomyocytes.² In their study, Chen et al. found that the expression level of α_1B-AR was significantly increased in spontaneously hypertensive rats, although α_1A-AR expression was not changed.¹⁰ Moreover, the expression level of α_1B-AR and its downstream signaling pathways (PKCα and δ) were normalized only in the carvedilol-treated group. PKC represents a large gene family and has up to 12 isoforms, seven of which are expressed in the human heart.¹⁴ PKC isoforms are involved in a variety of chronic cardiac diseases, including hypertrophy and heart failure, as well as in acute cardiac injuries and preconditioning. One of the Ca²⁺-dependent PKC isoforms, PKCα, is the most abundant isoform in the human heart. Activation of this isoform has been linked to cardiomyocyte hypertrophy. PKCδ induces apoptosis in response to cardiac ischemia and reperfusion damage by mitochondrial translocation. The suppression of α_1B–AR–PKC signaling by carvedilol may also contribute to the attenuation of cardiomyocyte apoptosis.

Finally, why is the blockade of α₁-AR alone harmful but the combination of β- and α₁-AR blockade by carvedilol beneficial? This is possibly due to the specific pharmacological properties of carvedilol. Frishman showed that the α₁-AR antagonist activity of carvedilol was relatively weak compared with its blocking effect on β-ARs, which may have prevented harmful hemodynamic changes.¹⁵ In addition, carvedilol had a relatively high affinity to α_1B-AR compared with α_1A-AR,⁵ which contributed to the block of apoptotic and hypertrophic α_1B-AR signaling and maintained α_1A-AR-mediated increases in contractile function and survival. Finally, carvedilol is known to possess antioxidant properties unrelated to AR blocking.¹⁵ Further investigation is necessary to clarify the contribution of each of these pathways to the beneficial effects of carvedilol.

In summary, the work by Chen et al. showed that the overall blockade of ARs (α₁-, β₁- and β₂-ARs) by carvedilol had stronger effects on promoting cardiomyocyte survival and normalization of downstream AR signaling compared with other AR antagonists. However, they found that the suppression of LV remodeling was similar to the other specific AR antagonists tested. Their results imply that long-term treatment with carvedilol may be beneficial for preventing the progression of LV remodeling induced by hypertension. Future studies should be directed toward elucidating the molecular mechanisms of AR subtype-specific LV remodeling, which may lead to the development of novel approaches for the treatment of LV remodeling.