Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation

Abstract

Alpha-1-adrenergic receptors (ARs) are G protein-coupled receptors activated by catecholamines. The alpha-1A and alpha-1B subtypes are expressed in mouse and human myocardium, whereas the alpha-1D protein is found only in coronary arteries. There are far fewer alpha-1-ARs than beta-ARs in the nonfailing heart, but their abundance is maintained or increased in the setting of heart failure, which is characterized by pronounced chronic elevation of catecholamines and beta-AR dysfunction. Decades of evidence from gain and loss-of-function studies in isolated cardiac myocytes and numerous animal models demonstrate important adaptive functions for cardiac alpha-1-ARs to include physiological hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Clinical trial data indicate that blocking alpha-1-ARs is associated with incident heart failure in patients with hypertension. Collectively, these findings suggest that alpha-1-AR activation might mitigate the well-recognized toxic effects of beta-ARs in the hyperadrenergic setting of chronic heart failure. Thus, exogenous cardioselective activation of alpha-1-ARs might represent a novel and viable approach to the treatment of heart failure.

Figure 1. Adrenergic receptors in the failing cardiac myocyte

Radioligand binding levels of cardiac myocyte ARs are in the order β1 > β2 > α1B > α1A > β3. Some ventricular myocytes do not express all subtypes. New data localize the α1-ARs to the myocyte nucleus.^, The (patho)physiological roles of chronic activation are indicated.

Figure 2. Adrenergic receptors in cardiac non-myocytes

Cardiac ARs are also broadly expressed on cells other than cardiac myocytes. α1D-ARs constrict coronary vascular smooth myocytes. α2-ARs constrict coronary vascular smooth muscle cells and inhibit NE release from sympathetic nerves. β2-ARs stimulate NE release from sympathetic nerves, activate fibroblasts, and relax coronary smooth muscle cells. The roles of ARs in coronary endothelium are less defined.

Figure 3. Adrenergic receptors in non-failing and failing human myocardium

The β1-AR is dominant in the non-failing heart, but is markedly down-regulated in the failing heart, whereas the α1A, α1B, and β2 are not. Data are taken from Jensen et al. In that study, receptors in human left ventricular free wall were quantified by radioligand binding, using H-prazosin for α1-ARs and I-cyanopindolol for β-ARs. Specific binding at the H-prazosin Kd was 40%. The proportion of the α1A subtype was defined by competition with 5-methyl-urapidil; the proportion of β1, with CGP 20712A; and the proportion of β2, with ICI-118,551. Non-failing hearts were unused donors, and failing were from transplant. Mean data from 4-6 patients for non-failing and failing are normalized to the value of the α1A in non-failing set at 1 (1.44 fmol/mg protein). The preparation used for binding was a complete myocardial lysate, not a “membrane” preparation, so that fmol values relative to protein are low, but no receptors are “tossed out”. The rationale for this approach is that about 60% of total myocardial α1-ARs are in a typical 1000g pellet, and only 15% of total remain in a 40,000g “membrane” pellet used typically for binding. Use of “membrane” preparations can cause artifacts, as documented with myocardial β-ARs.^,