Distinct down-regulation of cardiac ?1- and ?2-adrenoceptors in different human heart diseases

Abstract

Cardiac beta-adrenoceptor density and beta 1- and beta 2-subtype distribution were examined in human left ventricular myocardium from transplant donors serving as controls and from patients with mitral valve stenosis, aortic valve stenosis, idiopathic dilated cardiomyopathy, and ischaemic cardiomyopathy respectively. The total beta-adrenoceptor density was similar in transplant donors and patients with moderate heart failure (NYHA II-III) due to mitral valve stenosis, but was markedly reduced in all forms of severe heart failure (NYHA III-IV) studied. A reduction of both beta 1- and beta 2-adrenoceptors was found in patients with severe heart failure due to mitral valve stenosis or ischaemic cardiomyopathy. In contrast, a selective down-regulation of beta 1-adrenoceptors with unchanged beta 2-adrenoceptors and hence a relative increase in the latter was observed in idiopathic dilated cardiomyopathy and aortic valve stenosis. It is concluded that the extent of total beta-adrenoceptor down-regulation is related to the degree of heart failure. Selective loss of beta 1-adrenoceptors is not specific for idiopathic dilated cardiomyopathy but also occurs in aortic valve stenosis. Changes in beta 1- and beta 2-subtype distribution are rather related to the aetiology than to the clinical degree of heart failure.

Lack of specificity of antibodies directed against human beta-adrenergic receptors

“…In failing IDCM myocardium, a downregulation of β 1 AR has been observed (Bristow et al 1991), while β 2 AR remained unchanged (Steinfath et al 1991). In contrast, a reduction of both β 1 AR and β 2 AR was reported in ISHD patients (Steinfath et al 1991;Bristow et al 1986Bristow et al , 1989.…”

“…In failing idiopathic dilated cardiomyopathy (IDCM) myocardium, a downregulation of β 1 AR has been observed, leading to a relative increase in β 2 AR, as illustrated by the altered ratio of β 1 AR and β 2 AR to 60:40 in the failing heart (Brodde 2007;Bristow et al 1986Bristow et al , 1989. Diverse alterations in myocardial βAR density have been reported in IDCM and ischemic heart disease (ISHD) patients (Bristow et al 1991;Steinfath et al 1991). In failing IDCM myocardium, a downregulation of β 1 AR has been observed (Bristow et al 1991), while β 2 AR remained unchanged (Steinfath et al 1991).…”

“…Diverse alterations in myocardial βAR density have been reported in IDCM and ischemic heart disease (ISHD) patients (Bristow et al 1991;Steinfath et al 1991). In failing IDCM myocardium, a downregulation of β 1 AR has been observed (Bristow et al 1991), while β 2 AR remained unchanged (Steinfath et al 1991). In contrast, a reduction of both β 1 AR and β 2 AR was reported in ISHD patients (Steinfath et al 1991;Bristow et al 1986Bristow et al , 1989.…”

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1‐, β1‐ and β2‐receptor‐mediated responses

“…In dilated cardiomyopathy (DCM) and possibly aortic valve disease, P,-adrenoceptors are selectively down-regulated (Brodde et al, 1989;Michel et al, 1990;Steinfath et al, I Author for correspondence. 1991) whilst P2-adrenoceptors are spared and in such cases, selective P2-adrenoceptor stimulation may be advantageous.…”

The GTP-binding regulatory proteins, Gs and G(i), are altered in erythrocyte membranes of patients with ischemic heart disease resulting from coronary atherosclerosis.

“…G, regulates adenylate cyclase and Ca 2+ channels, stimulates K + channels, and is involved in phosphoinositide metabolism; G,a is ADP-ribosylated by pertussis toxin. 4 There is evidence that in addition to /3-adrenoceptor downregulation, 5 organ-specific alterations in G-protein function contribute to the pathophysiology of human heart disease. 6 Moreover, /3-adrenoceptor defects may indeed be postreceptor defects.…”